-Hypersensitivity to gluten. Gliadin, a breakdown product of gluten, triggers an immune mediate reaction causing:
1) Vilous atrophy
2) Crypt hyperplasia
3) lymphocyte infiltration
Atrophy causes impairment of nutrient absorption in the duodenum and proximal jejunum, regions where concentration of gluten is the highest.
-presents 6-24 months after introduction of gluten with symptoms of malabsorption (eg, diarrhea, steatorrhea, flatulence, nutrient def and weight loss)
-delayed puberty and short stature
-IgA, anti-endomysial and anti-tissue transglutaminase Ab.
a. GI reflux is physiologic in healthy infants, Severe cases can lead to irritability, poor feeding and inadequate weight gain. Diagnosis is made clinically and treatment with conservative changes (eg, smaller feedings) and acid suppression (eg, ppi).
b. Anti-inflammatory meds (eg, glucocorticoids and aminosalicylates) are the mainstay of treatment for inflammatory bowel disease (ulercative colitis and Crohns disease). Symptoms include abdominal pain, bloody diarrhea and weight loss. Colonoscopy shows diffuse colonic inflammation in UC and focal areas of small intestine and colonic inflammation in CD.
c. Tropical sprue has similar histologic findings to celiac. No history of travel
d/e: lactase intolerance has solar symptoms however histology would show normal small intestinal architecture
Patient has stable angina (angina pectoris) d/t underlying CHD.
Aspirin irreversibly inhibits COX. Inhibiting COX1 in palettes prevent synthesis of thromboxane A2, a potent stimulator of platelet aggregation and vasoconstriction = reduce the risk of occlusive thrombus formation and subsequent MI.
Some patients are unable to tolerate aspirin d/t exacerbation of preexisting respiratory symptoms (eg, rhinos and asthma) or delveopment of allergy reactions (eg, urticaria, angioedema, anaphylaxis). A good alternative for these patients is Clopidogrel:
MOA: blocks the P2Y12 component of ADP receptors on the platelet surface and prevent platelet aggregation.
-it is as effective as aspirin for prevention of cardiovascular events and should be used in patents with aspirin allergy.
a/g. Apixaban is direct factor Xa inhibitor that prevents platelet activation and fibrin clot formation. Warfarin inhibits enzyme required for synthesis of active vitamin K, resulting in decreased synthesis of vitamin K-dependent clotting factors (II, VII, IX and X). Both of these meds are typically used for prevention and/or treatment of thromboembolic events, not CAD.
b. cilostazol is a phosphodiesterase inhibitor that occasionally used in patients with symptomatic peripheral vascular disease (i.e., claudication)
d. low molecular weight heparins (LMWHs; enoxaparin, dalteparin) are indirect thrombin inhibitors that bind with antithrombin and convert it form a slow to a rapid activator of thrombin and factor Xa. They are used in patients with acute coronary syndrome (unstable angina or MI) but have no role in the management with stable angian.
e. eptifibatide is a platelet glycoprotein IIb/IIIa inhibitor that inhibits the final common pathway of platelet aggregation. It is occasionally used in some patients with acute coronary syndrome, but not for stable CHD.
f. naproxen is an NSAID used for pain and management in patients with osteoarthritis. Use of both nonselective and selective COX2 NSAIDSs increases the risk adverse CVS event.s
This patient is given GH.
MOA: binds to cell surface receptors that stimulate the production of IGF-1, primarily located in the liver.
-Once bound to 2 receptors on the cell surface, it activates Janus Kinase (JAK), a non receptor tyrosine kinase.
-JAK phosphorylates several tyrosine residues in the intracellular domain of GH receptor
-Phosphorylation of tyrosine serves as a docking sites for STAT (single transducer and activator of transcription), where it will be phosphorylated also by JAK.
-STAT then dimerizes and translocates to the nucleus to induce IGF-1 gene transcription by binding to the promoter region.
a. steroids and thyroid hormones bind to intracellular receptors.
b. several hormones (eg, PTH, ACTH, TSH & ADH (V2)) activates cAMP/PKA.
c/d: various hormones (eg, GnRH, TRH, angiotensin II, ADH (V1)) function by binding to the DAG/IP3/PKC pathway.
The lung apices and cervical pleura extend above the clavicle and first rib through the superior thoracic aperture into the neck. Stab wound would cause tension pneumothorax.
-increasing volume of air accumulates within the pleural space, the lungs and mediastinum would deviate contralaterlly.
-Signs and symptoms of tension pneumothorax include:
-tachycardia, hypotension, tachypnea, hypoxemia, and absence of breath sounds and hyperressonance to percussion of the affected side.
Treatment: needle thoracotomy or chest tube
a. Spinal Accessory Nerve may be injured during surgrey involving the posterior triangle of the neck ( a region bounded by the SCM, traps and clavicle)
b. ansa cerivxclis arises form C1-3 nerve roots and innervates the sternohyoid, sternothyroid and omohyoid muscles of the anterior neck. Penetrating trauma too the neck love the cricoid cartilage can injure this nerve
c. carotid body, which contains O2, CO2, and H chemoreceptors, lies at the bifurcation of common carotid artery (just inferior to the hyoid bone).
d. the inferior thyroid artery arises from the thyrocervical trunk and courses posterior to the carotid artery and jugular vein to supply the inferior pole of the thyroid gland. Injury to the inferior thyroid artery is commonly associated with coarseness because it runs adjacent to the recurrent laryngeal nerve.
Cyanide toxicity is dependent upon its ability to bind to Fe+3 (ferric) with high affinity, inhibiting cytochomre c oxidase in the mitochondria. This inhibits oxidative phosphorylation causing lactic acidosis and death as a result of cells switching to anaerobic metabolism
-REDDISH SKIN DISCOLORATION
-nausea/vomiting, confusion and weakness.
Labs: lactic acidosis in conjunction with narrowing of the venous arterial PO2 gradient, resulting for the inability of tissue to extract arterial oxygen.
Treatment: inhaled amyl nitrite oxides ferrous iron present in hemoglobin to ferric iron generating methemoglobin. Methemoglobin is incapable of carrying oxygen but has high affinity for cyanide; it binds and sequesters cyanide in the blood, freeing cytochrome oxidase and limiting its toxic effects. Hydroxycobalamin, a vitamin B12 precursor, and sodium thiosulfate are also antidotes for cyanide poisoning. there interaction with cyanide generate relatively nontoxic metabolites that are easily excreted in the uric.
a/b: 2,3-BPG causes a rich shift in the oxygen-hemoglobin dissociation curve, decreasing hemoglobin affinity to O2 but increasing its affinity to CO@
c. Hemoglobin has much higher affinity for CO than it does for oxygen. This is the basis for carbon monoxide poisoning, which is treated with high for oxygen.
e. the affinity of hemoglobin for iron is not affected by nitrite administration, although nitrites do oxide the heme iron to its ferric state.
f. Lead poisoning causes defect heme synthesis. If lead is acutely ingestion, chelation therapy with dimercaprol and edentate disodium calcium (CaNaEDTA) should be initiated. 0
This kid has HUS
Etiology: E. coli O157:H57 or Shigella dysenteriae.
Path: Verotoxin induces endothelial damage = platelet activation = formation of micro thrombi = platelet consumption = thrombocytopenia. Micro thrombi also damage RBCs = hemolytic anemia
-Anemia (eg, pallor, weakness, tachycardia)
-Acute kidney injury (eg, oliguria/anuria, increased creatinine)
-Decreased hemoglobin and haptoglobin
-Increased lactate dehydrogenase and unconjugated bilirubin
-Bleeding time elevated (however PT and PTT not affected because there are clotting factor def or DIC in HUS)
e. Coombs test, or direct anti globulin test, detects autoantibodies against RBCs if they are present in the serum. Hemolytic anemia in HUS is a mechanical problem in stead of an autoimmune one
f. streptozyme detects antibodies against Progenies and can be used to retrospectively diagnose strep infections (eg, when evaluating PSGN). However, PSGN will have edema and HTN, but no hemolytic anemia.
Hansen disease affects skin and nerves
Etiology: Mycobacterium lapra. Transmission via respirator or prolonged skin to skin contact. Associated with the armadillo in the southwestern US.
It likes low temperature which makes sense why the clinical manifestations occur in the skin, balls and superficial nerves.
Path: depends on how strong Cell Mediated Immune responses are, which gives us two types of leprosy
1) tuberculoid (TL): least severe. patient has intact CMI that will launch a Th1-mediated response. Mild skin plaques will develop that are hypo pigmented. Hair follicle loss and focally decreased sensation.
2. lepromatous (LL): most severe. patient has weak CMI that will launch a Th2-mediated response. Macrophage signaling to kill M leprae is limited which will lead to: skin thickening, plaque like hypo pigmentation (often with hair loss), leonine facies, paresis, regional anesthesia, testicular destruction and blindness
a. B. burgdorferi cause Lyme diseases. Erythema chronicum migrant with fever and malaise. Systemic disease can cause arthritis, facial paresis or cardiac involvement (eg, condition abnormalities). Prolonged untreated diseases will have CNS involvement.
b. Campylobacter fetus, a gram - rod, causes mild enteritis in immunocompetent and mild systemic bacteremic illness in immunocompromised
c. C. dish is a gram + rod. Clinical manifestations are often toxin mediated that can lead to lower respiratory tract infection. Complication can cause polyneuritis and myocarditis.
e. T. palladium causes syphilis.
-Primary: painlesss chancre
-Secondary: diffuse erythamtous macule over the entire body including palms and soles and condyloma late formation
-Tertiary: syphilis results in skin and bone gammas and ascending aortitits
Hepatic processing of bilirubin
1. carrier mediated uptake of bilirubin at the sinusoidal membrane
2. conjugation via UGT (urdine diphosphate-clucuronyltransferase) in ER
3. Biliary excretion of water-soluble, nontoxic bilirubin glucuronides.
Disruptions of these processes can lead to Crigler-Najjar syndrome.
-Type 1: AR. Lack of UGT enzyme. Unconjugated hyperbilirubinemia will develop.
Conjugated bilirubin is water soluble and loosely bound to albumin = easy excretion
Unconjugated bilirubin are less soluble and binds tightly to albumin = not excreted, that will graduallydeposited into various tissues, including the brain. Kernicterus (bilirubin encephalopathy), can be fatal.
b. Dubin-Johnson is AR. Absence of biliary transport protein, MRP2 (multi drug resistance protein 2), used in the hepatocellular excretion of bilirubin glucuronides into bile canaliculi. Liver is darkly pigmented, however disease is asymptomatic
c. rotor syndrome is rare AR d/t asymptomatic conjugated hyperbilirubinemia that results from numerous defects in the hepatic uptake and excretion of bilirubin pigments. Although patients are often jaundiced, they enjoy normal life expectancies.
d. High amount of anaerobes and S. aureus can deconjugate bile acids (via removal of glycine and taurine), rendering them less soluble and therefore less able to form micelles. This beconjugation impedes the active reabsorption of bile acids into portal circulation at the terminal ileum, resulting in lipid malabsorption. However, there are no neurologic abnormalities associated with bilirubin beconjugation in the gut
e. in the colon, bacterial enzymes reduce bilirubin into urobilinogens, where a small fraction returns to the liver where they will later either re-enter GIT or excreted via urine. Urobilinogens that remain in the colon are excreted in the feces as stercobilin, contributing to its dark color. Fortunately, there are no neurologic abnormalities associated with impaired gut reabsorption of bilirubin.
PAH is filtered from the blood in the glomerulus and screwed by the PCT. Because it is both filtered and secreted, it can be use to estimate RPF.
Filtration cannot be saturated, however excretion mediated career enzyme mediated process that can be saturated. Therefore, as blood concentrate not PAH increases, the secretion of PAH by PCT increases, but only up to a maximum value of approximately 80 mg/min. Pass this point, secretion plateaus and any increases in the uric PAH concentration are d/t increased filtration.
a. excretion of a substance is defined as = filtration + secretion - reabsorption. Once carrier mediated secretion and reabsorption mechanisms are saturated, these processes are at their maximal rater. However, filtration is not enzyme or protein mediated, so it doesn't show maximal value. Because filtration cannot be saturated neither can excretion.
b. the maximal reabsorption rate doesn't apply to PAH, which is a secreted substance. Glucose is example of substance that is aggressively reabsorbed in the proximal tubule. Under normal conditions, no glucose is lost in the urine, despite the fact that glucose filtered into Bowman's space. In uncontrolled diabetes, however, glucose is seen in the urine because the reabsorption carrier proteins become saturated at very high glucose concentration
d. filtration fraction is decreased by decrease in GFR or increase in RPH
e. RPF is decreased by factors that constrict blood vessels in the kidney such as epinephrine, NE and angiotensin II
Methionine can be metabolized into S-adenosyl-methionine (SAM), which acts as a methyl donor for many methyltransferase reactions.
After transfer of methyl group, SAM is converted into S-adenosyl-homocysteine (SAH), which is broken down to form adenosine and homocysteine.
Homocysteine can be converted to cystathionine (via cystathionine synthase and B6). Cystathionine can then be converted into cysteine (via cystathionase and B6).
Homocysteine can be converted back into methionine (via methionine synthase and B12).
Homocystinuria is a condition that can lead to hyper coagulability and thromboembolic occlusion b/c homocysteine is prothrombotic. People with deficiency of methionine synthase can develop premature acute coronary syndrome, ectopic lentil (ocular lens displacement) and intellectual disability.
-this is the most common cause of homocystinuria, thus cysteine is an essential amino acid to them.
a. asparagine synthase converts aspartate to asparagine, the amino acid that is essential for rapidly dividing tumor cells that cannot produce it quickly enough on their own. The chemotherapy drug asparginase decreases asparagine contraption in tumor cells and leads to lysis of these rapidly growing cells.
c,d,f. maple syrup urine (def of alpha-ketoacid DH). Def can lead to buildup of branched chain amino acids (valine, leucine and isoleucine) and their metabolites, resulting in feeding difficulties, seizures, cerebral edema and sweet odor urine
e. phenylalanine hydroxylase catalyzes the hydroxylation of essential acid phenylalanine into tyrosine. Def of phenylalanine hydroxylase is the most common cause of phenylketonuria, which results in severe intellectual disability if left untreated.
The radial nerve enters the forearm anterior to the lateral epicondyle (near the humeroradial articulation) and divides into the:
1. superficial which provides purely somatic sensory innervation to the radial half of the dorsal hand.
2. deep branch that innervates the extensor compartment muscles in the forearm. After passing through the supinator canal (eg, between the superficial and deep parts of the supinator muscle), the deep branch continues to become the posterior interosseous nerve, which innervates muscle involves extension of the finger and thumb.
Injury to the radial nerve during its passage through the supinator canal may occur d/t repetitive pronation/supination of the forearm (eg, frequent screwdriver use), direct trauma or dislocation of the radius.
-weakness on finger and thumb extension ("finger drop"_
-tricpes brachia (elbow extension) and extensor carpi radials longs (wrist extension) are typically preserved as the radial nerve branches supplying these muscles come off proximal to the supinator canal.
-Cutaneous sensory branches are similarly preserved.
A/E: Injury to the radial nerve at the axilla (eg, "crutch palsy") typically causes weakness of the forearm, ahdn and finger extensor muscles (eg, wrist drop, absent trips reflex) with sensory loss over the posterior arm, forearm and dorsolateral hand. Injury to the nerve at the mid shaft humerus (eg, radial groove) usually causes weakness of the hand/finger extensor muscles with sparing the triceps brachia and sesonry loss over the posterior forarm/dorsolateral hand.
b. carpal tunnel syndrome can result form any condition that reduces the size of the carpal tunnel and compresses the median nerve (eg, pregnancy, hypothyroidism). patients typically have pain/apresthesias affecting the first 3-1/2 digits. Thenar atrophy with weakness on thumb abduction/opposition may also be seen.
c. the coracobrachialis muscle lies deep to the biceps brachia and is perforated and innervated by the musculocutaneous nerve. Nerve injury may result in decreased strength on forearm flexion and sensory loss over the lateral forearm.
d. In the wrist, the ulcer nerve passes between the hook of hamate and the pisiform bone in the fibroosseous tunnel known as Guyon's canal. Ulnar nerve injury at this site can cause weakness on finger abduction/adducition and clawing of the 4-5th digits.
g. fracture of the surgical neck of the humerus is usually associated with axillary nerve injury. Patients may have weakness of the deltoid and trees minor muscles as well as loss of sensation in the lateral upper arm.
Mitochondrial encephalopmyopathy: neuromuscular lesions, ragged skeletal muscle fibers and lactic acidosis.
Mitochondrial disorders follow a maternal inheritance pattern because an embryo's mitochondria are inherited from the ovum only.
Mitonchdronia contain their own genome, which is vulnerable to mutations. Each cell has hundred of mitochondria, and defects in their genome may occur in any number of the mitochondria within the cel.
HETEROPLASMY: describes the condition of having different mitochondrial genomes within a single cell. The severity of mitochondrial diseases is often directly related to the proportion of abnormal to normal mitochondria within a patient's cells.
a. anticipation refers to increased severity or earlier onset of an inherited disease in successive generations.
c. penetrance is the probability that a person with a given genotype will express its associated phenotype. If all individuals within gene express its phenotype , that gene is said to have complete penetrance.
d. Mosaicism refers to the presence of 2 or more cell lines, each with unique nuclear genome, within the same individual. While patients with both somatic and gremlin masocicsm can demonstrate disease traits and also pass the disease on to their offspring, it doesn't best explain the pattern of female only transmission.
e. uniparental disomy occurs when both members of a chromosomal pair are inherited from one parent, which can cause problems d/t genomic imprinting. For instance, although most often d/t chromosomal deletions, uniparental disomy can also cause Prader-Willi and Angolan syndrome d/t loss of expression of maternal/paternal imprinted components of a critical region of chromosome 15.
In this experiment, the repeated deoxythymidine on the latex beads most likely bind to the poly A tail of a mature mRNA. Post-strancription modification of mRNA is as follows:
1. 5' capping: a 7-methyl-guanosine cap is added to the 5' end of the mRNA
2. Polyadenylation: poly-A tail is added to most eukaryotic mRNA, which are not transcribed from the DNA template, but instead, has a consensus sequence (AAUAAA) located near the 3' end of the RNA molecule directs the addition of poly-A tail. This trial protects the mRNA from degradation within the cytoplasm after it exits the nucleus.
3. Splicing. The initial pre-MRNA contains sequence from coding and noncoding regions of DNA, aka exons and introns, respectively. SPliceosomes (complex of snRNPs and other shits) remove introns containing GU at the 5' splice site and AG at the 3' splice site.
a. aminoacyl-tRNA charged with its amino acid. the clover leaf structure of tRNA consist of a 3'CCA tail (amino acid binding site); a T loop abundant in ribothymidine, pseudouridine and cytidine residues; a D loop rich in dihydrouride residues and an anticodon loop.
c. DNA promoter regions help initiate transcription by binding transcription factors and RNA pol II. Promoter regions contain consensus sequences that are typically AT-rich (eg, TATA and CAAT boxes) or GC-rich (eg, GC box)
d. rRNA is a component of the ribosome that catalyzes peptide bond formation during translation
f. telomeres are located at the ends of chromosomes and contain TTAGGG repeats, which are added by the enzyme telomerase (RNA-dependent DNA polymerase). Craig chsortening in tolemere length is though to signal programmed cell death.
contractile mechanism in skeletal muscle depends on calcium ions and proteins (myosin II, actin, tropomyosin, and troponin).
Thick filaments in skeletal muscle are comprised of myosin molecules, with the heads of the myosin molecules forming cross links with actin during muscle contraction.
The actin chains composed the thin filaments in the skeletal muscle. Tropomyosin sits in the groove between the two actin chains, covering the myosin binding sites on actin when the muscle is at rest.
Troponin molecules are small globular proteins situated alongside the tropomyosin molecules which are comprised of three subunits: T, I and C. T binds the other troponin components to tropomyosin, troponin I binds to the troponin-tropomyosin complex to actin, and troponin C contains the bind sites for calcium. During excitation contraction coupling, Ca is released from the SR. When Ca binds to troponin C, tropomyosin shifts to expose the actin binding sites for myosin, allowing contraction to occur.
a. Ach is a NT that initiates muscle contraction in response to motor neuron stimulation. Act release form the motor neuron opens post-synaptic ligand-gated ion channels, resulting in depolarization of the muscle cell Depolarization then causes release of Ca from the SR.
b. Epinephrine is a catecholamine that is not directly involved in skeletal muscle contraction. However, epinephrine stimulates beta2-adrenergic receptors to increase skeletal muscle blood flow, glycogenolysis and lipolysis.
c/d: calmodulin and MLCK are components of smooth muscle contractile mechanism.
Patient has acute angle closure glaucoma and has been treated with acetazolamide, a diuretic that works by inhibiting carbonic anhydrase, which is found in high concentrations in the proximal tubule and is responsible for catalyzing reactions necessary for NaHCO3 reabsorption. By inhibiting carbonic anhydrase, acetazolamide and other carbonic anhydrase inhibitor effectively block HCO3 reabsorption in the proximal tubules resulting in the enhancement HCO3 and water excretion as well as increased urinary pH and potential metabolic acidosis
Carbonic anhydrase is also present in the eyes, pancreas, GIT, CNS and RBCs. In the eye, carbonic anhydrase modulates HCO3 formation in the aqueous humor. Inhibition of carbonic anhydrase will decrease HCO3 and aqueous humor formation; thus, a number of carbonic anhydrase inhibitors are used to relieve intraocular pressures in open angle and angle closure glaucoma. Common side effects of carbonic anhydrase inhibitors include somnolence, paresthesias and urine alkalization. Rare side effects include metabolic acidosis, dehydration, hypokalemia and hyponatremia.
Loop diuretic work in the thick ascending limb and is the most potent diuretic
DCT actively transport Na and Cl and is impermeable to water. Thiazide works here.
Collecting duct system includes the collecting tubules and ducts. Here, aldosterone and ADH make final adjustment to eye trolleys and water content. Potassium-sparing diuretics and aldosterone antagonists work in the collecting duct
NF-kB is a family of transcription factors that perform critical role in the immune response to infection and inflammation. In inflammatory cells, NF-kB is normally present in a later, inactive state bound to its inhibitor, IkB.
When extracellular signal, such as binding of bacterial antigens to a toll like receptor, causes activation of IkB kinase. This results in ubiquitination and subsequent destruction of IkB with release of free NF-kB. Once free, NF-kB enters the nucleus and promotes the synthesis of number of inflammatory proteins such as cytokines, acute phase reactions, cell adhesion molecules, and leukocyte related growth factors. The inflammatory cascade is self-limiting as NF-kB also stimulates the transcription of more IkB, ultimately rebinding the freed NF-kB.
a/e: G-CSF is the principal protein the stimulates the production and relate of neutrophils from bone marrow. TNF-alpha plays a role in response to infection by increasing neutrophil chemotaxis and stimulating macrophage phagocytosis. Although nfkB up regulates transcription of G-csf AND tnf-A, IKB DEGRADATION IS NOT DIRECTLY INVOLVED IN ACTIVATION OF THESE FACTORS
B. JAK2 is a TK involved in the signaling pathway for myeloproliferation. Constituent activation of JAK 2 is associated with polycythemia vera, essential thrombocytosis and myelofibrosis. It doesn't play a major role in the immune response to infection
d. although transforming growth factor -beta (TGF-beta) plays a role in immune response and is triggered by inflammatory pathways, it is complexed to TGF-beta binding protein and latency associated peptide not IkB.
Kid has complete AV canal defect, most common type of cardiac defect seen in Down syndrome.
Failure of endocardial cushion results in osmium primum atrial defect: a ventricular septal defect; and a single AV valve.
Significant left-to-right shunting an dAV valve reguregurgitation lead to excessive pulmonary blood flow and symptoms of heart failure (eg, tachypnea, poor feeding)
Auscultatory findings of AV valve regurgitation (holsystolic, best heard at the apex) and increased pulmonary venous return (mid diastolic rumba) are characteristic.
a. DiGorge is characterized by thyme aplasia (T cell def) and hypoparathyroidism (hypocalcemia). it is associated with tetralogy of Fallot, trunks arterioles and transposition of the great arteries.
c. Marfan syndrome (fibrillin-1 mutation) is associated with cystic medial necrosis of the aorta, which may result in dissecting aortic aneurysms and aortic valve regurgitation. Mitral valve prolapse is also common, but septal defects are not
d. mutations of frataxin, a mitochondrial protein important in iron homeostasis and respiratory function, cause Freidrecih ataxia. It is characterized by spinocerebellar degernation and is associated with hypertrophic cardiomyopathy, but not septal defects.
e. mutations in tubers and harmartin are seen in tuberous sclerosis. These patients may develop cardiac rhabdomyomas in ventricular walls and AV valves, cutaneous angiofibromas (adenoma sebaceous), CNS hamartomas and renal cysts.
f. turner is associated with bicuspid aortic valve (most common cardiac lesion) and coarctation of the aorta.
Regulation of the hypothalamus-pituitary-thyroid axis:
-The hypothalamus releases TRH triggering TSH to be released from pituitary.
-TSH stimulates release thyroid T4 (thyroxine) and T3 (triiodothyronine), the latter being more active that are produced primarily via deiodination of T4 in peripheral tissues.
Hypothyroidism may occur rd/t to
1. dysfunction involving the thyroid gland (primary hypothyroidism, most common)
2. Disorders of pituitary (secondary)
3. Hypothalamus (tertiary)
The number one cause is d/t Hashimoto, which is what this person has. It is an autoimmune destruction of the thyroid gland. As this happens, there will be low levels of thyroid hormones, which causes an elevated level of TSH d/t lack of inhibition from the thyroid hormones. However, T3 levels usually remain normal until relatively late-stages hypothyroidism.
TSH and T4 is normal. Total T3 increase
-thyroid hormones circulate mostly in protein bound form primarily to thyroxine biding globulin, transthyretin and albumin. When TBG levels are elevated (eg, pregnancy or oral contraceptive use), total thyroid hormone levels are high but the free hormone levels are normal. Their TSH is also normal. Euthyroid.
Elevated levels of TSH, T4 and T3 are consistent with hyperthyroidism d/t a TSH secreting pituitary adenoma.
Secondary hypothyroidism will have decreased everything.
Suppressed TSH will elevate thyroid hormone levels are characteristic of thyrotoxicosis (eg,Graves disease).
Genetic information flows from DNA to RNA to proteins. Post uekaryotic DNA sequences consist of coding exon, noncoding introns, and 2 promoter regions ( the CAAT box and the TATA box).
The CAAt box is located 70-80 bases upstream of the beginning (5' end) of the coding region, and the TATA box is located 25 bases upstream from the beginning of the coding region.
Gene transcription begins when RNA polymerase II attaches to one of the promoter regions in a process that requires general transcription factors. A DNA enhancer region then binds activator proteins that associate with transcription factors and RNA polymerase II at the promoter, thereby increasing gene expression. Although promoters are not directly translated into protein, promoter mutations can cause abnormal gene expression by altering ability of RNA polymerase II and transcription factors to bind.
a. DNa methylation is part of the epigenetic code. This process sis carried out by DNA methyltransferases and serves to silence the genes it affects
b. folding of a formed polypeptide into its secondary adntertiary structures is entirely spontaneous and is determined by the amino acid sequence in the protein's primary structure. heat shock proteins assist in the spontaneous refolding of proteins.
c. Posttranscriptional RNA splicing is facilitated by snRNPs that remove introns from heterogeneous nuclear RNA (hnRNA) containing GU at the 5' splice site and AG at the 3' splice site
d. the TATA box only participates in the initiation of transcription. The addition of nucleotides to th forming RNA molecule (RNA elongation) continues until RNA polymerase II encounters a termination signal.
f. In eukaryotes, translation initiation requires both ribosomal subunits (60S and 40S) with their associated rRNA, mRNA, initiation factors, initiator tRNA charged with methionine, and GTP. The assembled ribosome then recognizes the AUG start codon on mRNA to being the process
Contact dermatitis, granulomatous inflammation, the tuberculin skin test and the Candida extract skin reaction are all examples of delayed type hypersensitivity reactions (DTH).
The cells that mediate DTH are T-lymphocytes. This reactions don't involve antibody or complement. These actions are referred to as "delayed' responses because, unlike reactions mediated by antibody that occurs MINUTES after antigen exposure (i.e.. ABO blood group incompatibility, hyper acute rejection, erythroblastosis fettles), delayed reaction occur one to two days following antigen exposure (this is why you need to wait 48 to 72 hours for your annual PPD test to be read).
In DTH antigen is taken up by the dendritic cells and presented to to CD4 Th-lymphocytes on MHC Class II molecules. These stimulated Th-lymphocytes (usually of the TH1 lineage) then release interferon-g, which acts to stimulate and recruit macrophages leading to a monocytic infiltration of the area where the antigen is introduced. This is also responsible for the "walling-off" of M. tuberculosis infection in the lung and other forms of granulators inflammation with monicytic and giant cell infiltrates.
b. B-lymphocytes are the major effector cells in the humoral immunity because they synthesize and secrete immunoglobulin. Hypersensitivity reactions mediated by antibodies include Type I (IgE mediated, i.e.. asthma, anaphylaxis), TYPE II (antibody mediated, i.e. ABO incompatibility hemolysis) and Type III (immune complex (ie. PSGN). B-lymphcoytes are stimulated by IL03 release from the TH2 subset of Th lymphocytes.
c. Neutrophils are the primary phagocytes of the innate immune system and do not play a role in any of the four immune hypersensitivity reactions. Neutrophils are produced in the bone marrow and have a multi lobed nucleus. They are usually the first leukocytes to arrive at the site of inflammation and they are able to ingest and kill organisms by enzymatic and oxidative burst pathways. their presence in increased numbers in the blood is indicative of infection, especially with predominance of band forms referred to as a "left shift," but their numbers in the blood can be falsely elevated in a patient who has recently been administered corticosteroids. This effect of corticosteroids on the leukocyte count is attributable to the fact that corticosteroids cause" demmargination" (release from vascular walls) of these cells.
d. eosinophils are phagocytic cells that are believed to play a role in the defense against parasitic organisms. These cells are present in small numbers in the blood stream and are believed to play a role in the pathogenesis of asthma as they are often found in increased numbers in the bronchial mucosa of patients with this illness, but asthma is primarily a Type I hypersensitivity response.
e. Mast cells are granulocytes that exist in many tissues in the body and are primary mediators of the clinical effects of allergic reactions. They express Fc receptors for IgE, and IgE acts as the primary antigen receptor for these cells. When two membrane-bound molecules of IgE bind the same antigen, "cross-linking" occurs that directly leads to mast cell degranulation and release of mast cell granular contents such as histamine and heparin. Disorders of mast cells include urticaria pigments nd systemic mastocytosis.
This patient has typical symptoms of hypoglycemia (eg, disorientation, sweating, tremors, palpitations), which are relieved by intake of glucose. the 3 most important predisposing factors for hypoglycemia in patients with type 1 dm are excessive insulin dose, inadequate food intake, and physical activity/exercise.
GLUT-4 expressed on skeletal muscle cells are translocated to cell membrane and transverse tubules (deep invaginations in the cell membrane) in response to insulin. It translocation also occurs during muscle contraction by insulin independent mechanism, which is mediated by several cellular factors, including AMP-activated kinase, nitric oxide, and calcium calmodulin activated protein kinase.
In normal individuals, over hypoglycemia doesn't occur with exercise because a drop in blood glucose will stop insulin release from the beta cells and counter-regulatory hormones (eg, glucagon) will increase endogenous glucose production via glycogenolsyis and gluconeogenesis. However, patients taking exogenous insulin are vulnerable to exercise induced hypoglycemia as insulin will continue to be released from the injection site despite falling glucose levels. In addition, strenuous exercise may cause changes in skin perfusion that can lead to increased insulin absorption (especially if the insulin is injected into an exercising limb rather than the abdominal area).
b/c/d. infection, pain and sleep deprivation tend to cause hyper-rather than hypoglycemia. Stressful situations increase catecholamine release, which raises glucose by decreasing pancreatic insulin secretion and by increasing glycogenolysis and gluconeogeneiss.
e. weight gain is associated with insulin resistance insulin-treated patients who gain weight usually develop hyperglycemia and require increased doses of insulin to maintain control of glucose
this patient's clinical findings are highly suggestive of Klinefelter syndrome, the most common cause of male hypogonadism.
In klinefelter syndrome, progressive destruction and hyalinization of the seminiferous tubules cause the testes to be small and firm.
-Sertoli cells are damaged causing inhibin levels to be low
-Leydig cells are usually dysfunctional as well thus patient will have low level of testosterone
-The loss of feedback leads to elevated FSH and LH. Patients can also develop high estrogen levels and gynecomastia d/t increased aromatase activity (stipulated by gonadotropin excess).
Most patients with classic (47, XXY) Liefelter syndrome have azoospermia and are infertile, but those with mosaic variants may have variable degrees of spermatogenesis.
a. Low LH and FSH, along with low testosterone, are consistent with hypogonadotropic (central) hypogonadism, which can result form damage to the hypothalamus or pituitary gland The congenital def of GnRH, called Kallmann syndrome, is generally associated with anosmia. In addition, hypogonadotropic hypogonadism is less likely to cause gynecomastia as the decrease in gonadotropins reduces aromatase activity.
b. patient with normal hormonal profile but lacking sperm may have an obstruction somewhere along the path from the testes to the seminal fluid. For example, this occurs with congenital absence of the vas deferent in cystic fibrosis.
c. decreases LH , normal FSH and elevated testosterone in setting of a low sperm count is suggestive of exogenous testosterone use. High androgen levels suppress LH secretion,d decreasing endogenous testosterone production. Despite the high circulating levels of exogenous androgens, these patients have a low sperm count as local androgen contractions in the seminiferous tubules are suboptimal for spermatogenesis. Over time, this leads to atrophy of the seminiferous tubules and a decrease in testicular size.
e. normal LH and testosterone, elevated FSH and a low perm count can be seen in patients with cryptorchidism. In this condition, the seminiferous tubules are damaged (resulting in elevated FSH levels) and the interstitial Leydig cells are preserved (maintaining normal LH and testosterone levels).
Patient has abetalipoproteinemia, a disease caused by the impaired formation of apolipoprotein B containing lipoprotein.
Dietary lipids are normally processed in small-bowel enterocytes and secreted as chylomicrons; endogenously produced lipids are secreted from the liver hepatocytes as VLDL. Chylomicron and VLDL has apoB-48 and apoB-100, respectively. During the synthesis of api-b-containing lipoproteins, microsomal triglyceride transfer protein functions as a chaperone protein necessary for proper folding of apoB and also participates in the transfer of lipids to newly formed chylomicrons and VLDL particles.
this is the most commonly caused by an AR, loss-of-funcito mutation int he MTP gene. It manifests during the first year of life with symptoms of malabsorption (eg, abdominal distention, foul-smelling stool). Lab shows very low plasma TAGs and cholesterol levels, and chylomicrons, VLDLs and apoB are entirely absent form the blood. Poor lipid absorption auses deficiency of fat soluble (particularly vitamin E) and essential fatty acids. This results in RBC with abnormal membrane and thorny projections called acanthocytes as well as multiple neurologic abnormalities (eg, progressive ataxia, retinitis pigmentosa)
b. celiac biopsy will have atrophy and blunting of the villi in celiac disease. Chronic inflammatory infiltrate of the lamina proper is also present.
c/e/g: no abnormalities are found in LM of the SI in chronic pancreatitis, Zollinger-Ellison syndrome or lactase def.
d. LM of Crohn's shows chronic inflammation of all layers of the intestinal wall and noncaseating granulomas
f. Whipple has distended macrophages in the lamina propria of the SI> Macrophages contain PAS-positive and diastase-resistant granules and rod-shaped T. whippelii bacilli.
Adverse effects of succinylcholine
1. malignant hyperthermia (especially with halothane) in genetically susceptible patients
2. severe hyperkalmeia in patients with burns, myopathies, crush injuries and denervation
3. bradycardia from parasympathetic stimulation or tachycardia from sympathetic effects.
Succinylcholine is a depolarizing NMJ blocking agent. Like Ach it attaches to the nicotinic acetylcholine receptor (nAChR) and depolarizes the euromuscular end plate. Unlike Ach, succinylcholine is not degraded by acetylcholinesterase, resulting in continuous stimulation of the endplate (reflected by intimal transient fasciculations).
However, the Na channels surrounding the end plate rapidly become inactivated and cannot reopen until the end plate is depolarized. Thus, succinylcholine-induced depolarization remains isolated to the endplate, resulting in development of flaccid paralysis (phase 1 block).
Eventually, with continued administration of succinylcholine, the continuous depolarization of the endplate gives way to gradual depolarization as the nAChR becomes desensitized to the effects of succinylcholine. This in termed phase II block and is similar to non-depolarizing block.
Because the nAChR is a nonselective cation channel, its opening not only allows Na influx but also K release. Exaggerated hyperkalemia nd life-threatening arrhythmias can occur in patients with crush or burn injuries, denervating injuries or diseases (eg, quadriplegia and Guillain-Barre syndrome), and myopathies. These pathogloic states cause up regulation of muscle nAChRs and and/or rhabdomyolysis, which can result in the release of large amount son K when succinylcholine is administered. IN these patients, non-depolarizing agents such as vecuronium and rocuronium are better choices.
a. atracurium is a nondepolazizing NMJ blocking agent releases histamine and can produce a fall in blood pressure, flushing and bronchoconstricition. It is also metabolized to laudanosine, which can provoke seizures.
b. baclofen is a muscle relaxant that affects GABAb receptors at the level of the spinal cord
c. dantrolene is a muscle relaxant effective in malignant hyperthermia. It acts on ryanodine receptors on the sarcoplasmic reticulum and prevents release of Calcium in to the cytoplasm of muscle fibers.
The unit in this study is population not individuals. This is consistent with an ecological study, in which the frequency of a given characteristic (eg, vitamin D intake) and a given outcome (eg, multiple sclerosis (MS)) are studied using population date. Ecological studies are useful to generate hypotheses but should not be used to make conclusion regarding individuals within these populations.
a/b: case control and cohort studies would start with individuals rather than populations.
-In case-control studies, the odds of exposure to a certain characteristic (eg, high or low vitamin D intake) is compared between affected individuals (eg, patients with MS) and unaffected individuals who serve as controls.
-In cohort studies, individuals (with and without different exposures such as high or low vitamin D intake) are followed over time to determine incidence of disease of interest (such as MS).
c: cross-sectional surveys would also evaluate the exposures and outcomes of interest in individuals (not populations) at a given point in time ("snapshot").
e. nested case control designs start with cohort studies in which participants are followed over time,a nd those participants who develop an outcome of interest become cases for a case-control study.
f. qualitative studies are focused discussion groups, interviews (structured and semi-structured), and other anthropologic techniques to obtain narrative information that can be crucial in explaining quantitative results.
g. randomized controlled trials enroll individuals who will be randomly assigned into a treatment group or a control group. the groups differ only in terms of intervention (treatment) of interest).
h. systematic reviews and meta-analyses take several studies (with an emphasis on high-quality randomized controlled studies) and attempt to group the results to obtain a pooled effect estimate .
Focal dystonia is a localized uncontrollable muscle contraction causing pain or discomfort as well as physical deformity in some cases.
Local injection of botulinum toxin type B into the dystonic SCM results in muscular relaxation because toxin prevents presynaptic release of ACh, the NT responsible for muscle contraction, from the nerve terminal at the NMJ.
This effect is temporary, however, because regeneration of the nerve terminal eventually occurs. (this process takes approximately three months.) For this reason, therapeutic botulinum toxin injections must be repeated when the effects begin to diminish.
Botulinum toxin can also be used cosmetically to reduce the appearance of glabellar and other facial wrinkles. It is also used to relax the lower esophageal sphincter in esophageal achalasia, to treat the muscle spasms of MS and Parkinson's disease, and for other conditions resulting form involuntary muscle contraction.
C. botulinum is a gram positive spore-forming anaerobic bacillus that synthesizes its point neurotoxins intracellularly and releases them by autolysis.
a. antiphagocytic capsule is the primary virulence factor for S. pneumonia, H. influenza and Neisseria bacteria.
b. hyper variable pili are characteristics of Neisseria meningitides and N. gonorrhoeae.
c. S. aureus has an IgG-binding outer membrane protein, the Protein A virulence factor. Protein A binds to the Fc portions of IgG molecules thereby preventing opsonization, phagocytosis and complement fixation.
d. intracellular polyphosphate granules are characteristics of C. diph. Granules within the cytoplasm are evident with methylene blue staining.
This patient has appendicitis, which can cause both visceral (dull,non-localized) and somatic (severe, well-localized) abdominal pain.
Visceral abdominal pain is most often d/t luminal distention and stretching of smooth muscle and is carried by general visceral afferent fibers of the autonomic nervous system. The pain typically occurs int he midline region and is poorly localized and of a dull, constant, or cramping quality. Patients can also develop nausea, vomiting, or sweating d/t the autonomic stimulation.
Somatic pain is usually d/t irritation of the parietal peritoneum and is well localized, more severe, and worsened with deep inspiration or pushing on the abdominal wall.
the afferent pain fires for the appendix , proximal colon and overlying visceral peritoneum cross through the superior mesenteric plexus and enter the spinal cord at the t10 level to produce vague, referred pain at the umbilicus. As the appendix becomes more inflamed, it irritates the parietal peritoneum and abdominal wall and causes a more severe somatic pain that shifts from the umbilical region to McBurney point (two-third of the distance from the umbilicus to the anterior superior iliac spine). The abdominal wall becomes very sensitive to gentle pressure or sudden release of deep pressure (rebound tenderness).
b/c: the appendix is usually 2 cm beneath the ileocecal valve in the RLQ. Depending on its orientation, there can be additional clinical findings. An inflamed appendix lying against the right obturator interns muscle can cause right lower quadrant pain with internal rotation of the right hip. If the inflamed appendix lies against the right tpsoas muscle, there can be pain with hip extension.
d. the cecum is innervated by the superior mesenteric plexus and has only visceral sensation.
e. patients with retrocelcal appendix may not have significant right lower quadrant tenderness,as the inflamed appendix doesn't contact the anterior parietal peritoneum and the cecum (distended with gas) acts as a cushion that blocks the examiner's hand.
This patient has obstructive sleep apnea (OSA), which is characterized by recurrent obstruction of the upper airway during sleep; each nocturnal episode of reduced ventilation causes transient hypercapnia and hypoxemia. These blood gas derangements result in reflexive systemic and pulmonary vasoconstriction, endothelial dysfunction, abnormal venous return and CO, and sympathetic cardiac stimulation.
Prolonged, untreated OSA can cause pulmonary HTN and RH failure. Most patients with OSA will develop systemic hypertension d/t chronic sympathetic stimulation and elevated plasma NE levels Patients also lose the normal diurnal variation in blood pressure. Other CVS complications of OSA include
-afib (and other arrhythmias)
-sudden cardiac death
a. acquired bronchiectasis may be seen in patients with recurrent infection, impaired drainage (eg cystic fibrosis ), airway obstruction (eg, foreign body aspiration), or inadequate host defense (eg, hypogammaglobulinmemia).
b. systemic HTN, as seen in OSA, can lead to mild-to moderate left ventricular hypertrophy and impaired systolic and diastolic function. In contrast, hypertrophic cardiomyopathy is an autosomal dominant disease of the cardiac sarcomere characterized by severe myocardial hypertrophy. It is not associated with HTN or SOA
c. laryngeal carcinoma is associated with cigarette smoking and heavy alcohol use
d. like OSA< narcolepsy can also cause daytime drowsiness. However, narcolepsy is also associated with cataplexy (sudden loss of muscle tone), sleep attacks, sleep paralysis, and hypnagogic hallucinations. OSA is not a risk factor for narcolepsy.
Causes of ostemelitis:
Childhood age: hematogenous seeing during an episode of bacteremia. Most frequent pathogen is S. aureus. Typical location is long bones.
Sickle cell disease: Hematogenous seeding to infarcted bone. Most frequent pathogens are Salmonella and S. aureus. Typical location is long bones.
Post disease: hematogenous seeding from lungs. Most frequent pathogen is mycobacterium tuberculosis. Typical location vertebrae.
DM: contiguous spread from infected foot ulcer. Most frequent path is poly micro affecting the bones of the feet
Recumbent patients with impaired mobility. Contiguous spread from pressure sores. Most frequent pathogen polymicrobial affecting the sacrum and heels
Recent trauma or orthopedic surgery. Direct inoculation. Polymicrobial and location is variable.
Osteomyelitis is an infection of the bone and bone marrow that occurs by 1 of 3 mechanisms:
1. hematogenous seeding d/t an episode of bacteremia
2. spread from a contiguous focus infection, as occurs in an infected diabetic foot wound
3. direct inoculation of bone, such as with a compound fracture
Hematogenous osteomyelitis occurs predominantly in children and most frequently affects the long bones the tibia, fibula, and femur are most often involved. Adults who develop the condone are more likely to have vertebral involvement and frequently have a predisposition to bacteremia d/t risk factors such as IV drug abuse or indwelling vascular catheters.
S. aureus is implicated in most cases of acute hematogenous osteomyelitis in otherwise healthy children
a. enterococcus faecalis causes a variety of infections, including endocarditis, meningitis, and urinary tract infections. Enterococcus can cause vertebral osteomyelitis after a recent UTI via bacteremic spread.
b. moraxella catarrhalis is part of the normal flora of the URT. It causes otitis media and sinusitis in healthy individuals and is frequently responsible for causing exacerbation of COPD.
d. S. epidermis is ubiquitous in nature and is commonly isolated in cultures as contaminant. However,r S. epidermis can also be pathogenic, colonizing IV catheters and the foreign bodies such as prosthetic heart valves and orthopedic hardware, leading to bacteremia and sepsis.
e. S. agalactiae (group B strep) frequently colonizes the GI and urogenital tracts. Infants porin vaginally to colonized mothers can develop serious neonatal infections, including sepsis, pneumonia, and meningitis. For this reason, pregnant women testing positive for group B strep are treated with antibiotic prophylaxis during labor and delivery.
f. s. pneumoniae is the most common etiologic agent of community acquired pneumonia. It also causes otitis media in children, sinusitis, meningitis and sepsis
g. S. aureus, S. pyogenes (group A strep) is the second most common cause of hematogenous osteomyelitis in children. Group A strep are also responsible for strep pharyngitis and skin infections such as impetigo and necrotizing fasciitis.
After transcription, the preliminary, unprocessed mRNA is known as precursor mRNA, or heterogenous nuclear RNA (hnRNA). Eukaryotic pre-mRNA undergoes significant post transcriptional processing before leaving the nucleus, including 5' capping, poly A tail addition, and intron splicing.
Once mRNA is finalized, it leaves the nucleus bound to specific packaging proteins. Upon entering the cytoplasm, these mRNA complexes often associated with ribosome to undergo translation. However, certain mRNA sequences instead associate with proteins that are found in P bodies.
P bodies are distinct foci within eukaryotic cells that are involved in MRNA regulation and turnover. They play a fundamental role in translation repression and mRNA decay, and captain numerous proteins including gRNA exonuycleases, mRNA recapping enzymes, and constituents involved in mRNA quality control and microRNA-induced mRNA silencing. P bodies also seem to function as a form of mRNA storage, as certain mRNAs are incorporated into P bodies only to be alter related and utilized for protein translation.
a/b: The 4' end of all mRNA is capped with a 7-methylguanosine residue by a unique 5' to 5' linkage, which occurs in two stages. The first step is addition of guanine triphosphate to the 5' end of mRNA in reaction catalyzed by guanylytransferase. Methylation of the guanosine cap is then catalyzed by guanine-7-methyltransferase. Capping of the precursor RNA occurs in the nucleus as the ran is being transcribed. This methylated cap protect mRNA from degradation by cellular exonuclease, and allows it to exit the nucleus.
c. mRNA is polyadenylated at the 3' end by the polyadenylate polymerase complex, which recognizes a specific sequence (AAUAAA), cleaves the pre-mRNA molecule a few residues downstream from the sequence, and then adds a stretch of 20-250 adenine residue called the poly A tail. The addition of the poly A tail occurs before th emRNA exits the nucleus. IN the cytosol, th poly A tail is gradually shortened, eventually leading to mRNA degradation.
d/e: since pre-mRNA contains both introns and exon, and only exon code for proteins, introns must be excised before translation through process known as splicing. Splicing of pre-mRNA occurs within the nucleus and is facilitated by interaction of pre-mRNA with small ribonucleoprotein particles called snRNPs (or "slurps" for short).
Ingeneticially normal (46, XX) females, on eX chromosome is normally randomly deactivated each cell during early embryonic development. X-incativaiton (lionization) is maintained across cell division, resulting in clusters of cells throughout the body that express either the maternal or paternal X chromosome.
this mosaic pattern of X-chromosome expression generally prevents X-linked recessive conditions from naifestating in female carriers. However, in rare cases, skewed lionization (uneven inactivation of maternal/paternal X chromosome d/t chance alone may result in females developing an X-linked recessive condition (eg, classic hemophilia).
The process of lionization converts the inactive X chromosome into condense heterochromatin, which can be identified on microscopy as a compact by at the periphery of nucleus (Barr body). Heterochromatin consist of heavily methylated DNa (eg, cytosine converted to methyl cytosine) and deacetxyalted histones, which cause it to have a low level of transcriptional activity.
A small proportion of genes rain transcriptionally active on the inactivated X chromosome. For this reason, inheritance of an abnormal number of X chromosomes can cause clinical manifestations d/t a gene dosage effect, as seen in Turner (45, XO) and Klinefelter (47, XXY) syndromes.
a. during DNA replication, positive supercoiling occurs in the region ahead of the replication fork and must be removed for DNA replication to proceed. Topoisomerase's reduce DNA supercoiling by nicking the DNa strands, introducing negative coiling, and relegating the strands.
b. double strand DNA breakage can occur following exposure to ionizing radiation. Compared to single strand breakage, double stranded breaks are more prone to result in faulty repair, leading to mutations, malignancy or cell death
d. repair mismatched bases occurs throughout the genome during DNa replication. Impaired mismatch repair is associated with hereditary non polyposis colorectal cancer.
Dude has HIV given his oral thrush (usually seen with CD 4 count lower than 200), cervical and inguinal lymphadenopathy, and brain lesions.
HIV patient with headaches, seizures, and multiple ring enhancing CNS lesion on MRI suggest tosoplasmic encephalitis.
Seizures ar common complication of such brain lesions and their surrounding edema. Extensive pet (cat) exposure is not essential for the diagnosis, as toxoplasmosis can also be transmitted through contaminated foods.
a. aspergillum is not a leading opportunistic pathogen in patients with HIV, possibly because they have relatively intact phagocytic function despite their T cell dysfunction. Aspergillum typically affects the lungs; however, ti can cause brain abscesses in patients who are immunocompromised d/t neutropenia or transplant.
b. Glioblastomas are ring enhancing, they are typically solitary and often have characteristic butterfly appearance.
c/d: neurocysticercosis (d/t Tania sodium (pork tapeworm) ingestion) can cause multiple brain lesions but would be unlikely in this patient with no travel history to South and Central America. Similarly, TB cis infection, which can cause similar lesion, si a consideration in developing countries but is a less lily diagnosis in the US
selective estrogen receptor modulators
MOA: competitive inhibitor of estrogen binding. Mixed agonist/antagonist action
Indications: prevention of breast cancer in high-risk patients.
-Tamoxifen: adjacent treatment of breast cancer
-Raloxifene: postmenopausal osteoporosis
A/Es: hot flashes, venous thromboembolism and endometrial hyeprplaisai and carcinoma (w/ tamoxifen only).
Estrogen plays a critical role in bone and reproductive organs, including skeletal homeostasis and proliferation of the endometrium. Because estrogen decreases bone resorption, estrogen def in postmenopausal women increase the risk of osteoporosis. In the uterus, unopposed estrogen exposure (eg, estradiol therapy) canc cause excessive endometrial proliferation resulting in endometrial hyperplasia and cancer.
Selective estrogen receptor modulators (eg, raloxifine, tamoxifen) are non steroidal compounds that bind to estrogen receptor and exhibit estrogen antagonist and agonist properties in a tissue specific manner.
RALOXIFENE: excellent choice for prevention of breast cancer and osteoporosis because it has estrogen antagonistic activity on breast. Furthermore, raloxifine has estrogen antagonistic activity on uterus and doesn't increase the risk of endometrial cancer.
TAMOXIFEN: has a strong estrogen antagonist activity in the brest and is used in the treatment of estrogen receptor positive breast cancer. Although tamoxifen produces estrogen-like effects on bone and can reduce the risk of osteoporosis, it agonist activity on the uterus (eg, increased risk of endometrial yperplasia/cancer) limits its potential in osteoporosis management.
a. alendronate is a synthetic bisphosphonate. As a bone resorption inhibitor it prevents and treats osteoporosis in postmenopausal women. Bisphosphonates do not protect against breast cancer.
c. leuprolide is a GnRH analog with estrogen agonist properties when administered in pulsatile manner and antagonist properties when administered continuously. Its use as an agonist increases estrogen and protects against osteoporosis. However, it use as an antagonist decreases estrogen, protecting against estrogen receptor psotivie breast cancer but not osteoporosis.
d. oral medroxyprogesterone reduces the incidence of endometrial hyperplasia and the risk of endometrial carcinoma in postmenopausal women on estrogen replacement therapy. Prolonged use of intramuscular medroxyprogesterone as a contraceptive is associated with decreased bone mineral density.
The atherosclerotic occlusion of a coronary artery develops very slowly over time, there can be compensation by the development of arterial collaterals around the point of occlusion. The pressure gradient across the stenotic region facilitates blood flow through the small anastomotic vessels, which progressively dilate. The collateral circulation can provide flow to the hypo perfused areas distal to the point of occlusion. In this case, the patient likely developed collaterals from the right coronary artery to distal vessels normally perfused by the LAD
a. when the fibrous cap overlying a coronary atherosclerotic plaque is thin, the plaque is unstable and predisposed to ulceration, fissuring, or rupture. Rupture of an atherosclerotic plaque can lead to overlying thrombosis and acute coronary occlusion, which resultant ischemic myocardial injury. This process occurs too quickly to be compensated by the development of new arterial collaterals.
b. atherosclerotic rookery plaques with a rich lipid core are more prone to plaque rupture, and thus more lily to cause an acute ischemic coronary syndrome d/t superimposed thrombosis.
c. activated macrophages in an atheroma contribute to collagen degradation by secreting metalloproteinases. When there is a high degree of intimal inflammation, release of these metalloproteinases is increased, which can destabilize the mechanical integrity of the plaque, Statins (HMG Co-A reductase inhibitors) decrease this inflammation and are useful in acute coronary syndrome to stabilize the plaque,
e. the total coronary artery calcium content correlates modestly with the coronary artery atherosclerotic plaque burden. Thus, patients with advanced coronary calcification may be at increased risk fro ischemic myocardial injury. However, the calcium content of an individual plaque is not correlated with the probability of rupture or degree of plaque stability. Thus the presence of intra-plaque calcium could be consistent with either an acute contrary syndrome or with gradual occlusion without myocardial necrosis.
f. An postal location of a coronary artery plaque would not give a finished tendency to cause ischemic myocardial injury. IN fact, it might promote such injury by compromising blood flow to a larger area of the myocardium. However a more important determinant of whether or not coronary plaque causes myocardial necoriss is the rate of arterial occlusion. A slowly progressive postal obstruction would not necessarily prevent the development of an adequate collateral circulation
This patient has cerebrovascular and coronary atherosclerosis ( causing transient ischemic attacks and angina), which increases the risk of atherosclerosis in other organ systems. Atherosclerosis involving renal arteries can cause bilateral renal artery stenosis (RAS) in such patients.
Reduced renal blood flow (eg, from dehydration or RAS) decreases GFR d/t fall in hydrostatic pressure. This stimulates renin production, which leads to angiotensin II formation.
Angiotensin II causes systemic vasoconstriction with a resultant rise in BP.
In the kidney, angiotensin II preferentially constricts the efferent arteriole. Blocked of this response by ACE inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) causes the filtration pressure to fall, thereby reducing GFR. In unilateral RAS, the normal kidney compensates for decreased GFR< and overall creatinine clearance is maintained. However, patients with bilateral RAS may develop acute renal failure. Therefore, renal function should be monitored closely after starting gACEI/ARBs in patients with evidence of diffuse atherosclerosis.
a/e: ACEI/ARBs have multiple cardiac benefits. They cause peripheral vasodilation that reduces after load. This decreases the contractile force needed to maintain CO, reducing myocardial oxygen demand. These drugs also slow the progression o left ventricular hypertrophy (in aortic regurgitation) and myocardial scar formation in expansion (eg, aneurysm formation after infarction).
c/d: ACEI/ARBs may lead to hyperkalemia, which in turn can cause conduction abnormalities. However, in the absence of this side effect, ACEI have no direct effect on heart conduction. They can be used safely in patients with atrioventricular block or polymorphic ventricular extrasystoles
f. angiotensin II is involved in atherogenesis. Hypertensive patients with iliofemoral atherosclerosis would therefore benefit form ACEI/ARBs that reduce the effects of angiotensin II.
PSGN is a nephritic syndrome (eg, periorbital edema, hematuria, HTN, red cell casts and mild proteinuria).
-elevate titers of streptococcal antibodies (eg. anti-DNAse B, anti-hyaluronidase, antistreptolysin O (aka ASO, no detectable with impetigo)
-LM: hyper cellular glomeruli (from leukocyte infiltration (eg, neutrophils and monocytes)) and mesangial and endothelial cell proliferation.
-IM: granular deposits of IgG, IgM and C3 (showing a "starry sky" appearance).
-EM: sup epithelial humps (from deposition of antigen-antibody complexes).
b. PSGN activates the alternative/lectin complement pathway, resulting in glomerular C3 deposition without significant C1 or C4 deposits.
-Sub endothelial C1q deposits are characteristic of type 1 membranoproliferazive GN.
d. fibrin is found in rapidly proliferative (crescentic) GN
e. IgE is sometimes seen in lupus nephritis and are confined to the capillary wall.
f. M protein is a component of the streptococcal cell wall that acts as an antiphagocytic virulence factor. PSGN is caused by nephritogenic antigens such as sure. pyogenic exotoxin B, not M.
Tay-Sachs is an AR neurodegenerative disorder commonly seen in the Ashkenazi Jews.
beta-hexoaminidase A def, resulting in accumulation of membrane glycolipid GM2 ganglioside within lysosome.
Patients are usually asymptomatic in the first few months, followed by progressive neurologic deterioration as glycolipids accumulate in the brain.
-weakness, hypotonia, developmental regression, seizures, blindness and spasticity.
-macrocephaly and abnormal startle reflex
-cherry red macula where fovea is surrounded by white macula appearing as a halo. The halo is d/t ganglioside buildup in ganglion cells.
a. galactocerebroside builds up in Krabbe disease. Neurodegenration like Tay Sachs however, patients will also have peripheral neuropathy and optic atrophy.
b. globotriaosylceramide accumulates if Fabry. Angiokeratomas (benign cutaneous lesion of capillaries), peripheral neuropathy and glomerulopathy and typically present in adult hood.
c/g: cherry red macula is also found in Gaucher and Riemann-Pick. These guys however have hepatosplenomegaly
-beta-glucocerebroside accumulates in Gaucher
-Sphingomyelin accumulates in Neimenn-Pick
d. glycogen storage diseases include von Gierke disease and Pompe.
-von Gierke (glucose-6-phsphatase def) typically have hepatomegaly, hypoglycemia, seizures and/or lactic acidosis.
-Pompe disease (lysosomal alpha-1,4-glucosidase def) classically cause cardiomegaly and severe hypotonia.
f. mucopolysaccharidosis (eg, Hurler syndrome, Hunter syndrome) are lysosomal storage diseases that cause build up of GAGs such as heparin and derma tan sulfate. GAG accumulation causes nerucognitive decline as well as coarse facial features and skeletal abnormalities.
Rett is a neurodevelopmental disorder mainly in girls that is characterized by:
1. normal until 5-18 months
2. loss of motor and language skills
3. stereotypic hand movement
4. Deceleration of head growth
a. autism spectrum disorder is characterized by impaired social communication/interactions and restricted, repetitive interests or behaviors typically presenting by age 3. Autism doesn't explain this patient decelerated head growth, stereotypic hand movement and regression from earlier milestones
b. fragile X: CGG triple repeat. Features include intellectual disability, a long narrow face, large protruding ears, macrocephaly and macroorchidism.
Leech-Nyhan is X-linked recessive def in HGPRT, leading to increase uric acid. Clinical features are gout, poor muscle control, intellectual disability, writhing or repetitive involuntary movements, and self-mutilaitng behaviors.
Sickling is promoted by conditions associated with
1. LOW OXYGEN levels
2. increased acidity
3. low blood volume (dehydration)
Sickled cells are not flexible enough to pass through small blood vessels. Organs where blood moves slowly (eg, spleen, liver) are predisposed to lower oxygen levels or acidity.
Organs with high metabolic demands (eg, brain, muscles, placenta) promote sickling by extracting more oxygen from the blood (OXYGEN UNLOADING).
a/c: 2,3-BPG binds to 2 beta global chains and stabilizes the taut (T) deoxyhemoglobin, this biding decreases hemoglobin's oxygen affinity, facilitating oxygen relate at the tissue level. Depletion would cause an increase in hemoglobin affinity to oxygen (left shift), which would result in uptake of oxygen by hemoglobin. Therefore, sickling will decrease.
-Similarly, increased acidity or low pH is associated with sickling, so decreased acidity with elevated pH would not promote sickling.
PAO2 (alveoli) = 104 mm Hg
pO2 generally reaches PAO2 by the time it passes through the first third of the alveolar capillaries d/t a high rate O2 diffusion through the respiratory membrane.
However, by the time oxygenated blood enters the systemic circulation, the pO2 drops to about 100 mm Hg d/t addition of deoxygenated blood from the bronchial circulation, intrapulmonary arteriovenous anastomoses, and Thebesian veins of the heart.
The discrepancy between alveolar and arterial O2 concentration is termed (A-a) gradient, which is normally between 5-15 mm Hg, with older individuals having a higher A-a d/t age related decrease in O2 diffusing capacity.
This patient has low PaO2 and PAO2 and a normal A-a gradient (71-60=11). This indicates that his low PaO2 is directly d/t his low PAO2 and not caused by V/Q mismatch or O2 diffusion impairment. Possible causes of hypoxemia in the setting of normal A-a gradient include
1. alveolar hypoventilation common in patients with suppressed central respiratory drive (eg, sedative, overdose, sleep apnea) or those with diseases that decrease inspiratory capacity (eg, myasthenia gravid, obesity).
2. inspiration of air at high altitude
a. diffusion impairment can be cause by thickening of the alveolar capillary membranes, such as alveolar hyaline membrane diseases. A-a gradient will increase because O2 in the alveoli cannot be transported into blood.
c. left to right shunt happens when the left heart (or systemic arterial circulation) is shunted into the right heart (or pulmonary artery). because blood in the left heart is oxygenated, left to right shunts doesn't lead to hypoxemia. This can occur with atrial or ventricular septal defects or patent ductus arterioles
d. right to left shunt occurs when venous blood bypasses the lung and enters the arterial circulation, thereby decreasing PaO2. The A-a gradient would increased. This type of hypoxemia occurs in patients with cyanotic congenital heart defects
e. V/Q mismatch is a common cause of hypoxemia. Poor ventilation of a lung segment with normal perfusion (eg, pneumonia, COPD) results in physiologic shunting, leading to increased A-a gradient.
This medication inhibits neprilysin, a metalloprotease that inactivates several peptide hormones, including bradykinin, glucagon, enkephalins and natriuretic peptides.
ANP is made by atrial cardiomyocytes in response to atrial stretch, which is indicative of systemic volume expansion.
-Lower blood pressure through peripheral vasodilation, natriuresis and diuresis.
Organs affected are:
1. kidney: dilates afferent arterioles = increase GFR and urinary excretion of Na and H20.
-it also limits Na reabsorption (in PCT and inner medullary of th recollecting duct)
-inhibits renin secretion
2. Adrenal gland: restrict aldosterone secretion, leading to an increase in Na and H2O excretion by kidneys
3. blood vessels: ANP relaxes vascular smooth muscle in arterioles and venues, producing vasodilation. It also increases capillary permeability, leading to fluid extravasation into the interstitium and a decrease in circulating blood volume.
b. duodenal mucosal cells produce many GI hormones such as gastrin, secretin and CCK. But none of them increases urinary output or decreases TPR
c. glomerular zone of the adrenal gland secretes aldosterone. Which would increase H2O and Na reabsorption causing the extracellular fluid to expand and BP to increase
d. oxytocin and ADH are 2 hormones produced by the posterior pituitary gland. Vasopressin increases water permeability of the renal collecting ducts, thereby increasing water reabsorption. Oxytocin stimulates uterine contractions in late pregnancy and facilitates breast milk ejection postpartum
e. JG cells secrete renin, which catalyzes the formation of angiotensin I from angiotensinogen. Angiotensin I is converted in the lungs into angiotensin II , which causes vastconstriction and aldosterone please.
Antiemetic drugs clinical uses:
1. motion sickness/hyperemesis gravid arum (promethazine)
a. antimuscarinics - scopolamine
b. antihistamines - diphenhydramine, meclizine, promethazine
2. Chemotherapy induced emesis
a. dopamine receptor antagonist - prochlorperazine, metoclopramide
b. 5-HT3 receptor antagonists - ondensetron and granisetron
c. neurokinin 1 (NK1) receptor antagonist: aprepitant, fosaprepitant
1. area postrema (4th ventricle) has chemoreceptor trigger zone that can respond to many neurotransmitters, drugs or toxins.
2. nucleus tracts solitaires (NTS) in medulla. Receives information from the area postrema, GI via the vagus nerve, vestibular system and CNS (eg, meninges, hypothalamus).
Neurons from the NTS project to other medullary nuclei and coordinate the vomitting process. The 5 major receptors involved in stimulating the vomiting reflex in the area postrema and adjacent vomiting center nuclei are M1, D2, H1, t-HT3, serotonergic and NK1.
5-HT3 receptor antagonists (eg, ondansetron, granisetron, dolasetron) are highly effective in preventing chemotherapy-inducedvomiting. 2 primary MOAs:
1. blocking vagus-mediated nausea and vomiting
2. blocking serotonin receptors in the area postrema and NTS
Other shit you can use is:
-NK1 receptor antagonists (eg, aprepitant), which inhibit substance P and help prevent both acute vomitinga nd delayed emesis
-Dopamine receptor antagonists (eg, metoclopramide), associated with drowsiness and dystonic reactions
a/d: histamine blockers and antimuscarinic/anticholinergic agents are most helpful for vestibular nausea and vomiting.
b. motion regulates inter digestive migrating contractions. Erythromycin is a motion receptor agonist used for gastroparesis
c. Mu opioid receptor agonists (eg, morphine) are useful for cancer related pain control but often have side effects such as nausea and vomiting.
Primary hyperPTH classic symptoms:
-GI disturbances (eg, peptic ulcer disease)
"bones, stones, abdominal groans and psychic moans."
asymptomatic hypercalcemia is the most common presentation nowadays d/t routine measurement of calcium in the chemistry profile.
1. PTH increases renal tubular Calcium reabsorption (although most patients have hypercalciuria).
2. increased production of calcitriol (1,25 dihydroxyvitamin D) in the kidneys causing increased GI calcium absorption.
3. PTH mediated increase in bone resorption (via osteoclast activation)
-Hypophosphatemia as PHP decreases phosphate resorption in the proximal renal tubules.
Morphology, skeletal finding
-involves cortical (compact) bone in the appendicular skeleton ( the pectoral girdle, pelvic girdle and limbs).
-subperiosteal erosions in phalanges of the hand, a granular "salt and pepper" skull, and osteolytic cystic the long bones
a disorganized lamellar bone structure in a mosaic pattern = Paget disease. Serum calcium and phosphorous are normal.
b. osteoid matrix accumulation around traveculae is seen in osteomalacia. Hits shows excessive unmineralized osteoid with widened osteoid seams. patients will typically have low urinary calcium.
c. persistence of the primary spongiosa in the medullary cavity with no mature trabeculae is a classic fining of osteoporosis (i.e., "marble bone disease"). Osteoporosis is caused by decreased osteoclastic bone resorption, which results in accumulation of woven bone and diffuse skeletal thickening
e. trabecular thinning with fear interconnections is characteristics of osteoporosis. Although longstanding PHP causes thinning of cortical bone, the trabecular architecture remains relatively preserved.
Phenytoin: neural tube defects, orofacial clefts, microcephaly, nail or digit hypoplasia
Lithium: Ebstin anomaly, nephrogenic diabetes insidious, hypothyroidism
Valproate: neural tube defects
Isotretinoin: microcephaly, thyme hypoplasia, small ears, hydrocephalus
Methotrexate: limb and craniofacial abnormalities, neural tube defects, abortion
ACE inhibitor: renal dysgenesis, oligohydraminos
Warfarin: nasal hypoplasia, stippled epiphysis
Valproate can interfere with folate metabolism and increase fetus chance of having neural tube defects.
Use levetiracetam instead. Give high dose of folate.
a. First trimester exposure to warfarin can lead to warfarin embryopathy characterized by depression of the nasal bridge and stippling (pinpoint calcification) of the epiphysis. It can also cause nail hypoplasia and fetal bleeding.
b/g: Lithium can cause hypothyroidism and Ebstein anomaly. Neonatal hypothyroidism can also be a result from exposure to maternal antithyroid drugs (eg, propylthyiouracil, methimazole)
d. phenytoin is an anti epileptic that can cause orofacial clefts, microcephaly, nail or digit hypoplasia, cardiac defects and dysmorphic facial features.
e. renal dysgenesis and fetal anuria/oligohydraminos is caused by ACE inhibitors and angiotensin receptor blockers.
f. short palpebral fissure, smooth philtrum and thin vermillion border are key dysmorphic features of fetal alcohol syndrome.