General Path must knows Flashcards
Bence Jones Proteins
found in urine with Multiple Myeloma
carcinoembryonic antigen in serum
pancreatic or colon cancer
Sclerotic lesions on bones
Osteoblastic lesion (not osteolytic)
Bladder control via Pharmacology
Muscarinic M3 receptor stimulation is responsible for bladder contraction
antagonism of muscarinic M3 receptors fixes urge incontinence (sudden urge to urinate resulting in frequent involuntary loss of small amounts of urine and nocturia) example is Oxybutynin
Overflow incontinence!! can be fixed with Bethanechol which is a muscarinic M2 receptor agonist, usually causes continuous dribbling and no sudden urge to void
alpha 1 antogonism (tamsulosin, used to treat BPH which can cause overflow incontinence secondary to urinary retention in men) would cause bladder next relaxation and would worsen symptoms of detrusor overactivity
Adrenergic drug receptor types
Gq - a1, H1, V1, M1, M3
Gs - b1, b2, b3, d1, h2, v2
Gi- m2, a2, d2
Drug Trial Phases
Phase 0 - very small number of volunteers (healthy or with desired disease of interest), uses <1% of therapeutic dose, no safety or toxicity assessment
Phase 1 - Is it safe?, small number of patients again but more than phase 0, assesses safety/toxicity/dosage/pharmacokinetics/pharmacodynamics
Phase 2 - Does it Work?, moderate number of patients with disease of interest, assesses tx efficacy and adverse effects
Phase 3 - Is it as good or better?, large number of patients with disease of interest randomly assigned to either treatment or placebo, compares new tx to others
Phase 4 - Can it stay on the Market?, postmarket surveillance, detects rare or long-term adverse effects and evaluates cost effectiveness
CYP450 Inducers, Inhibitors
Inducers - CHRONIC ALCOHOLics Steal PHEN-PHEN and NEVer Reuse GReasy CARBs (chronic alcohol use, St. John’s wort, Phenytoin, Phenobarbital, Nevirapine, Rifampin, Griseofulvin, Carbamazepine)
Inhibitors - “sickfaces.com group” Sulfonamides, Isoniazid, Cimetidine, Ketoconazole, Fluconazole, Alcohol (binge drinking), Ciprofloxacin, Erythromycin, Sodium valproate, Chloramphenicol, Omeprazole, Metronidazole, Grapefruit Juice
CGD (chronic granulomatous disease)
X linked recessive or Autosomal recessive
defect in superoxide production with neutrophils (Nicoinamide adenine dinucleotide phosophate oxidase, NADPH), LOOK FOR PHOX RELATED GENE ISSUES AS WELL
Diagnosis: abnormal dihydrorhodamine flow cytometry test (DHR) indicates decreased NADPH oxidase activity (decreased green fluorescence), and a nitroblue tetrazolium dye reduction test that is negative (incubated leukocytes fail to turn blue
Clinical features: recurrent severe infections (chronic skin/lymph node/bone/resp/GI/UTI) with catalase positive organisms (S.aureus, Nocardia spp., E. coli, Candida, Klebsiella, Pseudomonas, Aspergillus, Serratia)
S. Pneumoniae virulence factor
polysaccharide capsule
acts by masking subcapsular antigens
S. aureus virulence factor
Protein A
binds to the Fc portion of IgG which protects bacteria from opsonization and phagocytosis
S. pyogenes virulence factor
M protein
blocks the alternative complement pathway protecting from phagocytic cells
Fungal virulence factors
Beta-glucan cell wall
normal fungal cell wall component
Lipopolysaccharide
expressed on gram - bacteria membrane
endotoxins that trigger macrophage, complement and tissue factor activation which enhances inflammation
Shigella, Salmonella virulence factor
Type III secretion system
inject toxins into host cells
Flagella virulence factor
Vibrio cholerae, Salmonella, Campylobacter
facilitate movement through rotation of microtubules
Pseudomonas aeruginosa virulence factor
gram -, catalase +
has lipid A endotoxin in lipopolysaccharide, responsible for hypotension in gram - bacteremia
Lipooligosaccharide
Neisseria meningitidis endotoxin, can cause hypotension
Bordatella pertussis virulence factor
AB exotoxin, binds to surface of host cells and endocytosis, once in cytosol it catalyzes ADP-ribosylation and impairs inhibition of adenylate cyclase
crowded environment pneumonaie
atypical PNA, Mycoplasma pneumoniae,
Food poisoning times
preformed cereulide toxin can effect minutes to hours
ETEC (enterotoxigenic E. coli) 1-3 days after with diarrhea
C. perfringens, diarrhea 6-24 hours after undercooked meat
Salmonella, nausea and vomiting 3-7 days after undercooked poultry or eggs
Listeria monocytogenes, nausea and vomiting, 6hours to 10 days after, unpasteurized dairy products or ready to eat deli meats
S. aureus enterotoxin, rapid onset nausea and vomiting, inadequate refrigeration (mayonnaise, potato salad, custard)
Genital Ulcer
nontender with inguinal lymphadenopathy, spirochete is Treponema pallidum, primary syphilis
Painful is Haemophilus ducreyi “so painful you Du-Cry”
Fitz-Hugh-Curtis syndrome
PID can cause, perihepatitis, infection and inflammation of liver capsule can lead to violin string attachments
Hepatitis
jaundice, fever, increased ALT and AST
naked viruses (A and E) lack an envelope and arent’ destroyed by the gut “the vowels hit your bowels”
HBV is only DNA virus
HAV - shellfish, good prognosis, Councilman bodies (eosinophilic remnant of apoptotic hepatocytes
HBV - parenteral (blood), sexual (bedroom), perinatal (birthing), granular osinophilic “ground glass” appearance due to accumulation of surface antigen within infected hepatocytes, cytotoxic T cells mediate the damage
HCV - primarily blood (IV drugs, posttransfusion), may progress to cirrhosis or carcinoma, lymphoid aggregates with focal areas of macrovesicular steatosis
HDV - superinfection if after HBV depends on HBV HBsAg coat for entry into hepatocytes
Alcoholic Hepatitis - hx of ETOH abuse, Asparatate aminotransferase:Alanine Aminotransferase ratio > 2:1
Hepatitis serologic markers
HBsAg - surface marker, means you have HBV infection
Anti-HBs - antibody to HBsAg indicates immunity by prior infection or vaccination
HBcAg - antigen associated with core of HBV
Anti-HBc - antibody either IgM (acute/recent infection) or IgG (prior exposure or chronic infection)
HBeAg - secreted by infected hepatocyte into circulation, indicates active viral replication and therefore high transmissibility and poorer prognosis
Anti-HBe - indicates low transmissibility
Porphyria cutanea tarda vs AIP vs Lead poisoning
Porphyria cutanea tarda - uroporphyrinogen decarboxylase (cytoplasm), tea colored urine (uroporphyrin accumulation), blistering cutaneous photosensitivity and hyperpigentation, most common, worse with alcohol consumption, causes are familial and Hepatitis C
AIP - porphobilinogen deaminase (aka uroporphyrinogen I synthase in cytoplasm) which converts porphobilinogen to hydroxymethylbilane, accumulates porphobilinogen and ALA, !!!5 P’s: Painful abdomen, Port wine colored Pee, Polyneuropathy, Psychological distrubances, Precipitated by factors that increase ALA synthase
Lead Poisoning - Ferrochelatase (mitochondria) and ALA dehydratase (mitochondrial membrane), acumulate protoporphyrin and ALA in blood, microcytic anemia (basophilic stippling with ringed sideroblasts in bone marrow), child exposed to paint can have mental deterioration, adults environmental exposure lead to headache memory loss and demyelination (peripheral neuropathy)
AIDs CD4 count precautions
x<250 coccidioidomycosis recommend fluconazole (inhibits ergosterol synthesis)
x<200 Pneumocystis pna and cystoisoporiasis recommend TMP/SMX
x<150 Histoplasmosis recommend Itraconazole (inhibits ergosterol synthesis
x<100 Toxoplasma gondii recommend TMP/SMX
x<50 Mycobacterium avium complex recommend Azithromycin or clarithromycin
“My Tough Hiv Cd4 count Precuations Confuse me”
HIV positive pregnant woman drug treatment
Zidovudine - NRTI, similar to thymidine, prevents formation of 3-5 phosphodiester linkages needed for DNA replication there after incorporated will prevent the elongation of viral DNA
Entamoeba histolytica
amebiasis, abd pain and bloody stool, incubation for 1-4 weeks then symptoms, presence of cysts or trophozoites containined phagocytosed erythrocytes in fresh stool
Campylobacter jejuni
comma shaped, grows in 42 celcius stool, bloody diarrhea
Plasmodium differences and details of dx
falciparum - anopheles mosquito, incubation 1 week, irregular fever spikes, blood smear shows RBC inclusion bodies, Chloroquine resistant
ovale - tertian malaria, incubation 1 week, RBC inclusion bodies, fever pattern every 48 hours, chloroquine sensitive
malariae - quartan malaria, incubation and RBC inclusions bodies the same, fever every 72 hours, chloroquine sensitive
Malaria - would show ring shaped inclusions in erythrocytes
Clinical features: joint pain and anemia, high fever with periodic spikes as well as flu like sx
Trypanosoma cruzi and brucei
cruzi - Chagas disease (dilated cardiomyopathy, fever, generalized lymphadenopathy, GI disease), circulating parasite in blood smear
GI disease via destruction of myenteric plexus anywhere along GI tract, can result in inability to relax the lower esophageal sphincter
increased chance in Central to souther america
brucei - parastie in africa, causing sleeping sickness
Babesia microti
Ixodes tick, NE and midwest regions of US, noncyclical fever, flu like sx, hepatosplenomagaly, anemia, blood smear show intra-erythrocyte rings with maltese cross
Dengue virus
endemic to tropical and subtropic areas, noncyclical high grade fever, flu like sx, arthralgias, headache, sx onset 2-10 days after, peripheral smear would exhibit elevated lymphocytes and plasmacytoid cells
Leishmania donovani
noncyclical fever, flu like symptoms, hepatospleomegaly, pancytopenia, amastigotes on blood smear
Cryptococcus Neoformans
pathogenic fungus with thick polysaccharide capsule,
stains bright red with mucicarmine (also india ink stain),
transmitted via soil or pigeon droppings and infects resp tract especially immunodeficient,
usually PNA but can manifest as cryptococcal meningoencephalitis
narrow budding encapsulated yeast
Tx: amphotericin B and Flucytosine
Aspergillus fumigatus
causes aspergillosis can manifest with PNA, H&E/silver/PAS staining show septate hyphae with fruiting bodies branching at 45 degree angles
Blastmomyces dermatitidis
staining shows multinucleated yeast the form broad-based buds, thin mucopolysaccharide layer so mucicarmine stains light red, SE and central US along with midwest near great lakes more common around wet soil and decaying wood
Histoplasma capsulatum
asymptomatic but can cause histoplasmosis in immunocompromised pts, ovoid yeast on stain
Cocciodoides immitis
methenamine silver stain shows spherules filled with endospores, no stain with mucicarmine
Candida albicans
fungus in lungs of immunocompromised, KOH staining show budding yeasts with hyphae and pseudohyphae
Pneumocystis jirovecii
commonly associated with immunodeficiency, disc shaped cysts with central spores
BV vs Trich vs Candida vulvovaginitis
BV - bacterial vaginosis, Gardnerella vaginalis, gray or milky fish odor discharge, clue cells (vaginal epithelial cell covered in bacteria)
Candida - vaginal discharge, pruritus and dysuria, odorless and white/curdy cottage cheese like discharge appearance, pseudohyphae
Trichomonas vaginalis - vaginal pruritus, dysuria, strawberry cervix (punctate hemorrhages on the cervix), yellow-green malodorous discharge, motile trophozoites with discharge pH >4.5, tx with metronidazole
Prodominent cells fighting fungus and virus?
T cells
T-cell immunodeficiencies (4 types)
Thymic aplasia - thymic shadow absent, more commonly DiGeorge syndrome 22q11 microdeletion, failure to develop 3rd and 4th pharyngeal puches, “CATCH-22”: Cardiac defects Abnormal facies Thymic hypoplasia Cleft palate Hypocalcemia
IL-12 receptor deficiency - decreases Th1 response, disseminated mycobacterial and fungal infection may present after BCG vaccine, decrease in Interferon gamma
AD hyper IgE syndrome (Job syndrome) - Th17 cells deficiency due to STAT 3 mutation, impaired recruitment of neutrophils to sites of infection, “ABCDEF gets the JOB done”: Abscesses/RETAINED BABY TEETH/Coarse facies/Dermatologic problems/increased IgE/bone Fractures in minors, increased IgE and Eosinophils “Nuertophils have trouble getting to their JOB to get the monEy, and I need it JAK-STAT” (JAK-stat issue resulting in bad chemotaxis of neutrophils and increased IgE)
Chronic mucocutaneous candidiasis - T-cell dysfunction, classic form caused by defects in AIRE, absent in vitro T-cell proliferation in response to Candida antigens
B-Cell immunodeficiences (3 types)
X-linked agammaglobulinemia - Bruton, defect in BTK (tyrosine kinase gene) leading to no B cell maturation, recurrent infections after 6 months because mom’s IgG has decreased, absent B cells in peripheral blood, decrease IgG in all cases, live vaccines contraindicated
Selective IgA deficiency - unknown cause, majority are asymptomatic, decrease IgA with normal IgG and IgM levels, increase susceptability of giardiasis and can cause false-negative celiac disease test
Common variable immunodeficiency - defect in B cell differentitiation, usually diagnosed after puberty, increase autoimmune disease risk, decrease plasma cells and immunoglobulins
Combined B and T cell disorders (4 types)
SCID (severe combined immunodeficiency) - defective IL-2R gamma chain is most common and adenosine deaminase deficiency is Autosomal recessive, RAG mutation to VDJ recombination defect, failure to thrive/chronic diarrhea/thrush, screened for in newborns, absence of thymix shadow, germinal centers, and T cells
Ataxia telangiectasia - defects in ATM gene (failure to detect DNA damage, failure to halt cell cycle, mutations accumulate), Triad: GAIT ATAXIA, spider Angiomas, IgA deficiency, prone to Giardia infection
Hyper-IgM syndrome - most common is defective CD40L on Th cells (class switching defect), severe pyogenic infections in early life, normal or elevated IgM with decrease in IgG/IgA/IgE, failure to make germinal centers, prone to Pneumocystis jirovecii infection
Wiskott-Aldrich syndrome - mutation in WAS gene, WATER: Wiskott-Aldrich, Thrombocytopenia, Eczema, Recurrent (pyogenic) infection. increase IgE and IgA with fewer and smaller platelets, leukocytes and platelets unable to reorganize actin cytoskeleton
LYST
lysosomal trafficking regulator gene, Chediak Higashi syndrome shows defect in LYST
LFA-1 integrin (CD18)
used for migration and chemotaxis of WBC
defect brings Leukocyte adhesion deficiency (type1), increase in neutrophils but are absent at infection site, impaired wound healing
Late seperation of umbilical cord, Absent pus, Dysfunctional neutrophils (recurrent skin and mucosal bacterial infections)
defect in NADPH oxidase
CGD, increases susepctability to catalase + organisms (nocardia), abnormal dihydrorhodamine test (decrease in green flourescence), Nitroblue tetrazolium dye reduction test fails to turn blue
Hypersensitivity Type I (immediate)
preformed IgE antibodies
cell degranulation results in release of histamine
anaphylaxis, drug reactions, allergies, insect venom, food allergies, reactions to inhaled environmental factors
Hypersensitivity Type II (cytotoxic)
IgM or IgG antibodies bind to antigens on cells of particular tissue types
complement system activation
Goodpasture, Rheumatic fever, hyperacute transplant rejection, Graves disease, myasthenia gravis, bullous pemphigoid, pemphigus vulgaris
Hypersensitivity Type III immune complex
IgG antibodies bind to circulating antigens and form a complex that deposits in tissue, neutrophillic lysis or phagocytosis of cells
serum sickness, polyarteritis nodosa, Poststreptococcal glomerulonephritis, SLE
Hypersensitivity Type IV (T-cell mediated)
contact of antigen with presensitized T lymphocytes
T cell CD4 activation to release cytokines and attract macrophages or CD8 cells recognize antigens on somatic cells and go through cell mediated cytotoxicity
acute and chronic transplant rejection, graft versus host disease, contact dermatitis, Mantoux tb skin test, stevens johnson syndrome, MS, hashimoto’s thyroiditis
Type 1 DM
Tetanus Vaccine
denaturated bacterial product of C. tetani toxoid
Conjugate Vaccine
capsular polysaccharide vaccine
S. pneumoniae, H. influenzae type b, and N. meningitidis
Whole-cell or Chemically inactivated virus vaccine
polio, hep A, influenza
Post-exposure prophylaxis of Rabies
human immunoglobulin against a viral protein
Live attenuated vaccine
viable but weakened microorganisms
measles, mumps, rubella, varicella zoster, rotavirus
C5-C9 deficiency suceptible to ???
Neisseria bactermia
EBV
double stranded DNA virus that causes mono
infection is associated with hodgkin lymphoma, burkitt lymphoma, primary central nervous system lymphoma, gastric cancer, nasopharyngeal carcinoma
Rheumatic fever
delayed inflammatory sequela of group A streptococcus (pyogenes) pharygitis 2-4 weeks after infection, sx include: fever, malaise, fatigue, pancarditis, migratory polyarthiritis, skin findings.
commonly cause mitral stenosis (diffuse fibrous thickening and distortion of the mitral leaflets, and narrowing of the mitral valve orifice)
Kaposi Sarcoma
caused by HHV 8, malignant spindle cell tumor, originates from endothelial cells, predominantly in immunosuppressed pts, cause solitary or multiple nodular purplish blue-violet painless skin plaques
HHC (hepatocellular carcinoma)
Hep B and C are risk factors along with obesity and chronic alcohol use, sx of fatigue and liver injury
Mycotic aneurysm
potential complication of infectious endocarditis or vascular trauma (drugs), sx change whether peripheral or central aneurysm
Newborn with jaundice and hepatospleomegaly in first 24 hours
Hemolytic disease of newborn
some of Mom’s IgG can cross placenta
fetal A and B antigens are not fully developed at birth so direct Coombs test is usually only weakly positive
Parvo B19 virus
“fifth disease”
infiltrates erythroid progenitor cells in bone marrow which leads to suppression of erythropoiesis
anemia with low reticulocyte count
myocarditis leading to dilated cardiomyopathy
flu like sx
“slapped-cheek” rash with perioral sparing
smallest known DNA virus, non-enveloped with linear single-stranded genome, causes erythema infectiosum aka fifth disease
Sickle cell anemia
results from a substitution of glutamic acid with valine at the 6th amino acid of beta globin protein
polymerization of deoxygenated hemoglobin, normally not symptomatic until 5 months of age when Hemoglobin F production decreases and hemoglobin S production begins
Hemoglobin F formation can be prompted via HYDROXYUREA
Howel-Jolly bodies on blood smear (purple dot in RBC, described as NUCLEAR REMNANTS)
G6PD deficiency
can be prompted via pharmacology (sulfa drugs)
impaired regeneration of reduced glutathione
G6PD catalyzes the first step of pentose phosphate pathway oxidation of glucose 6 phosphate to 6-phosphogluconolactone with the concomitant reduction of NADP to NADPH
Beta vs Alpha thalassemia
Beta would have an abnormal hemoglobin electrophoresis
Beta - decreased production of Beta globin proteins occurs due to mutations at promotor site of Beta globin gene,
homozygous is major (skeletal deformities, hepatosplenomegaly, severe anemia at 6 months of age),
minor is heterozygous and cause minor microcytic anemia findings
Alpha - cis deletion of alpha globin genes is common in asian populance and is normally clinically silent,
loss of 2 alleles brings mild symptoms,
3-4 alleles lost causes aberrant hemoglobin formation that would be visible on hemoglobin electrophoresis and cause clinical symptoms
*loss of 1 = alpha minima, 2 = alpha minor, 3 = HbH, 4 = Barts (fetal hydrops)
HbA = (alpha2, beta2), HbA2 = (alpha2, delta2), HbF (alpha2, gamma2)
Iron deficiency anemia
microcytic, hypochromic anemia, normal hemoglobin electrophoresis, increased RDW (due to decreased RBC production), and decreased ferritin
Polycythemia Vera
JAK 2 (gain of function mutation)
nonreceptor tyrosine kinase increased acivity
erythropoietin independent proliferation of the myeloid cell lines
increase blood cell mass
hyperviscosity and slow blood flow
increase risk of thrombosis and poor oxygenation
elevated myeloid cell lineages (pancytosis) including hemoglobin yet the EPO is low
Clinical features: PRURITIS (worse when skin is in contact with warm water), sx of thrombotic and hemorrhagic complications
Langherans cells histiocytosis
Cluster of differentiation 1a is a protein expressed by Langerhans cells that mediates the presentation of antigens to T cells.
Unregulated proliferation of Langerhans cells leads to Langerhans cell histiocytosis, which typically manifests in childhood with lytic bone lesions (most commonly in the skull), skin rash, fever, hepatosplenomegaly, and lymphadenopathy.
Multiple Myeloma
hypercalcemia, anemia, elevated serum creatinine, and lower back pain!!!!
plasma cell dyscrasia characterized by overproliferation and diffuse infiltration of monoclonal plasma cells in the bone marrow
plasma cell proliferation increases the secretion of proosteoclastogenic factors (e.g., TNF-α, IL-1, RANKL) which leads to osteolysis, and, consequently, hypercalcemia and diffuse bone pain
neoplastic plasma cell infiltration in the bone marrow suppresses hematopoiesis, resulting in pancytopenia
Kidney injury from deposition of light chain
excess production of monoclonal protein by malignant plasma cells leads to increased serum viscosity and, consequently, elevated ESR
BACK PAIN WITH RADIOLUCENT LESIONS IN THE VERTEBRAL BODIES, LYTIC LESIONS WOULD HAVE A ROUND PUNCHED-OUT RATHER THAN BAND-LIKE APPEARANCE
isolated PTT increase (no BT, PT, or platelets abnormality) with hx of bleeding issues?
Factor X conversion issue
Hemophilia
Glanzmann Thromboasthenia
autosomal-recessive bleeding disorder caused by deficient fibrinogen receptor GpIIb/IIIa in platelets, leading to defective platelet !! aggregation !! and subsequent increased mucosal bleeding (e.g., epistaxis, gingival bleeding), petechiae, and ecchymoses.
Bleeding time increased , no change in platelets/PT/PTT
Kartagener Syndrome
subset of primary ciliary dyskinesia
triad: situs inversus (dextrocardia), chronic sinusitis, and bronchiectasis
may also have reduced fertility, chronic ear infections, and conductive hearing loss
ASD vs VSD vs PFO
ASD - impaired growth of the septum, associated with down syndrome and fetal alcohol syndrome, primum ASD usually associated with other defects (15-20%) and secundum is usually isolated (70%), low pressure minor left to right shunt, SYSTOLIC EJECTION MURMUR OVER SECOND LEFT ICS STERNAL BORDER WITH WIDELY SPLIT S2 THAT IS FIXED
VSD - ventricular septal defect, more commonly in the membranous part (pars membranacea), defect leading to left to right shunt resulting in RV essentric hypertrophy and pulmonary hypertension, more common with down/edward/patau syndromes, HARSH HOLOSYSTOLIC MURMUR OVER LEFT LOWER STERNAL BORDER
PFO - variant where the foramen ovale remains open beyond 1 year of age, problems with fusion of primum and secundum,
Patent foramen ovale vs patent ductus arteriosus location
PFO between left and right atrium
PDA between Aorta and pulmonary artery
Machine like murmur
PDA
Tetralogy of Fallot
RVOTO: right ventricular outflow tract obstruction due to pulmonary infunidibular stenosis
RVH: right ventricular hypertrophy (also RIGHT AXIS DEVIATION on ECG)
VSD: ventricular septal defect
Overriding aorta
most common congenital heart lesion
associations: ASD, PDA, anomalous coronary arteries
Eisenmenger syndrome
central cyanosis, weakness, clubbing
ASSOCIATION WITH DOWN SYNDROME
endocardial or atrioventricular cushion defect
left to right blood shunt that over time leads to right ventricular hypertrophy and then reversal of the shunt
Asymmetric septal Hypertrophy seen in which heart condition?
hypertrophic obstructive cardiomyopathy
left sided heart hypertrophy
Cause of Edema with right sided heart failure?
increase in capillary hydrostatic pressure
Right ventricle output reduced - systemic vascular congestion - increase in capillary hydrostatic pressure - fluid leakage into the interstitium - edema
hypovolemic shock effects on CO, PCWP, SVR, CVP
CO goes down as there is less preload
PCWP goes down as there is less blood going into pulmonary arteries
SVR goes up as the body tries to compensate for loss of volume
CVP goes down as there is less venous return to the right atrium
Dilated vs Hypertrophic vs Restrictive cardiomyopathy
Dilated: eccentric hypertrophy, most common, notable associations: chagas disease, coxsackie B virus, hemochromatosis, wet beriberi. Notable S3 heart sound
Hypertrophic: 60-70% of cases are familial (genes encoding myosin binding protein C and beta-myosin heavy chain), notable S4 heart sound with possible mitral regurgitation as valve has trouble closing
Restrictive: PLEASe Help!! Postradiation fibrosis, Loffler endocarditis, Endocardial fibroelastosis, Amyloidosis, **Sarcoidosis, Hemochromatosis. can have low voltage ECG despite thick myocardium
ventricular aneurysms post MI timing
portion of free wall affected by MI outpouches
between 2 weeks and several months after MI
most form on anterioror apical walls due to occlusion of the LAD
Post MI Stent thrombosis
very similar signs of regular MI
blood circulation cut off, causing MI, acute onset chest pain and tachypnea
pain typically retrosternal, tightness, pressure
Infiltration of pericardium post MI timing
1st week after MI
neutrophils and fibrin found in pericardium adjacent to eh necrotic myocardium
Rupture of interventricular septum post MI timing?
3-5 days
VSD
chest pain, new onset systolic murmur, heart failure, left to right shunt
WPW on EKG
slurred upstroke of QRS complex (delta wave) and shortened PR interval
Torsades de pointes on EKG
cyclic alteration of the QRS axis
can result from prolonged QT interval
Giant cell arteritis
fever, malaise, weight loss
pulse-synchronous throbbing dull headache, temporal tenderness, jaw claudication
associated with polymyalgia rheumatica (x>50y/o women with diffuse joint pain)
Polyarteritis nodosa
absence of p-ANCA
involves multiple organs but NO LUNGS
ASSOCIATED WITH HEPATITIS B AND C
muscle biopsy shows transmural inflammation of the arterial wall with leukocytic infiltration and fibrinoid necrosis
high ESR, proteinuria, and hematuria
Granulomatosis with polyangitis
malaise, arthralgias, skin lesions, renal (glomerular crescent) and cardiac symptoms
UPPER RESPIRATORY TRACT disease (sinusitis, otitis media) and oculer involvement (conjunctivitis, diplopia)
P and C-ANCA (mostly C)
biopsy: necrotic, partially granulomatous vasculitis of small and medium sized vessels
Thromboangitis obliterans (beurger disease)
tobacco smoking male <40 years old
intermittent claudication may lead to gangrene
rayaud phenomenon
segmental thrombosing with vein and nerve involvement
Eosinophilic granulomatosis with polyangitis
p-ANCA and c-ANCA (rarely)
asthma association
formerly Churgg strauss
Takayasu Arteritis
aka aortic arch syndrome or pulseless disease
large and medium vessels
most common in women < 40 years old
Imaging (e.g., MR angiography) is used to confirm the diagnosis; findings include vascular wall thickening and contrast enhancement, and luminal stenosis or occlusion
syncope, angina, raynaud, skin findings
Microscopic Polyangitis
pANCA
similar to GPA but without granulomas
fibrinoid necrosis without granulomas
Familial hyperchilomicronemia
Type I - hyperchilomicronemia,
AR,
deficiency of lipoprotein lipase or apolipoprotein C-II,
no increased risk of atherosclerosis,
chylomicron elevated, triglycerides massively elevated,
CREAMY TOP LAYER of plasma
Familial Hypercholesterolemia
Type IIa - AD,
defective LDL receptors or ApoB-100, missing LDL receptors,
premature atherosclerosis may lead to MI early (x<20 years old), tuberous/TENDON XANTHOMAS ESPECIALLY ACHILLES TENDON, corneal arci
LDL elevated, triglycerides normal
clear overnight plasma
Familial combined hyperlipidemia
Type IIb
AD
defective LDL receptors or ApoB-100, missing LDL receptors,
premature atherosclerosis may lead to MI early (x<20 years old), xanthelasma
LDL and VLDL elevated, cholesterol massively elevated, triglycerides elevated
clear overnight plasma
Familial dysbetalipoproteinemia
Type III
AR
defective !!ApoE!!
premature atherosclerosis, palmar and tuberoeruptive xanthomas
chylomicrons, VLDL, cholesterol and triglycerides elevated
turbid overnight plasma
Familial hypertriglyceridemia
Type IV
AD
hepatic overproduction of VLDL or defective ApoA-V
premature atherosclerosis, tuberoeruptive xanthomas, acute pancreatitis (if triglycerides > 900 mg/dL), features of hyperglycemia
elevated VLDL and massively elevated Triglycerides
turbid overnight plasma
Superior Laryngeal Nerve
cut during 30% of thyroid dissections
external branch of SLN innervates cricothyroid muscle
directly adjacent to superior thyroid artery at upper pole of thyroid lobe
Perioral parasthesias after thyroid surgery?
sx of hypocalcemia
thyroidectomy with unintentional loss of some parathyroid glands
superior parathyroid glands are most commonly found inferior to the superior thyroid artery and the recurrent laryngeal nerve
Recurrent Laryngeal nerve
innervates all intrinsic muscles of the larynx except the cricothyroid muscle
also carries sensory input from larynx below the vocal cords
passes close to the inferior thyroid artery on its ascent to the larynx
BILATERAL DAMAGE may cause difficulty swallowing, and shortness of breath
UNILATERAL DAMAGE could result in ineffective cough
Accessory nerve
damage can cause weakness of shoulder shrug
passes through posterior triangle of the neck (clavicle inferiorly, sternocleidomastoid muscle anteriorly, trapezius posteriorly)
most common injury during biopsy of cervical lymph nodes
Graves disease
thyrotropin receptor autoantibodies that activate TSH receptor
***Neonates born to mother’s with Grave’s disease are at risk of neonatal hyperthyroidism due to placental transmission of thyroid stimulating immunoglobulins
metabolically active free t3 increases the basal metabolic rate and lipolysis (weight loss, high blood pressure, increased body temp)
TSH receptor antibodies also bind to orbital TSH receptors and stimulate adipocyte proliferation and orbital fibroblast secretion of glycoaminoglycans causing expansion of retro-orbital tissue, also PRETIBIAL MYXEDEMA ***DERMAL ACCUMULATION OF GLYCOAMINOGLYCANS
HLA-DR3 and HLA-B8
Histology: tall, follicular, epithelial cells with scalloped colloid spaces
cardiac effects: increased contractility, increased HR, increased systolic pressure, increased pulse pressure, DECREASED SYSTEMIC VASCULAR RESISTANCE
Thyrotropin function
thyroid stimulating hormone or TSH
Hashimoto Thyroiditis
subacute lymphocytic thyroiditis
enlarged painless thyroid gland
hyperthyroidism secondary to transient thyroxine release from destroyed thyroctes
autoantibodies to THYROID PEROXIDASE, anti-microsomal antibodies
NONGRANULOMATOUS THYROID INFLAMMATION
Histology: lymphoid aggregates with germinal centers and Hurthle cells
HLA-DR5
De Quervain thyroiditis aka Subacute thyroiditis
GRANULOMA FORMATION and multibucleated giant cells
hyperthyroidism caused by thyroxine release from destroyed thyroctes
TENDER GOITER and jaw pain
Hypothyroid
can result in hyperprolactinemia: low Thyroid leads to increased TRH and increased TSH, increased TRH by hypothalamus leads to increased TSH in anterior pituitary, excessive TRH can stimulate lactotroph cells of anterior pituitary to release prolactin
medullary thyroid cancer
hyperplasa of parafollicular (C) cells that release calcitonin (inhibit osteoclast activity)
ovoid cells of C cell origin and therefore without follicle development, amyloid in the stroma stains with congo red
MEN2 (RET genes) for 25% and sporadic for 75%
mostly 50-60 years of age
Papillary thyroid carcinoma
most common, prior history of radiation is risk factor
palpable lymph nodes due to metastatic spread
can be multifocal
RET/PTC rearrangements and BRAF mutations, also associated with ionizing radiation
30-50 years of age
cells with nuclear inclusions and psammoma bodies on histology along with orphan annie eyed nuclei “Papi and Moma adopted Orphan Annie
Follicular thyroid carcinoma
hematogenous metastasis especially to Lungs and Bone (lytic lesions)
rarely multifocal
vascular and capsular invasion
40-60 years old
uniform follicles
PAX-PPAR[gamma rearrangement and !!RAS mutation!!
Anaplastic thyroid carcinoma
rapid local growth
sx of compression of structures of neck (dysphagia, dyspnea)
lymph and hematogenous metastasis
very poor prognosis
normally after 60 years of age
undifferentiated giant cell, areas of necrosis and hemorrhage
TP53 mutation
Toxic Multinodular goiter
constitutively active TSH receptors can lead to this
nodular neck swelling, painless
histology: focal patches of hyperfunctioning follicular cells distended with colloid
Thyroid levels with pregnancy (Thyroid-binding globulin, Free T3, Free T4, Total T3+T4)
Thyroid-binding globulin elevated
Free T3 normal
Free T4 normal
Total T3+T4 elevated
hyperestrogenic state stimulates synthesis of thyroid binding globulin by the liver and increases the glycosylation of TBG which slows its clearance, as more T3 and T4 bind to TBG the level of free thyroid decreases, therefore more TSH is released and new equilibrium is set
Sick Euthyroid syndrome
normal free T4 levels in setting of decreased TBG free T3 and total T3+T4
Primary Hyperparathyroidism
hyperCA due to abnormally active PTH glands
PTH high
CA high
Phosphate Low
ALP high
PTH induces RANKL expression in osteoblasts, RANKL to RANK on osteoclasts activates osteoclasts*
tx with parathyroidectomy
Secondary hyperparathyroidism
Hypocalcemia and/or hyperphosphatemia cause reactive hyperplase of PTH glands with overproduction of PTH
CKD, Calcium deficiency, Vitamin D deficiency
Ca normal or low
PTH high
Phosphate normal or high in CKD, low in other causes
ALP high
Treat the underlying cause
***RUGGER JERSEY SPINE = ALTERNATING SCLEROTIC AND RADIOLUCENT BANDS IN THE LUMBAR AND THORACIC VERTEBRAL BODIES
Tertiary hyperparathyroidism
Hypercalcemia caused by autonomous and refractory secretion of PTH secondary to untreated secondary hyperparathyroidism
persistent sHPT
CA high
PTH very high
Phosphate high
ALP high
usually tx with surgery
THINK SECONDARY HYPERPARATHYROIDISM BUT haS HYPERCALCEMIA!!
Primary Hypoparathyroidism
mostly post surgery
tetany, laryngospasm, seizures, arrhythmias are acute
chronic - extrapyramidal disorders, ocular disease
CA low
PTH low or inappropriately normal
Phosphate typically elevated
pseudo hypo parathyroidism
end-organ resistance to PTH despite sufficient PTH synthesis due to defective Gs protein alpha subunit
Posterior vs ANterior pituitary
Posterior -
stores then releases ADH (made in supraoptic and paraventricular nucleus of hypothalamus), and oxytocin (same as ADH)
develops from neural ectoderm (neurohypophysis)
Anterior -
release ACTH, TSH, LH, FSH, and MSH from basophilic cells
release prolactin, and GH from acidophil cells
Neuroblastoma
paraneoplastic syndrome
opsoclonus-myoclonus syndrome
urine may have elevated homovanillic acid and vacillylmandelic acid (produced when neuroblastoma cells metabolize catebholamines
“Homer Wright rosettes” on histology. halo like clusters of neuroblast cells surrounding a central pale area containing neuropil
Rhabdomyosarcoma
rare malignant mesenchymal tumor of primitive muscle cells
primarily occur in orbital cavity
children in first year of life
blastic skeletal muscles cells arranged in nests and sheets
Nephroblastoma (Wilm’s Tumor)
most common renal malignancy in children 2-5 years old
commonly incidental finding
large abd mass, hematuria, abd pain
histology: abortive glomeruli and tubules with spindle cell stroma
can metastasis to lung or liver
***ORIGINATE FROM RESIDUAL METANEPHRIC BLASTEMA
Hepatoblastoma
most common hepatic malignancy in children
elevated AFP
Addison’s Disease
fatigue, nausea, weight loss, orthostatic hypotension, hyperpigmentation
cortisol(normal = 3-23micrograms/dL) failure to increase after COSYNTROPIN stimulation test confirms diagnosis
hyperpigmentation is due to excess MSH (byproduct of ACTH synthesis
Glucagonoma
functional neroendocrine tumor derived from pancreatic alpha cells
secretes glucagon which increases gluconeogenesis and glycogenolysis thus resulting in hyperglycemia
chronic diarrhea, weight loss, neuropsychiatric symptoms, DVT, normocytic anemia (glucagon inhibitory effect on erythopoiesis), and necrolytic migratory erythema
Insulinoma
pancreatic beta cells
produce insulin and facilitate weight gain and hypoglycemia
Somatostatinomas
pancreatic delta cells secrete somatostatin
weight loss and glucose intolerance
abd pain, steatorrhea, cholelithiasis
Gastrinoma
gastric G-cells
secrete gastrin
weight loss and recurrent diarrhea
abd pain, dyspepsia (and discomfort >1 month)
Carcinoid tumors
enterochromaffin cells
produce serotonin
weight loss, diarrhea, skin lesions caused by niacin deficiency, flushing, wheezing
DM type 1
insulin dependent
autoimmune response with production of autoantibodies (anti-glutamic acid decarboylase or anti-GAD, and anti-islet cell cytoplasmic antibody or anti-ICA) that destroy beta cells in pancreatic islets leading to insulin deficiency and decreased glucose uptake in tissues
HLA-DR3 and HLA-DR4
DM type 2
peripheral insulin resistance
central obesity cause - increase plasma levels of free fatty acids to impaired insulin dependent glucose uptake
increased serine kinase activity in fat and skeletal muscle cells phosphorylates insulin receptor substrate 1 decreasing affinity of IRS-1 for PI3K leading to decreased expression of GLUT4 channels
Panreatic beta cell dysfunction: accumulation of pro-amylin in the pancreas leading to decreased endogenous insulin production
Hemochromotosis
HFE gene - membrane protein that regulates iron uptake by facilitating interaction of transferrin with its receptors
gene is mutated leading to DEFECTIVE BINDING OF TRANSFERRIN TO RECEPTOR and signals decreased iron stores
Response is the liver stops producing the hormone hepcidin allowing iron reabsorption resulting in iron overload
hyperpigmented skin, DM, risk of cirrhosis,
LIVER BIOPSY SHOWS BLUE HEMOSIDERIN DEPOSITS
inability to excrete iron, transferrin/hepcidin/iron storage all increased but iron binding capacity is decreased
Wilson Disease
impaired binding of copper to ceruloplasmin
AR mutations in the ATP7B gene which also leads to impaired biliary copper excretion
hepatic damage, CNS manifestations, renal damage, kayser-Fleischer rings (1-2mm copper color on periphery of iris)
alpha1-antitrypsin deficiency
serine protease inhibitor that is made in liver and protects cells from breakdown by neutrophil elastase
mutation in SERPINA1 gene
Several genotypic expressions:
PiMM 100% expression of normal protein
PiMS 80% normal protein
PiSS, PiMZ, PiSZ 40-60% normal levels of protein
PiZZ 10-15% normal levels of protein
Autosomal codominant
Liver: accumulation of AAT in ER leading to hepatocyte destruction (hepatitis and liver cirrhosis)
Lungs: deficient AAT to uninhibited neutrophil elastase activity to destruction of pulmonary parenchyma to panacinar emphysema
Clinical Features: cough, wheeze, dyspnea, diminished breath sounds, barrel chest, prolonged neonatal jaundice, hepatitis, cirrhosis
Diagnostics: serum low AAT levels, Electrophoresis decreased alpha 1 peak,
pheochromocytoma
paroxysmal headaches, palpitations, sweating, HTN, pallor
catecholamine secreting tumor originating from chromaffin cells (epinephrine, norepi, dopamine)
MEN2B
Barrett Esophagus
metaplastic columnar epithelium in lower esophagus
chronically exposed to stomach acid in GERD
heart burn
Eosinophilic esophagitis
mucosal fragility and inflammation, dysphagia
barium swallow may show formed rings or small strictures in consequent ridges/furrows (“corrugated esophagus”)
Histology: infiltration of eosinophils in epithelium
Limited systemic sclerosis vs diffuse
loss of esophageal smooth muscles cells in lower 2/3 of esophagus and incompetence of lower esophageal sphincter
subtype of systemic sclerosis
cutaneous sclerosis of NECK, FACE, DISTAL LIMBS with sparing of trunk, raynaud phenomeneon
anticentromere autoantibodies
CREST syndrome: CALCINOSIS CUTIS, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, Telangiectasia
diffuse systemic sclerosis
cutaneous sclerosis of TRUNK, FACE, EXTREMITIES
SCLERODERMA RENAL CRISIS IS COMMON (collagen deposition in kidney parenchyma)
INTERSTITIAL LUNG DISEASE
rapid onset and normally with raynaud phenomenon*
Mallory Weiss syndrome
mucosal lacerations at the gastroesophageal junction
epigastric pain, foreceful hematemesis, unstable vitals (hypovolemic shock)
associated with frequent foreful vomiting
PUD (peptic ulcer disease)
break in continuity of mucosal lining in stomach or duodenum, clean based gastric ulcer
common with H. pylori infection or use of NSAIDS
H. pylori is strongest predisposing factor 25-50% of gastric and 50-75% of duodenal ulcers**
epigastric pain, hematemesis
Whipple Disease
chronic polyarthritis that precedes development of diarrhea/abd pain/weight loss
PAS positive stain with foamy macrophages in lamina propria confirms diagnosis
Tropheryma whipplei is an intracellular, gram positive bacillus
multinucleated trophozoites in stool indicates?
Entamoeba histolytica or Giardia lamblia
severe diarrhea
Celiac disease markers? and extra
anti-tissue transGLUTaminase antibodies (most common), also anti-endomysial antibodies, and anti-deamidated gliadin peptide antibodies
weight loss, diarrhea, abd pain
histology include villous atrophy, crypt hyperplasia, lymphoctic infiltration
Rheumatoid arthritis marker?
anti-cyclic citrullinated peptide antibody (ACPA), Anti-IgG antibodies
long standing arthralgia, chronic inflammation, pain, swelling, stiffness, destruction to synovial joints
clinical features: RHEUMATOID NODULES AND PULMONARY FIBROSIS
HLA-DR4 and HLD-DR1
elevated CRP and ESR
sx BETTER throughout the day
Chrohn disease vs ulcerative colitis
anti-saccharomyces cerevisiae antibodies in Chrohn’s and p-ANCA in ulcerative colitis
Chrohn’s - typically terminal ileum and colon with rectal sparing, transmural inflammation with cobblestone sign, constant RLQ pain with palpable abd mass, typically nonbloody diarrhea, Th1 cell activity releases proinflammatory IFNgamma
UC - colon and rectum, confined to mucosa and submucosa, no granulomas, friable mucosa with crypt abscesses, painful defecation and pain location LLQ, bloody diarrhea with mucus and urgency, increased secretion of IL-4 and IL-13 mediated by Th2 cells
Hirschsprung Disease
impaired migration of neural crest cells (parasympathetic) in a rostral to caudal direction
aganglionic distal sigmoid and rectum
internal anal sphincter fails to relax in response to rectal distention leading to intestinal obstruction and dilation of colon
immediate relief after finger is removed from checking shpincter tone
Portal Hypertension anastomosis
caput medusa after shift to SUPERIOR EPIGASTRIC VEINS
Esophageal varices after shift to left gastric vein then azygous vein
superior, inferior, and middle rectal veins dilate causing rectal varices
Gallstone Ileus
gallstone obstructing ileus
common to find when there is a fistula between gallbladder and small intestine
primary sclerosing cholangitis
fibrosis of common bile duct
RUQ pain, and fever
markedly elevated cholestasis parameters (ALP, GGT, and bilirubin)
Rubella Virus
togavirus
German (3 day) measles
fever, postauricular and other lymphdenopathy, arthralgias, fine maculopapular rash that start on face and spreads out to involve trunk and extremities
TORCH: congenital rubella “blueberry muffin” baby, sensorineural deafness, cataracts, PDA
Varicella Zoster virus
hhv3
chickenpox and shingles
fever, malaise, exanthem typically starts on trunk and includes scalp while sometimes oral mucosa that is severely pruritic
latent in dorsal root or trigeminal ganglia
Human herpesvirus 6
exanthem subitum maculopapular truncal rash sometimes spreads to face and extremitites normally fading after 2 days
abrupt fever, rash starts 2 days after fever, cervical and postauricular lymphadenopathy
Measles
4C’s: cough, coryz, conjunctivitis, “C”oplik spots
Koplik spots are bright red spots with blue-white center on buccal mucosa
PNA is most common death
VITAMIN A DEFICIENCY CAN BECOME WORSENED - NORMALLY TRANSPORTED VIA MICELLE-MEDIATED TRANSPORT
COMMON CAUSE OF BLINDNESS IN UNDEVELOPED COUNTRIES
Tinea Versicolor
post travel to warm climate, nonpruritic skin rash also nontender and fine scaling
most commonly increased growth of Malasezia globosa (normal skin flora)
abnormal pigmentation involving trunk, back, and/or abdomen
Vitiligo
autoimmune destruction of melanocytes
nonscaling, depigmented macules
acne vulgaris
increased sebum production
presence of comedones
in areas with sebaceous activity
Oculocutaneous albinism
deficiency of tyrosinase that produces melanin from dihydroxyphenylalanine
greatly reduced or complete lack of pigmentation in the skin, hair, and eyes of newborns
Allergic Contact Dermatitis
type IV hypersensitivity
antigen uptake via langerhans cells
intensely pruritic erythematous and papular rash in pattern of contact with external irritant
Tinea corporis/corpora
“Ringworm”
common caused by trichophyton
round pruritic erythematous plaque that grows centrifugally with central clearing and scaling and raised border
Pemphigus vulgaris vs bullous pemphigoid
PV - IgG autoantibodies to desmosomal components, loss of cell-cell adhesion, ORAL CAVITY INVOLEMENT, Nikolsky sign positive (rubbing on skin makes blisters)
Bullous pemphigoid - IgG autoantibodies to hemidesmosomes,
Basal cell carcinoma vs Squamous cell carcinoma
Basal cell is most common type, slow growing non healing ulcer with rolled borders, pearly white nodule with superficial telangiectasis or a scaling plaque, location usually above the line joining the earlobe and corner of mouth
Squamous cell is second most common type, ulcer normally on cheek and lower lip that has everted edges
seborrheic keratosis
benign skin tumor common in elderly
greasy wax like darkly pigmented macule
Nodular melanoma
often arise from skin damaged by UV light
grows rapidly over weeks
dark pigmented or red nodule that occasionally ulcerate at the surface
Trichoepithelioma
tumor of the hair follicle common on cheeks and nose
Myasthenia gravis
antibodies against post-synaptic ACh receptors compete with ACh at post-synaptic membrane
Clinical Features: WEAKNESS AND REDUCED endurance with repetitive muscle use, EXTRAOCULAR EYE WEAKNESS
Tx: Acetylcholinesterase inhibitors
Lambert Eaton
rare neuromuscular junction disorder characterized by proximal muscle weakness and autonomic dysfunction
autoantibodies directed against presynaptic voltage gated calcium channels (anti-VGCC) - decreased calcium influx - decrease presynaptic vesicle fusion - impaired acetylcholine release in NMJ
Clinical Features: PROXIMAL muscle weakness, (strength IMPROVES with ongoing use), reduced or absent reflexes, DRY MOUTH, constipation, ED
ASSOCIATED WITH SCLC
Muscle contraction myosin blah blah process
upon initiation of muscle contraction calcium is released from Sarcoplasmic reticulum and binds to troponin C which shifts tropomyosin and exposes myosin binding site, myosin head binds actin allowing for shortening of the sarcomere
SLE (Systemic Lupus Erythematous)
Anti-dsDNA antibodies in 70%
Anti-Smith antibodies 30% (both are highly specific)
nonspecific antibodies include: anti-ssDNA, antibodies directed against Fc region of IgG (rheumatoid factor), phospholipid-binding proteins, and antihistone antibodies (drug induced via hydralazine, phenytoin, procainamide
multisystem autoimmune disease
more common in women of childbearing age
fever, fatigue, malar rash, myalgia, arthritis
affects skin, kidney, joints
“Full house” immunofluorescence pattern (IgG, IgM, IgA, C3, C1q)
Differentiate synovial fluid findings
rheumatoid arthritis, sarcoidosis, osteoarthritis, gout, pseudogout, scleroderma
rheumatoid arthritis - proliferation of granulation tissue
sarcoidosis - noncaseating granulomas
osteoarthritis - normally no WBC, cartilage fragements
gout - monosodium urate crystals, negative birefringent, crystal shaped
pseudogout - calcium pyrophosphate crystals, positive birefringment, rhomboid shaped
scleroderma - noninflammatory superficial fibrin deposits
Reactive arthritis
response to infection (chlamydia, shigella, campylobacter, among others)
HLA-B27 genotype in 2/3 of pts
Dermatomyositis
increased risk of malignancies particularly ovarian adenocarcinomas
PROXIMAL muscle weakness, HELIOTROPE RASH OVER EYELIDS, flat topped erythematous papules over dorsal surface of interphalangeal joints (Gottron papules)
anti-Mi-2 and anti-Jo-1 antibodies (anti-nuclear antibodies)
Paget disease of bone
enlargement of skull
deposition of lamellar bone interspersed with disorganized, woven bone creates a mosaic pattern
accelerated rate of bone remodeling resulting in poor quality bone
Carbamezepine use during pregnancy
neural tube defects
same as valproic acid
Aminoglycoside during pregnancy
sensorineural hearing loss
Tetracycline during pregnancy
discolored teeth
Ebstein anomaly
pregnancy lithium exposure
kidney stone shapes
Uric - tear drop ish
calcium oxalate - envelope
calcium phosphate - phosphate needles
Magnesium ammonium phosphate - coffin lid struvite stone
Cystine - hexagonal
TORCH infections (O#1)
TrepOnema pallidum - congenital syphilis
premature birth
low birth weight, neonatal JAUNDICE, seizures, chorioretinitis, HEPATOMEGALY, hemolytic anemia, mucocutaneous rash (MACULOPAPULAR RASH ON PALMS AND SOLES), SADDLE NOSE, HUTCHINSON TEETH (widely spaced)
Hutchinson triad - dental abnormalities, sensorineural deafness, interstitial keratitis
hydrops fetalis
spirochetes on dark field microscopy
TORCH infections
Toxoplasmosis
Others (trepOnema pallidum, varicella zOster, parvO b19, and listeriOsis)
Rubella
Cytomegalovirus
Herpes Simplex
great rule out is if mother has been vaccinated
TORCH infections (T)
Toxoplasmosis gondii
classic triad: Chorioretinitis, hydroCephalus, diffuse INTRACRANIAL CALCIFICATIONS (ring-enhancing lesions), Covulsions
TRASMITTED THROUGH CAT FECES
blueberry muffin rash
TORCH infections (O#2)
ListeriOsis
contamination of RAW MILK PRODUCTS
spontaneous abortion and premature birth
sepsis, DISSEMINATED ABSCESSES, LISTERIA MENINGITIS, RESPIRATORY DISTRESS
vesicular and pustular skin lesions (granulomatosis infantiseptica
TORCH infections (O#3)
Varicella zOster virus
low birth weight, CHORIORETINITIS, CATARACTS, and seizures
80% have dermatomal HYPERTROPHIC SCARS
hypoplastic limbs
TORCH infections (O#4)
ParvOvirus B19
aplastic ANEMIA
FETAL HYDROPS, MISSCARRAIGE
high output cardiac failure
TORCH infections (R)
Rubella
sensorineural deafness (COCHLEAR DEFECT), CATARACTS, HEART DEFECTS (PDA, pulmonary artery stenosis)
CNS abnormalities
blueberry muffin rash
TORCH infections (C)
Cytomegalovirus
jaundice, hepatosplenomegaly
chorioretinitis
sensorineural deafness
PERIVENTRICULAR CALCIFICATIONS, blueberry muffin rash
microcephaly
seizures
TORCH infections (H)
Herpes simplex virus
premature birth
skin, eyes, mouth involvement (VESICULAR SKIN LESIONS)
localized CNS involvement (MENINGOENCEPHALITIS)
multiple organ involvement, sepsis
PCOS
associated with insulin resistance and obesity
Diagnostics” Rotterdam criteria
Oligovulation or anovulation
Hyperandrogenism (acne, alopecia, hirsutism, increased testosterone)
enlarged or polystic ovaries on ultrasound
obese, hirsuism, acne, hair thinning, alopecia, depression, azanthosis nigricans (darkening of some spots of skin), infertility
Endometrioma
“chocolate cyst”
yellow-brown (sometimes reddish-blue) blebs
most pt are asymptomatic
chronic pelvic pain that worsens before onset of menses
infertility
dysmenorrhea
uterosacral tenderness
Cervical carcinoma
high risk strains of HPV (16,18,31, 33)
early onset of sexual activity, multiple pregnancies, smoking, STD’s
Choriocarcinoma
gestational trophoblastic neoplase
can arise from molar pregnancy, abortion, ectopic, prior pregnancy
bleeding form these is common
Mature cystic teratoma
most common type of ovarian germ cell tumor
contain any type of tissue (hair, teeth, sebaceous glands)
palpable mass
sx of hyperthyroidism
struma pearl may be present
Androgen insensitivity syndrome
X-linked recessive
insensitivity to androgens
female phenotype
blind ended vaginal pouch
uterine agenesis
crytochid testes
primary amenorrhea
infertility
scant or missing pubic hair
Aromatase deficiency
AR
CYP19A1 gene mutation
defective or absent aromatase (decreased estrogen and increased androgen production)
46XX - ambiguous external genitalia, normal internal genitalia, amenorrhea
46XY - abnormal sperm production, small or undescended tests
Both - tall stature, oseoporosis, hyperglycemia, weight gain and fatty liver
5-alpha reductase deficiency
AR
decreased conversion of Testosterone to dihydrotestosterone
female external genitalia
MALE INTERNAL GENITALIA
pseudovaginal perineoscrotal hypospadias
development of secondary sexual male characteristics in puberty
Klinefelter
47 XXY trisomy
barr body present with male phenotype
testicular dysgenesis
testosterone deficiency
gynecomastia
reduced facial and body hair
testicular atrophy
mitral valve prolapse
FIBROSIS OF SEMINIFEROUS TUBULES CAUSING DECREASED LEYDIG CELL FUNCTION (RESULTING IN LOW TESTOSTERONE)
Turner syndrome
45 XO
nondisjuction during meiosis
no Barr body
chromosomal nondisjunction, X chromosome monosomy, impaired ovarian development, malfunctioning streak gonads with connective tissue instead of normal germ cells, Estrogen and progesterone deficiences
clinical features: female phenotype, average to short height, delayed puberty, primary amennorhea, infertility (can with IVF),
webbed neck
coartation of aorta, and BICUSPID AORTIC VALVE, hypertension,
low set posterior hairline
high arched palate
osteoporosis
SHIELD CHEST
horseshoe kidney
type II diabetes
Genital dysgenesis
46XY - mutation of SRY gene on chromosome Y
impaired testicular development and underproduction of testosterone and anti-mullerian hormone
persistance of mullerian ducts (develops female genitalia despite Y chromosome
46XX - female phenotype
impaired maturation of secondary sexual characteristics
primary amenorrhea
Kallman syndrome
46xx or xy
hypogonadotropic hypogonadism with hyposmia or anosmia
Failure of GnRH-secreting nuerons to migrate from olfactory placode to their normal anatomic location in the hypothalamus
can be defect in KAL-1 gene or FGFR-1 gene(fibroblast growth factor receptor-1)
Factitious disorder vs conversion disorder
Factitious - pt consciously produce symptoms, purposely injure themselsves or self administer insulin for primary gain which is to be cared for
Conversion - function neurological disorder that involves neuro symptoms that are not fully explained by objective findings, findings are subconciously produced and not fabricated
Metabolic syndrome
HTN, abd obesity, insulin resistance with hyperglycemia, increased serum triglyceride levels and decreased HDL
Tuberous Sclerosis
AD
mutation in TSC1 or TSC2 mutation
defective tuberin-hamartin complex
Classic findings: ASH LEAF SPOTS, Shagreen patches, CNS hamartomas (subependymal nodules lining lateral ventricles and cortical glioneuronal hamartomas), GIANT CELL ASTROCYTOMAS, INTELLECTUAL DISABILITY
Dobutamine
Beta 1 receptor agonist
Central vs Peripheral chemoreceptors
Peripheral - Carotid bodies and aortic body detect ph/Oxygen/Carbon dioxide levels and stimulate a change in breathing
Central: Medullary has stimulatory receptors for inspiration (dorsal) and expiration (ventral). These receptors send impulses down phrenic nerve to diaphragm. Pontine respiratory group sends messages to medullary for rate and depth as well as the chemoreceptors
Pseudo allergy vs real allergy
Pseudo - direct mast cell degranulation (example is morphine after anesthesia
Real - IgE mediated type 1 hypersensitivity
Osteomalacia
often vitamin d deficiency
means bone softening
Osteopetrosis
persistence of spongiosa in the medullary cavity
impaired osteoclast activity
abnormal and overdense bone
hyperparathyroid bone details
subperiosteal bone resorption and cystic degeneration
Intussusception
when your bowel folds over itself
more common in children 6 months to 3 years
abd pain
following a viral infection that leads to lymphoid hypertrophy (peyer patches) that get caught during peristalsis and are pushed forward in bowel tract
most common in ileocecal junction
Pulse Pressure
difference between systolic and diastolic pressure
Cholinergic toxicity acronym
Muscarinic effects “Dumbels”:
diarrhea/diaphoresis
urination
miosis
bronchospasm/bronchorrhea/bradycardia
emesis
lacrimation
salivation
Nicotinic effects:
muscle weakness/paralysis/fasiculations
Granulosa cell tumor
estrogen and inhibin secreting
large unilateral adnexal mass
Granulosa cells: cuboidal cells with nuclear grooves (coffee bean nuclei)
Call-Exner Bodies: granulosa cells form follicle like structures around eosinophilic material
Yolk Sac Tumor
secrete alpha feto protein
shiller duval bodies: resemble glomeruli, mesodermal core with central capillary
Zolpedim, zaleplon, eszopiclone
nonbenzodiazepines
GABAa receptor agonists
primary hyponotic that doesn’t produce other sx benzos produce:anxiolytic, muscle relaxant, anticonvulsant
Insomnia medication
remelteon
melatonin receptor agonism
Fat emboli
24-72 hours following a long bone or pelvic fracture
norepinephrine effect on heart
a1>b1>b2
increase in Systemic vascular resistance
decrease in heart rate (reflex mediated decrease)
acyclovir
anti viral
guanosine analog
once entered to Herpes virus it is phosphorylated via viral-encoded thymidine kinase
then impairs DNA polymerase mediated replication
Glucagon effects on Liver, Fat, and heart
Liver: increase glycogenolysis, decrease lipogenesis, increase glucogenesis
Fat: increase lipolysis
Heart: increase heart rate, increase contractility
useful for beta blocker overdose
released from Pancreatic ALPHA cells
How do corticosteroids help with asthma?
upregulate beta 2 receptors
chronic asthma Beta 2 agonist use can result in fibrotic remodeling of lower airways making them less responsive to beta 2 agonists*
Type 1 collagen
skin, bones, ligaments, tendons, dentin, cornea, blood vessels, scar tissue
associated diseases: osteogenesis imperfecta
Type 2 collagen
cartilage, vitreous humor, and nucleus pulposus
associated diseases: skeletal dysplasia
Type 3 collagen
skin lungs, intestines, blood vessels, bone marrow, lymphatics, granulation tissue
associated diseases: Vascular Ehlos-Danlos syndrome (TYPE IV)
Type 4 collagen
basement membrane
associated diseases: alport syndrome
osteogenesis imperfecta
AD
COL1A1 or COL1A2 gene mutation
decreased formation of hydrogen and disulfide bonds
decreased synthesis of type 1 collagen
growth delay, brittle bones, bowing of bones, fractures during childbirth, BLUE SCLERAE, progressive hearing loss
tx with bisphosphonates
Bisphosphonates
Alendronate, Risedronate, Ibandronate, Zoledronate
primarily slow down bone degredation
moa: bind to hydroxyapatite binding sites on surface of bone tissue to interfere with osteoclasts, inhibit mineralization
impair adherence of osteoclasts to bone surface, decrease osteoclast proton production, induce osteoclast apoptosis, decrease development and recruitment of osteoclast precursor cells
adverse effects: hypocalcemia, ESOPHAGEAL INFLAMMATION and cancer (oral take, to avoid sit upright and drink sufficient water)
Ehlers-Danlos syndrome
AD
mutation in COL5A1 and COL3A1
Vascular type is COL3A1, affects type III procollagen, classic sx with thin translucent skin and easy bruising, spontaneous organ rupture, aneurysms, dissections
Classic - COL5A1 and A2, affects type V collagen,
Classical like - TNXB gene affecting Tenascin X protein,
Marfans syndrome
AD
FBN1 gene on CHR 15 affecting fibrillin protein
aortic aneurysm, mitral valve prolapse, berry aneurysms, tall stature, long extremities, joint hypermobility, arachnodactyly, pectus carinatum/excavatum, hyperextensive skin, ECTOPIA LENTIS (upward lens dislocation)
Kuppfer Cells
Liver
macrophage derived
lie within liver sinusoids
Merkel Cell
neuroendocrine cells that lie in basal layer of epidermis
often found in association with nerve projections
play a role in perception of touch
Melanocytes
pigment producing cells that deliver malanosomes to keratinocytes
Dystonia
sustained involuntary muscle contractions
focal means one muscle specifcally
can lead to muscle hypertrophy
Siderophages
hemorsiderin laden macrophages
Osteocytes
Osteoblasts that become trapped in bone matrix
Pericytes
maintenence cell
help with wound healing
help with maintaining BBB
Dynein vs Kinesis vs Lamin vs Selectin vs Spectrin vs Vimentin
DYnein - microtubular protein for retrograde transport (moving towards nucleus)
Kinesin - microtubular protein for anterograde transport (moving away from nucleus)
*Herpes goes into latent stage via dynein and reactivation stage via kinesin
DYN vs KINd = dine bringing food in and kind is giving food away*
Lamin - help form fibrillar network that lines insie of nuclear envelope, also help organize genome and regulate gene transcription
Selectin - adhesion cells that help migrate leukocytes on out of blood stream through endothelial cells during inflammatory response
Spectrin - cytoskeletal protein inside RBC that help maintain it’s shape (defects lead to sphereocytosis and elliptocytosis)
Vimentin - intermediate filament expressed in mesenchymal cells, responsible for securing organelles inside the cytosol and provides protection from mechanical stress
Variable Expressivity
Same mutation but differing degree of disesase manifestation and severity
Pleiotropy
one gene mutation is responsible for multiple seemingly unrelated phenotypic effects
Incomplete Penetrance
same gene mutation but phenotype is not expressed in everyone with mutation
Anticipation
when the succeeding generation develops a more severe form of the disease or develops it at a younger age
Loss of Heterozygosity
one allele of a gene is dysfunctional due to an inherited mutation, and the other allele is switched off via an acquired mutation
two hit hypothesis
retinoblastoma or Li Fraumeni
Condylamata Acuminatum
HPV caused gential warts
HPV 6 and 11
HPV likes stratified squamous epithelium (anal canal, vagina, cervix) and can be passed to baby resp system (true vocal cords)
Paget disease of the breast
malignant breast condition
unilateral, painful/pruritic, eczematous rash confined to nipple and areola
dx via tissue biopsy: epidermis, intraepithelial adenocarcinoma cells enlarged with abundant cytoplasm and prominent nucleoli
very likely to have underlying malignancy (DUCTAL BREAST CARCINOMA)
Stellate Cells
primary cells involved in hepatic fibrosis
transform into myofibroblasts in response to hepatic injury
Myofibroblasts are capable of proliferating, promoting chemtaxis, and producing large quantities of collagen
Collagen stains blue with Masson Trichrome
Hepatic Cirrhosis
end stage of multiple liver diseases
characterized by replacement of normal lobular architecture with regenerating nodules separated by bridging fibrous septa
Clinical Features: ascites, gynecomastia (decreased estrogen metabolism), palmar erythema (estrogen mediated vasodilation)
Rett Syndrome
sporadic de novo mutation of MECP2 gene on X chromosome
X linked dominant
almost female exclusive
normal development until 6-18 months of age then loss of motor skills (characteristic “hand wringing”, truncal ataxia, seizures, growth failure, intellectual and verbal disability, scoliosis
Cri-Du-chat
microdeletion at short arm of chromosome 5
Clinical features: cat like high pitched crying
congenital heart defects (VSD)
microcephaly
Intellectual disability
dysmorphic facial features
Williams syndrome
Autosomal recessive defect in chromosome 7 (includes deletion of elastin gene)
intellectual disability
hypersociability
elfin facies
hypercalcemia
low muscle tone
hyperacusis
periorbital fullness and widely spaced teeth
Fragile X syndrome
CGG repeat
FMR1 gene
2nd most common genetic intellectual disability after trisomy 21
premature (x<200 trinucleotide repeats) have ataxia, premature ovarian insufficiency and tremor
Mature (x>200 trinucleotide repeats) have intellectual disability with varying severity, delayed language development, autistic behavior, long narrow face, prominent forehead and jaw, large everted ears, hypermobile joints, mitral valve prolapse, above average head circumference
Trisomy 21 or Down Syndrome
meiotic nondisjunction during meiosis 1 is about 70% of cases
can also happen with robertsonian translocation
clinical features: upward slanting palpebral fissures, epicanthal folds, ocular hypertelorism, brushfield spots, APPEARANCE OF PROTRUDING TONGUE, brachycephaly, hypoplastic nasal bones,FLAT FACIES, short neck with excess skin at nape, TRANSVERSE PALMAR CREASE, SANDAL GAP, CLINODACTYLY (inward curvature of the 5th finger), atrioventricular septal defect is most common, duodenal atresia
Zellweger syndrome (cerebrohepatorenal syndrome)
AR
PEX gene that results in impaired peroxisome synthesis
CLinical Features: neonatal seizures and Hypotonia, hepatomegaly, death within 1 year
Cystic Fibrosis
2nd most common genetic metabolic disorder in individuals of northern European descent
CFTR defect located on long arm of chromosome 7 (most common is mutation in delta F508 codon deletion leading to absence of phenylalanine in position 508 of CFTR gene)
CFTR gene is mutated (misfolded) results in absence of ATP-gated chloride channel on cell surface of epithelial cells
normal Sweat Glands - Chloride goes from lumen into cell
defective sweat gland - inability to reabsorb Cl so sweat has excess NaCl in sweat
Normal other exocrine glands (GI and Lungs) - Cl- goes from in cell to Lumen
defective other exocrine glands - Cl unable to transport intrcellularly across the membrane therefore accumulation of intracellular Cl-, formation of hyperviscous mucus,
Clinical features:
meconium ileus (failure to pass meconium, typically first 3 days of life with abd distension), failure to thrive,
pancreatic disease: (foul smelling steatorrhea, malabsoption, abd distention, deficiency in fat-soluble vitamins ADEK),
liver and bile duct abnormalities: (cholecystolithiasis, cholestasis, fatty metamorphosis of liver progressing to cirrhosis, biliary cirrhosis)
intestinal obstruction, rectal prolapse
Repiratory: chronic obstructive lung disease with bronchiectasis, chronic sinusitits (nasal polyps), recurrent or chronic productive cough and pulmonary infections (S. aureus is most common cause of recurrent infection in infancy and childhood, P. aeruginosa for adulthood, S. pneumoniae common as well), digital clubbing
Salty sweat (electrolyte wasting)
Urogenital: men usually infertile, obstructive azoospermia most common with vas deferens being absent (obstruction of ejaculatory duct), women have reduced fertility with viscous cervical mucus and amenorrhea
newborn screening: Mandatory screening in USA, blood spot test via heel prick in first 48 hours of life, Elevated IRT (immunoreactive trypsinogen) means CF possible
Diagnostics: sweat chloride testing (Cl- > 60 mmol/L), evidence of 2 CF causing CFTR gene mutations and sweat Cl- > 30mmol/L, positive physiologic CFTR testing with abnormal nasal potetial difference test
***sweat losses similar to the effects of loop diuretics, increased NaCl and H2O reabsorption with loss of H+ and K+
Prader Willi and Angelman Syndrome
Genetic syndromes cause by microdeletion at 15q11-q13; Genomic Imprinting
Angelman Syndrome - deletion or mutation of maternal UBE3A (chr15) and paternal gene methylation (silencing)
roughly 5% cases results from paternal uniparental disomy
Clinical Features; intellectual disability, pronounced epileptic seizures, ataxia, characteristic happy demeanor with frequent laughing, strabismus, wide spaced teeth, thoracic scoliosis
Prader Willi syndrome- deletion or mutation of paternal gene copy and maternal uniparental disomy in about 20-35% of cases
Clinical features- muscular hypotonia, hyperphagia, obesity, hypogonadism, intellectual disability, ALMOND SHAPED EYES AND DOWNTURNED MOUTH
Myotonic dystrophy
CTG trinucleotide repeat expansion
DMPK gene - changes in myotonin protein kinase expression
AD
myotonia (slow relaxation of muscles after cessation of contraction)
Type 1 and 2 - myotonia, skeletal muscle weakness, myalgia, arrhythmia, cataracts, testicular atrophy or ovarian insufficiency, frontal balding, cognitive and behavioral impairment, hypogammaglobulinemia
Type 1 usually occurs younger
fetal alcohol syndrome
most preventable cause of intellectual disability in the US
failed neuronal and glial cell migration
Clinical features: THIN UPPER LIP, smooth hypoplastic philtrum, down slanting short palpebral fissues, hypertelorism (increased distance between two body parts), microcephaly, VSD, heart lung fistulas, liimb dislocations, holoprosencephaly (forebrain fails to divide into two hemispheres
Primary Ciliary Dyskinesia
rare autosomal recessive disorder
absent or dysmotile vilia
defect in dynein arm of microtubules
Clinical features: chronic productive cough, RECURRENT OTITIS/SINUSITIS/NASAL POLYPS, bronchiectasis, conductive hearing loss, displaced heart sound, KARTAGENER SYNDROME (SITUS INVERSUS/RECURRENT SINUSITIS/BRONCHIECTASIS,
diagnosistics: nasal nitric oxide test: reduced nasal nitric oxide
IL-12 function and receptor deficiency
IL-12 induces the maturation of naive T cells to helper T cells and the production of IFN gamma and TNF alpha by Th-cells
IL-12 receptor deficiency
AR
impaired Th1 response
macrophages cannot be activated by IFN-gamma so there’s no cytotoxicity in cells infected with intracellular pathogens (Mycobacteria, Salmonella)
underlying pathology in most cases of high Mendelian susceptibilty to mycobacterial disease
Clinical features: Mycobacterial infections (developing tuberculosis after BCG vaccination, fungal infections
Diagnosis: decreased IFN-gamma
IFN-gamma
cell signaling protein that medicates macrophage activity and expression of MHC molecules
activation of macrophages increases production of macrophage elastases
released by stimulated Th1 and NK cells
SCID (Severe combined immunodeficiency)
numerous genetic mutations that result in defective development of functional B and T cells
X-linked recessive = most common defect, defect in common gamma chain, efective IL-2R GaMmA CHAIN receptor linked to JAK3
Autosomal recessive = ADA (adenosine deaminase) deficiency, accumulation of toxic metabolites and disrupted purine metabolism, accumulation of dATP inhibitis the function of ribonucleotide reductase, impaired generation of deoxynucleotides
RAG mutation = faulty VDJ recombination
Clinical features: NORMAL AT BIRTH, severe recurrent infections, failure to thrive, chronic diarrhea, lymph noes and tonsils may be absent
Diagnosis: Quantitative PCR shows decrease T cell receptor excisions circles (TRECs), absent T cells, lymph node biopsy with absent germinal center, CXR shows absent thymic shadow
AVOID LIVE VACCINES, GIVE IV IMMUNOGLOBULINS< BONE MARROW TRANSPLANT OR STEM CELL TRANSPLANTATION NEEDED
micrognathia
lower jaw undeveloped
Edwards syndrome
47XX or 47XY +18
2nd most common autosomal trisomy in which fetuses can survive, after trisomy 21
meiotic nondisjunction
Clinical Features: LOW SET EARS (malformed auricle), MICROGNATHIA (congenital mandibular hypoplasia), PROMINENT OCCIPUT, CLENCHED FISTS with flexion contractures and overlapping finger, ROCKER-BOTTOM FEET, congenital heart defects (VSD/ASD/Tetralogy of Fallot), myelomeningocele, omphalocele, severe intellectual disablity
Diagnosis: quadruple test = decrease in free estriol/AFP/beta-HCG/and normal or decreased inhibin A
about 13% live past 1 year of age
Patau syndrome Trisomy 13
trisomy 13
meiotic nondisjunction
abnormal fusion of prechordal mesoderm, midline defects
clinical features: MICROCEPHALY, HOLOPROSENCEPHALY, CLEFT LIP AND PALATE, LOW-SET MALFORMED EARS, MICROPHTHALMIA, POLYDACTYLY, congenital heart defects (VSD/PDA), rocker bottom feet, aplasia cutis congenita(scalp lesions with a punched out appearance, omphalocele, PKD, capillary hemangioma
diagnostics: DECREASED PAPP-A (pregnancy associated protein A) and increased nuchal translucency
*****7 P’s: Patau, holoProsencephaly, cleft liP and Palate, Polydactyly, Pump disease (congenital heart disease), Polycystic kidney disease, cutis aPlasia
Omphalocele
congenital visceral malformation in which organs herniate at midline abd wall through the umbilicus into a hernial sac
Quadruple test purpose and results
prenatal screening test performed at 15-22 weeks gestation that includes measurements of beta-HCG, alpha-fetoprotein, estriol, and inhibin A in the materal serum
Left to right test order: beta-HCG, alpha-fetoprotein, estriol, and inhibin A
Trisomy 21 - increase, decrease, decrease, increase
Trisomy 18 - decrease, major decrease, major decrease, normal or decrease
Neural tube defects - normal, increase, normal, normal
Abd wall defects - normal, increase, normal, normal
Streak Gonads
gonadal dysgenesis and replaced by connective tissue (think turner’s syndrome)
Holoprosencephaly
failure of prosencephalon (anterior portion of embryonic brain) to develop into two cerebral hemispheres
Sturge-Weber syndrome
Congenital noninherited developmental anomy of neural crest derivatives
somatic mosaic mutation of GNAQ gene, gain of function mutation in one copy of gene - malformation of capillaries
Clinical Features: SKIN PORT WINE STAIN (nevus flammeus) commonly seen in CN V1 and V2 dermatomes of the face and typically unilateral, LEPTOMENINGEAL ANGIOMA (benign vascular tumor involving arachnoind and pia mater that is ipsilateral to port-wine stain), seizures/epilepsy, intellectual disability, recurrent stroke like sx, EYE EPISCLERAL ANGIOMA
SSTURGGE-weber = Sporadic, port-wine Stain, Tram-Track calcifications, Unilateral, Recurrent strokes, Glaucoma, Gnaq gene, Epilepsy
Dorsal midbrain syndrome aka Parinaud syndrome
PCA affected, often results from compression via pinealoma
Tectal plate and medial longitudinal fasiculus affected resulting in vertical gaze palsy, eyelid retraction (Collier sign), pupillary light near dissociation (pseudo-Argyll Robertson pupils) and convergence retraction nystagmus
Lateral Pontine Syndrome
Anterior inferior cerebellar artery affected
Spinal trigeminal nerve nucleus affected resulting in ipsilateral loss of facial sensation to pain and temp
Facial Nerve nuclei affected resulting in ipsilateral facial muscle weakness, decreased lacrimation and salivation, and loss of taste sensation from anterior 2/3 of tongue
Vesitbulocochlear nerve nuclei and labyrinth of inner ear affected resulting in ipsilateral vertigo, nystagmus, and hearing loss
Sympathetic fibers affected resulting in ipsilateral horner syndrome (miosis, partial ptosis, and anhidrosis)
AICA stroke
anterior inferior cerebellar artery
Facial droop means AICA has swooped
involves facial nuclei
Thiamine before glucose Why?
thiamine’s active form is thiamine pyrophosphate (TPP) which serves as a cofactor for dehydrogenases such as pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase which are both essential for ATP generation
thiamine deficiency leads to ATP depletion which damages aerobic tissues such as CNS neurons there fore giving glucose prior to thiamine can induce Wernicke encephalopathy
the excess glucose goes to pyruvate but can’t be synthesized into ATP so it goes to lactate accumulation
TPP is also essential for regeneration of the antioxidant glutathione, decreased glutathione regeneration impairs free radical neutralization causing further damage
wernicke encephalopathy
acute neuro syndrome cause by THIAMINE deficiency
triad of confusion, ophthalmoplegia (eye paralysis), and ataxia
suspect in pt with heavy alcohol use
acute and reversible
Labs: decreases thiamine and erythrocyte transketolase activity (thiamine dependent)
Korsakoff syndrome
late development in pts with persistent vitamin B1 (thiamine) deficiency
petechial lesions and small vessel hemorrhage in the mesencephalon/mamillary bodies/ventricle walls/ and dorsomedial nucleus of thalamus
Sx: Confabulation (produce fabricated memories to fill in lapses of memory), anterograde and retrograde amnesia, personality changes, disorientation to time/place/person
Cobalamin
Vitamin B12
cofactor in enzymatic reactions responsible for rbc formation and myelination of nervous system
deficiency leads to chronic neuro sx including gait abnormalities, macrocytic anemia, mild icterus, glossitis, symmetric peripheral neuropathy, subacute comined degeneration of spinal cord, neuropsychiatric disease
Reye Syndrome
rare type hepatic encephalopathy associated with aspirin use for viral illness in children < 19y/o
accumulation of salicylate metabolites in the liver, mitochondrial injury and reversible inhibition of enzymes required for fatty acid oxidation
hyperammonemia, cerebral edema, increased ICP
Clinical Features: acute encephalopathy, severe vomiting, altered mental status, coma, liver failure, hepatomegaly
Diagnostics: increased AST and ALT, hyperammonemia, hypoglycemia
LIVER BIOPSY: MICROVESICULAR HEPATIC STEATOSIS
Disulfiram
medication used to deter pt from drinking alcohol by precipitating a disulfiram-alcohol reaction (headache, nausea, vomiting)
Osmotic demyelination syndrome
damage to myelin sheath of nerves in the CNS caused by sudden rise in osmolarity of blood
commonly caused by rapid correction of chronic hyponatremia
sx appear 2-6 days after correction
sx: altered level of consciousness, coma, locked-in syndrome, dysarthria, dysphagia, diplopia, and/or worsening quadriparesis
Clindamycin
primarily used to tx anaerobes (Clostridium perfringens, Bacteroides spp.)
moa: binds 50s subunit to block peptide translocation
can cause pseudomembranous colitis (commonly caused by Clostridiodies difficile)
Antipsychotics (1st gen)
antipsychotic
Block D2 receptor, increasing cAMP
high potency (Haloperidol, fluphenazine, perphenazine, trifluoperazine, pimozide)
side effects include extrapyramidal symptoms (bradykinesia, rigidity, dystonia, atheosis, chorea, ballismus, akathisia, tics, tremors)
Low potency (Chlorpromazine, Thioridazine) also have anticholinergic and antihistaminergic properties use for less chance of extrapyramidal sx)
Antipsychotics 2nd gen
Clozapine, Olanzapine, Risperidone, Quetiapine, Amisulpride, Ziprasidone, Aripiprazole, Lurasidone, Asenapine, Iloperidone, Paliperidone
D2 receptor antagonism, 5-HT2A receptor antagonism, interaction with several other D3/D4/alpha adrenergic receptors,
**Aripiprazole is partial D2 agonist
Ziprasidone - associated with prolonged QT syndrome
**Olanzapine - associated with weight gain, sedation, dry mouth, constipation, tremors, muscle stiffness, metabolic changes
*Clozapine - neutropenia
Neruoleptic Malignant Syndrome
Caused by antipsychotics
underlying mechanism is not well understood, central D2 receptor blockade in nigrostriatal pathway
Presentation:
Mental status change, encephalopathy, delirium, confusion, stupor
Parkinsonism
Hyperthermia
Autonomic instability, tachycardia, dysrhythmias, labile blood pressure, tachypnea, diaphoresis
FALTER - fever, autonomic instability, leukocytosis, tremor, elevated enzymes, rigidity
Acid Maltase
enzyme that converts glycogen to glucose in the lysosome
Pompe disease
Type II glycogen storage disease
Lysosomal acid maltase (alpha-1,4-glucosidase) deficiency
enzyme normall used for glycogenolysis, hydrolyzes alpha-1,4- and alpha 1,6- linkages in the acidic environment of lysosome
Clinical features:
Cardiac - hypertrophic cardiomyopathy, conduction blocks, cardiomegaly
MACROGLOSSIA
Failure to thrive
proximal myopathy and hypotonia leads to resp insufficiency and early death
intercranial aneurysms
Myophosphorylase
enzyme that catalyzes the release of glucose-1-phosphate from glycogen
rate limiting step in glycogenolysis
McArdle Disease
Type V glycogen storage disease
Myophosphorylase deficiency
skeletal muscle glycogen phosphorylase
used in glycogenolysis
Clinical Features:
Generalized muscle weakness, exercise intolerance (with 2nd wind phenomenon: sx of muscle fatigue disappear after a period of activity because of increased blood flow)
Demanding physical exercise may cause rhabdomyolysis and myoglobinuria
Electrolyte imbalances can trigger cardiac arrhythmias
Normal serum glucose levels
Flat venous lactate curve with exaggerated elevations in blood ammonia during exercise
glycogen accumulates in muscles but can’t be metabolized
Iduronate Sulfatase
lysosomal enzyme responsible for the degradation of glycoaminoglycans such as dermatan sulfate and heparan sulfate
deficiency is hunter syndrome
Hunter syndrome vs Hurler Syndrome
Hunter: x linked recessive, deficiency of iduronate-2-sulfatase results in accumulation of glycoaminoglycans
Hurler: autosomal recessive, deficiency of alpha-L-iduronidase results in accumulation of glycoaminoglycans
Both clinical features: (typically milder in hunter syndrome) developmental delay, facial dysmorphism, frontal bossing, elongated skull, flattened nasal bridge, broad nasal tip, thickened gingiva, anteverted nostrils, constant nasal discharge, spaced and protruding eyes, airway obstruction, hepatosplenomegaly
Hunter clinical features: AGGRESSIVE BEHAVIOR, hyperactivity, NO CORNEAL CLOUDING
Hurler clinical features: CORNEAL CLOUDING, hypertrichiosis
Diagnostics: increased urinary levels of dermatan sulfate and heparan sulfate, enzyme assay to confirm specific enzyme deficiency
alpha-L-iduronidase
lysosomal enzyme responsible for hydrolysis of glycoaminoglycans
deficiency is hurler syndrome
Glucose-6-Phosphatase
enzyme responsible for catalyzing the final step of glycogenolysis and gluconeogenesis, the conversion of glucose-6-phosphate to glucose
von Gierke disease
Type Ia - Glucose-6-phosphatase deficiency
Type Ib - Glucose-6-phosphatse translocase deficiency (normally trasnports G6P into ER where it’s hydrolyzed by G6-phosphotase
Clinical features: renomegaly and hepatomegaly, SEVERE FASTING HYPOGLYCEMIA, mild ketosis, SEVERE HYPERLIPIDEMIA (especially triglycerides) leads to doll-like facies, HYPERURICEMIA, lactic acidosis, anemia, failure to thrive, dysfunctional glycogenolysis and gluconeogenesis
Beta-Glucocerebrosidase
lysosomal enzyme responsible for degradation of sphingolipid glucocerebroside during glycolipid metabolism
deficiency = gaucher disease
gene deficiency = increased risk of Parkinson disease
Gaucher disease
AR
most common lsosomal lipid storage disease
INCREASED INCIDENCE OF TYPE 1 WITH ASHKENAZI JEWISH POPULATION
deficiency of Beta-glucocerebrosidase which results in accumulation of glucocerebroside
Type 1: non-neuropathic
All Types: Hepatosplenomegaly, bones crises, osteoporosis ,avascular necrosis of the femur, anemia, thrombocytopenia, pancytopenia, pulmonary manifestations, growth delays
Type 3: neurodegeneration
Diagnostics: lipid rich macrophages with an enlarged cytoplasm with inclusions that resemble crumpled tissue on paper on microscopy
tx: recombinant glucocerebrosidase
Tay-Sachs
AR
COMMON IN ASHKENAZI JEWISH POPULATION
hexosaminidase A deficiency leads to accumulation of GM2 ganglioside to progressive neurodegeneration
Clinical features: RAPID REDUCTION OF physical and mental abiliteies begins around the age of 3-6 months
Developmental delay, MACULA SHOWING A “CHERRY RED” SPOT, hypotonia, seizures, hyperreflexia, hyperacusis, NO HEPATOMEGALY
diagnostics: lysosomes with onion-skin appearance
Alpha-galactosidase
responsible for breakdown of alpha-galactosides in lysosome
deficiency is Fabry disease
Fabry disease
X linked recessive
mainly affects boys
deficiency in alpha-galactosidase results in accumulation of ceramide trihexoside (aka globotriaosylceramide)
Clinical features:
Early triad - DYSTHESIA (caused by small fiber neuropathy), HYPOHIDROSIS, ANGIOKERATOMAS
Other early - corneal clouding, cataract Late sx: cardiomyopathy, CEREBROVASCULAR LESIONS, NEPHROPATHY
athetosis
slow writhing worm like movements
hypertrichiosis
excessive hair growth
hyperacusis
reduced tolerance to sound
Niemann-Pick disease
AR
COMMON IN ASHKENAZI JEWS
deficiency of sphingomyelinase results in excess sphingomyelin
Clinical features: progressive neruodegeneration, Cherry red spot in macula, hepatosplenomegaly
diagnostics: lipid lagen macrophages (foam cells), Zebra bodies (abnormal configuration of myelinoid membranes into parallel palisading lamellae in the lysosomal cytoplasm
hypohidrosis
inadequate sweating
dysthesia
abnormal physical touch sensation
angiokeratomas
hard bumps on skin
Telotristat
inhibits tryptophan hydroxylase which is the rate limiting enzyme of serotonin synthesis
used to reduce peripheral serotonin production in patients with carcinoid syndrome to treat diarrhea
Octreotide
it can mimic somatostatin
inhibits Adenyl Cyclase, inhibition of voltage gated calcium channels, stimulation of voltage dependent potassium channels
injection that is used to treat high levels of growth hormone in acromegaly
carcinoid syndrome
carcinoid tumors are neuroendocrine tumors that arise from mine precursor uptake and decarboxylation cells (APUD cells)
Tumor locations
55% GI tract are Carcinoid tumors
15% Pancreas as Insulinoma or Glucagonoma
10% in bronchopulmonary system as Carcinoid lung tumor or SCC
Thyroid medullary carcinoma
Adrenal Glands Pheochromocytoma
Clinical Features:
Carcinoid syndrome - diarrhea, cutaneous flushing, dyspnea, wheezing, palpitations
Carcinoid heart disease - Endocardial fibrosis (especially right heart), tricuspid insufficiency and/or pulmonary stenosis, sx of Right sided heart failure
Abd Pain
***in lung - cough, dyspnea, hemoptysis, recurrent pneumonia
Diagnostics: increased 5-hydroxyindoleacetic acid (5-HIAA) in 24 hour urine
Biopsy: prominent rosettes composed of numerous small monomorphic cells with salt-and-pepper chromatin
Dopamine Beta-hydroxylase
enzyme of catecholamine synthesis (dopamine to norepinephrine)
inhibitors of this enzyme are used for pheochromocytoma
Vasoactive intestinal peptide
polypeptide hormone primarily produced by duodenum, pancreas, and parasympathetic neurons in sphincters
relaxes sphincters and increases the secretion of water and electrolytes
Plasma kallikrein
part of kinin cascade which releases Bradykinin from high molecular weight kininogen
Bradykinin in excess can cause dyspnea, abd pain, diarrhea
Tryptophan hydroxylase
enzyme that converts tryptophan to serotonin
excess serotonin can be seen in carcinoid tumors
inhibited by Telotristat
Histidine decarboxylase
converts histidine to histamine
histamine can cause anaphylactic symptoms (dyspnea, wheezing, curateous flushing, abd cramps, diarrhea
Pheochromocytoma
tumor arised from chromaffin cells
90% adrenal medulla locatization (physiologically activated by acetylcholine)
25% are hereditary germline mutations (MEN2a, MEN2b, NF1, VHL)
CLinical features: episodic HTN, paroxysmal throbbing headache/diaphoresis/heart palpitations/tachycardia/pallor, signs of polycythemia if EPO is secreted
5P’s - Pheochromocytoma: increased blood Pressure, head Pain (headache), Perspiration, Palpitations, and Pallor
Diagnostics: plasma free metanephrines or urinary fractionated metanephrines (24 hour collection), fractionated catecholamines, Homovanillic acid and vaillylmandelic acid
Chromaffin cells
derived from the neural crest
found in adrenal medulla and other ganglia of SNS
release epinephrine and norepinephrine
VIPomas
neuroendocrine tumor that secretes VIP
Excess VIP leads to relaxation of gastric and intestinal smooth muscles and cAMP activity (similar to cholera toxin) which leads to secretory diarrhea and inhibition of gastric acid production
Tumor normally found in pancreas
Clinical Features: WHDA syndrome (watery diarrhea, hypokalemia, achlorhydria), tea colored watery diarrhea (>700 mL/day) leading to dehydration
Diagnostics: increased serum VIP concentration, hypokalemia, hypercalcemia, hyperglycemia, gastric achlorhydria or hypochlorhydria
TX: tumor resection or Octreotide
Topoisomerase II (DNA gyrase)
responsible for cleaving DNA to relieve supercoils after DNA is seperated by DNA helicase
inhibited by chemotherapeutic drugs like etoposide and teniposide
Irinotecan and topotecan inhibit cellular replication by reversibly binding to DNA topoisomerase I
DNA polymerase III
adding nucleotides 3 prime hydoxyl group of the leading strand
dicontinuous synthesis of the Okazaki fragments of the lagging strand using the RNA primers creating by primase
DNA ligase
joins the completed short DNA fragments (Okazaki fragments) of the lagging strand during DNA replication (after removal of the RNA primers
DNA polymerase I
remove RNA primers from lagging strand and fills the gap left behind
DNA helicase
unwinding of duplex DNA at origin of replication
replication protein A in eukaryotic cells
binding to single stranded DNA to prevent reannealing
Arylsulfatase A
lysosomal enzyme responsible for the degradation of sphingolipid (cerebroside sulfate)
deficiency = metachromatic leukodystrophy
metachromatic leukodystrophy
AR
lysosomal storage disease which arylsulfatase A deficiency leads to buildup of sphingolipid (cerebroside sulfate) causing central and peripheral demyelination
Clinical Features: hypotonia, developemental delay or regression, ataxia, seizures, choledocholithiasis (obstruction in common bile duct), optic nerve atrophy
no cure and death usually occurs 5 to 20 years after diagnosis
Galactocerebrosidase
lysosomal enzyme responsible for degradation of galactocerebroside
leads to accumulation of toxic myelin degradation products (psychosine)
Krabbe disease
AR
deficiency of Galactocerebrosidase leading to accumulation of toxic myelin breakdown products
Clinical features: developmental delay, peripheral neuropathy, visual impairment, hypertonia
pt usually die around age of 2 years
Insulin effects (glycolysis, glycogenesis, lipolysis, gluconeogenesis)
stimulates glucose uptake by increasing expression of GLUT4 on SKELETAL MUSCLE AND ADIPOSE TISSUE as well as increasing glucokinase activity in the liver
CORTICAL NEURONS AND ERYTHROCYTES UTILIZE GLUT1 AND WORK INDEPENDENT OF INSULIN
HEPATOCYTES AND PANCREATIC BETA CELLS UTILIZE GLUT2 AND WORK INDEPENDENT OF INSULIN
decreases protein kinase A activity which raises fructose-2,6-bisphosphate concentration which promotes glycolysis by increasing activity of phosphofructokinase-1
inhibits gluconeogenesis by reducing activity of fructose-1,6-bisphosphatase
promotes glycogenesis by activating glycogen synthase
inhibits lipolysis in adipose tissue by blocking expression of adipocyte triglyceride lipase
promotes lipogenesis by stimulating the activity of acetyl CoA carboxylase, HMG CoA reductase and endothelial lipoprotein lipase
incease glycolysis, increase glycogenesis, decrease lipolysis and decrease gluconeogenesis
methymalonyl-Coa mutase
requires b12 (cobalamin) as cofactor in metabolism of odd chain fatty acids
deficiency in b12 results in accumulation of methylmalonyl-CoA and its precursor propionyl-CoA
Succinate dehydrogenase
mitochondrial enzyme that participates in the TCA cycle and uses Vitamin B2 (RIBOFLAVIN) as cofactor
1-alpha hydroxylase
key enzyme necessary for the production of the active form of Vit D
deficiency could result in Rickets
Pyruvate carboxylase
participates in amino acid/carbohydrate/and lipid metabolism and uses Vitamin B7 (biotin) as a cofactor
Propionyl-CoA carboxylase
involved in conversion of propionyl-CoA to methylmalonyl-CoA and uses biotin as cofactor
deficiency of Biotin would impair said enzyme resulting in accumulation of propionyl-CoA causing demyelination within the spinal cord
Dopamine beta-hydroxylase
converts dopamine to norepinephrine and uses vitamin C as a cofactor (ascorbic acid)
deficiency results in scurvy
Vitamin D deficiency lab findings for calcium/phosphorus/PTH/calcitriol
decrease calcium, phosphorus, and calcitriol
increased PTH
reduces intestinal calcium reabsorption and low Ca increases PTH secretion
PTH decreases phosphate reabsoption in PCT
calcitriol
active form of Vitamin D
Vitamin B3 name and cofactor status
Niacin
precursor to NAD+ and NADP+
deficiency can cause pellagra and glossitis
pellagra
niacin deficiency
glossitis and “the 3 D’s” (diarrhea, dermatitis, dementia, with possible Death)
Vitamin B1 name and cofactor status
Thiamine
cofactor for several enzymes of carbohydrate and amino acid metabolism
can cause wenicke-korsakoff syndrome and beriberi
Vitamin B7 name and cofactor status
Biotin
cofactor for various carboxylation enzymes including acetyl-CoA carboxylase, methylcrotonyl CoA carboxylase and propionyl-CoA carboxylase
deficiency can cause dermatitis, enteritis, and alopecia
Vitamin C name and cofactor status
Ascorbic Acid
cofactor in hydroxylation and redox reactions
coenzyme to LYSYL TO PROLYL HYDROXYLASE which is essential for collagen synthesis
Vitamin B2 name and cofactor status
Riboflavin
precursor to flavin mononucleotide and flavin adenine dinucleotide
deficiency can cause cheilosis and conjunctivitis with corneal vascularization, glossitis, lip lesions
Vitamin B6 name and cofactor status
Pyridoxine (pyridoxal phosphate is active form)
important COFACTOR in the TRANSAMINATION reactions performed by AST and ALT
required for glycogen phosphorylase reactions, decarboxylation, and synthesis of cystathionine/heme/niacin/and histamine
Vitamin B9 name and cofactor status
folic acid or tetrahydrofolate(active form)
cofator for methylation reactions including nucleic acid synthesis
deficiency can result in megaloblastic anemia and materal deficiency can mean neural tube defects for child
Cheilosis
swelling and fissuring of lips
Bcl-2 function and what if overexpression?
antiapoptotic protein that inhibits the intrinsic pathway of apoptosis by maintaining the impermeability of the mitochondrial membrane
overexpression (seen in follicular lymphoma) impairs apoptosis and leads to tumor growth
BAX (Bcl-2-associated X protein) and BAD initiation
proapoptotic proteins
initiation results release of mitochondrial cytochrome C
Cytochrome C leads to activatin of caspases which cause destruction of the cytoskeleton, enter the nucleus, and cause DNA laddering and nuclear fragmentation
Apoptosis (visualization)
dense eosinophilic cytoplasm, nuclear shrinkage, and plasma membrane blebbing
Necrosis
denaturation of cytoplasmic proteins
biopsy show cellular swelling, cell membrane rupture, inflammation
Fas/FasL
complex of a death receptor and its ligand (FasL)
triggers extrinsic death receptor pathway of apoptosis by directly activating caspases
inhibition of Fas/FasL interaction would decrease apoptosis
Coagulative Necrosis
tissue ischemia in solid organs (heart, liver, spleen, kidneys)
acidosis from lack of aerobic oxygen, increase lactic acid and then denaturing proteins
temporary preserved cellular architecture either without cell nuclei or with nuclei that are still undergoing karyolysis
red infarct vs pale infarct
red typically occurs due to venous occlusion in tissue with multiple blood supplies (intestine, liver, lung)
pale in solid organs with singular blood supply (kidney, spleen, heart)
nonenyzymatic fat necrosis
fatty tissue (breast, subcutaneous tissue) following blunt trauma or surgery
histology: lipid laden macrophages with foreign body giant cells as well as fibrosis and dystrophic calcifications
Gangrenous necrosis
most common in pt with chronic limb ischemia (dry gangrene) or GI tract ischemia (wet gangrene)
HIstology: preservation of cellular architecture along with the absence of nuclei
Liquefactive necrosis
lysosomal enzymes are released in order to degrade and liquefy necrotic material
classically seen in cerebral infarctions but can also occur in bacterial abscesses
histology: liquified tissue with multiple macrophages and cyst formation
Fibrinoid necrosis
commonly seen in blood vessels in pt with vasculitides or malignant hypertension
immune complex and/or fibrin deposition in the blood vesel wall
histology: protein rich, eosinophilic acellular material in damaged vessels
Caseous Necrosis
granulomatous infection such as nocardiosis, tuberculosis (including renal tuberculosis), and histoplasmosis
Histology: acellular material that appears granular and is surrounded by macrophages, T-cells, and giant cells
Acute Methemoglobinemia
decreased %Oxygen saturation, normal Oxygen partial pressure, decreased oxygen content, and normal Hb concentration
abundance of methemoglobin (altered form of hemoglobin in which ferrous iron Fe2+ is oxidized to the ferric form Fe3+
since ferric form cannot bind oxygen the O2 saturation and O2 content decrease leading to functional anemia
pt show clinical signs of cyanosis
Pts with G6PD deficiency are prone along with medications (benzocaine, lidocaine, inhaled nitric oxide, nitroglycerin, dapson, sulfonamides)
Clinical features: least to most methemoglobin levels cyanosis, mild confusion, headaches, dyspnea, tachycardia, CNS depression, seizures, chest pain, arrhythmias, death
HMWK (high molecular weight kininogen
precursor of vasodilator bradykinin
Lactoferrin
glycoprotein component in innate immune system
binds free iron with high affinity limiting the amount of ions available for microbial metabolism
store in neutrophil granules and is released as an acute phase reactant
nitric oxide
gaseous free radical in some cells as a signaling molecule (produced by NO synthase)
once activated neutrophils secrete NO to kill pathogens with the free radical
Chemotactic agents
leukotriene B4, IL-8, kallikrein, C5a, platelet-activating factor
Thromboxane A2
arachidonic acid derivative produced by activated platelets
potent vasoconstrictor
Neutrophil with wound healing
early inflammatory stage (days 1-3)
help digest bacteria, foreign debris, and necrotic tissue by secreting lysosomal enzymes
Macrophages in wound healing
mainly derived from recruited monocytes
in inflammatory and proliferative stages (days 1-3, and 3-7)
assist in host defense, removal of apoptotic cells, and promotion of cellular proliferation and angiogenesis by secreting cytokines such as VEGF
Fibroblasts in wound healing
derived from local mesenchymal stem cells or migrate from nearby dermis in response to cytokines and growth factors (TGF-Beta)
produce collagen and other extracellular matrix components
Endothelial cells in wound healing
secretes VEGF to promote angiogenesis during proliferative phase
Angiogenesis involves vasodilation, basement membrane degradation, endothelial cell migration and proliferation, capillary tube formation and anastomosis then basement membrane formation
myofibroblasts in wound healing
derived from fibroblasts
generate a contractile force that draws wound edges together
present in proliferative stage (days 3-7) and are lost through apoptosis when wound healing is complete
excessive proliferation and persistence of myofibroblasts lead to patholgic fibrosis and contracture *skin is tense with thick epithelialezd scar and ROM is restricted
Edema from acute inflammatory reaction
mast cell degranulation and increased histamine
separation of endothelial junctions resulting in increased vascular permeability and paracellular movement of fluid
Langhans giant cells
multinucleated giant cell formed from fusion of epithelioid macrophages
associated with granulomatous diseases such as tb and sarcoidosis
Aldesleukin
IL-2 analog
IL-2 is cytokine released by all T-cell subtypes and triggers destruction of tumor vells via activation of cell types that recognize MHC I receptors
IL-6
induction of fever and stimulation of acute phase reactants (also IL-1beta, TNF-alpha, and IFN-gamma)
IL-10
inhibition of both MHC II expression and cytokine release from Th1 cells
anti-inflammatory along with TGF-beta
IL-2
stimulates the activation of NK cells and cytotoxic T cells
IL-3
supprots the growth of bone marrow stem cells
similar to GM-CSF
TNM classification system
tumor oncology staging
T - size or direct extent of primary tumor
N - involvement of regional lymph nodes
M - presence of distant metastasis
SPread determines stage and Stage detemines survival more than grade
N and M are typically most important prognostic factors for survival
Grading
G1 well differentiated (low grade)
G2 moderately differentiated
G3 poorly differentiated (high grade)
G4 undifferentiated/anaplastic (high grade)
Gx differentitation cannot be assessed
BRCA1 and BRCA2
Tumor supressor genes that code for DNA repair protein
associated with increased risk of breast cancer and ovarian cancer with lesser extent to colon,pancreas,stomach, and prostate cancer
BReast CAncer
mutation to BRCA+ would result in accumulation of double stranded DNA breaks
p53
tumor supressor gene - regulates cell apoptosis and cell cycle arrest at the G1 phase (by activating p21) and inhibits entry in the S phase of cell cycle
mutations lead to unrestrained division of cells
underlying defect in Li-Fraumeni syndrome
also associated with osteosarcomas, breast cancer, brain tumors, and adrenocortical carcinomas
Li-Fraumeni syndrome
AD
mutation to p53 tumor supressor gene
one abormal copy of TP53 gene is inherited and 2nd allele is somatically mutated or deleted resulting in unregulated cell proliferation and Cancer
BLAST53 - Breast cancer/Brain tumors, Leukemia/Lymphoma, Adrenocortical carcinoma, Sarcome, and Tp53
Nucleotide excision repair
mechanism of single stranded DNA repair in which endonucleases excise DNA containing damaged bases (pyrimidine dimers)
defective in pts with Xeroderma pigmentosum (cells can’t fix dimers after UV light exposure) pt has dry skin/photosensitivity/early skin cancers
MLH1
DNA mismatch repair gene
associated with hereditary nonpolyposis colorectal cancer (lynch syndrome or HNPCC) pts also have increased risk for colorectal, endometrial, gastric, urothelial, and ovarian cancers
Base Excision repair
replaces deaminated (no amino group) DNA bases throughout the cell cycle
defects associated with some familial colorectal cancer
RET
proto oncogene
mutations associated with MEN2A and MEN2B syndromes and medullary thyroid carcinoma
KRAS
proto oncogene encodes GTPase that regulates cellular growth
mutations associated with colon cancer, non-small cell lung cancers, pancreatic cancers
PTEN gene
tumor suprressor gene that negatively regulates the PI3k/AKT pathway
mutations associated with prostate cancer and Cowden syndrome
Rb
retinoblastoma protein which deactivates E2F transcription factors thereby preventing G1 phase to S phase transition
mutations associated with retinoblastoma and osteosarcoma
Brain metastases
most common from lung cancer, 2nd from breast, followed by melanoma and cancers of kidney and colon
approximately 50% of brain tumors are from metastatic disease
PSA
Prostate specific antigen
Bence Jones proteins
polypeptide consisting of one or two immunoglobulin light chains
detection in urine is suggestive of plasma cell disorders such as multiple myeloma or waldenstrom’s macroglobulinemia
Multiple Myeloma
IgA and IgG is typical multiple myeloma
Bence Jones myeloma (free ligh chains in urine) are 15-20% of multiple myelomas
neoplastic proliferation of plasma cells
bone marrow infiltration by malignant plasma cells leads to suppression of hematopoiesis to leukopenia to thrombocytopenia to anemia
Cell proliferation leads to pro-osteoclastogenic factors to osteolytic lesions to hypercalcemia
hyperviscosity syndrome
Clinical features: bone pain (primarily back pain), hypercalcemia, foamy urine
Carcinoembryonic antigen (CEA)
nonspecific tumor marker
especially associated with pancreatic or colon cancer
can metastasize to bone and present with osteoblastic metastases
Malignant melanoma
tumor highly malignant from melanocytes
risk factors are extensive sun exposure and family history
Genetic mutations include BRAF gene mutations or CDKN2s gene mutations
ABCDE criteria
Lentigo Maligna
peak incidence between 65-80 years old
sun exposed areas
Darkly pigmented macule, irrgular borders, varying size, gradual growth, color irrugularities, surrounding island like speckling
premalignant lesion, up to 50% untreated may transform into lentigo maligna melanoma
Desmopressin and Vasopressin
Desmopressin is synthetic vasopressin
Anti-diuretic hormone
V2 receptor is Gs protein-coupled receptor which leads to activation of adenylate cyclase
helps to reduce frequent urination and excessive thirst
used to tx bet wetting
Dose vs effect graph
efficacy = maximum effect
potentcy = how much of agonist drug is used to attain effect
shift to the right = decrease in potency
shift down = decrease in efficacy
non-competitive antagonist can not be overcome by increasing dose of agonist therefore decreases efficacy of agonist (down shift)
Inverse Agonist binds to same receptor but has a different binding site and typically elicits the opposite of the agonistic effect which lowers the agonist’s efficacy and can’t be overcome with more agonist
Functional antagonist doesn’t use the same receptor as the drug it’s antagonizing, therefore even when agonist binds the effect would be negated by action of functional antagonist lowering the efficacy
Full agonist has same potency and efficacy as original drug so curve is unchanged
Atropine
anticholinergic agent
antidote for acetylcholinesterase poisoning
Effect: increased heart rate, decrease secretions of exocrine glands, decrease tone and motility of smooth muscles, MYDRIASIS AND CYCLOPLEGIA
Scopolamine
anticholinergic agent
nonspecific muscarinic antagonist
used for motion sickness
area of effect: area postrema
Ipratropium bromide and Tiotropium bromide
Muscarinic antagonists
causes smooth muscle relaxation in lungs
adverse effects of antimuscarinics
Blind as a bat (mydriasis), Mad as a hatter (delirium), red as a beet (flushing), hot as a hare (hyperthermia), dry as a bone (decreased secretions and dry skin), the bowel and bladder lose their tone (urinary retention and paralytic ileus), and the heart runs alone (tachycardia)
Michaelis-Menton curve
shows the relationship between the concentration of a substrate and the rate of the corresponding enzyme
Vmax is maximum rate at which enzyme can catalyze a reaction
can be increased with more enzyme
Km is michaelis constant which is the substrate concentration at which half of the active sites of an enzyme are bound by substrate
Enterococcus faecium
gram + dipplococci
GI tract
growth in bile and NaCl 6.5%
may be triggered by GI/GU procedures
UTI
Actinomyces israelii
gram + with branching filaments(form yellow sulfur granules), anaerobic, non acid fast
oral cavity reservoir
oral caries and peridontitis (oral and facial abscess)
Penicillin G high dose
Serratia marcescens
gram - enterobacteriaceae, catalase positive
reservoir is water and starchy foods (bread)
multidrug resistance
nosocomial infections, wound infection, ocular infections
Streptococcus pneumoniae
gram + encapsulated lancet shaped diplococci OPTOCHIN SENSITIVE
ALPHA HEMOLYSIS
capsular polysaccharide
IgA1 protease
PNA with RUSTY COLORED SPUTUM
Clostridiodes difficile
gram + bacilli, obligate anaerobe, spore-forming rod
facultative pathogen
Toxin A (enterotoxin), Toxin B (cytotoxin)
Psuedomembranous colitis
TX: Metronidazole, Oral Vancomycin (inhibits cell wall synthesis or Fidaxomicin (macrolide)
Streptococcus pyogenes
gram +cocci,
BETA HEMOLYSIS
M protein
bacitracin sensitive
group A strep
Hyaluronic acid capsule (to prevent phagocytosis)
impetigo, erysipelas (bad skin lesion), acute rheumatic fever, PSGN,
Penicillin
M protein virulence factor
Streptococcal M protein
Streptococcus pyogenes
Beta-glucan cell wall virulence factor
important component of fungal cell walls
Lipopolysaccharide virulence factor
integrated into the outer bacterial membrane of gram-negative bacteria
Type III secretion system virulence factor
certain gram - bacteria
Shigella, Salmonella
