Property:Explanation
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Aspirin is an irreversible non-specific inhibitor of prostaglandin synthase, also called cyclooxygenase (COX), enzyme that also acts by acetylation of proteins. The COX enzyme normally leads to the conversion of arachidonic acid into endoperoxides, such as PGG2 and PGH2. With the action of aspirin, the pathway is inhibited; and platelet aggregation is not as effective due to the decreased synthesis of thromboxane A2 downstream in the pathway. Clinically, aspirin is used for its inhibitory effects of platelet aggregation. It is prescribed following percutaneous coronary interventions and is an important medication for secondary prophylaxis among patients with coronary artery disease. Aspirin causes a prolonged bleeding time, reflecting its role on the inhibition of platelet aggregation.
Salicylate, the active component of aspirin, is absorbed in the unionized form from the small intestine and is conjugated with glycine in the liver. Peculiarly, aspirin simultaneously causes primary high-anion gap metabolic acidosis and primary respiratory alkalosis; it increases the production of endogenous acids, leading to metabolic acidosis, and has a dose-dependent stimulatory effect of respiratory centers, resulting in hyperventilation and respiratory alkalosis.<br/>
'''Educational Objective:''' Aspirin is an irreversible inhibitor of cyclooxygenase enzyme.<br/>
'''References:''' Rocca B, Petrucci G. Variability in the responsiveness to low-dose aspirin: pharmacological and disease-related mechanisms. Thrombosis, vol. 2012, Article ID 376721, 11 pages, 2012.<br>
First Aid 2014 page 439 +
The medication described must have properties that reduce platelet aggregation to counteract the process of myocardial infarction. Prostacyclin (PGI2) is a potent inhibitor of platelet aggregation. Also, it plays a role in promoting vasodilation and bronchodilation, along with decreasing uterine tone. Since the drug increases compounds that inhibit platelet aggregation, the new compound must increase PGI2 levels, and thus promote inhibition of platelet aggregation.<br/>
'''Educational Objective:''' Prostacyclin inhibits platelet aggregation.<br/>
'''References:''' First Aid 2014 page 439 +
The patient is presenting with signs and symptoms consistent with gastrinoma or Zollinger-Ellison syndrome. The prognosis of gastrinoma is affected by several factors. Prognosis is poorer among patients with gastrin levels beyond 700 pg/mL, metastasis to the liver, co-secretion of other hormones such as ACTH, and overexpression of growth factors. The size of the tumor is more likely to be a prognostic factor than the actual location, as to whether it originates from the pancreas or the duodenum. Nonetheless, pancreatic gastrinoma is associated with poorer prognosis compared to its its duodenal counterpart.<br/>
'''Educational Objective:''' Pancreatic gastrinoma is associated with worse outcome compared to its its duodenal counterpart.<br/>
'''References:''' Ellison EC, Johnson JA. The Zollinger-Ellison syndrome: a comprehensive review of historical, scientific, and clinical considerations. Curr Probl Surg. 2009;46(1):13-106.<br>
First Aid 2014 page 329 +
Using the blinded technique, the cardiologist is reducing observer bias (also known as experimenter's bias or researcher's bias). Observer bias is defined as a bias due to the presence of a pre-existing knowledge among the physician/researcher that unconsciously alters results to change the study's outcome. Observer bias is also seen in clinical trials when an investigator knows beforehand which group of subjects is receiving a specific medication; this knowledge might unconsciously influence investigator to alter his findings to match the study's expectations. In this vignette, the cardiologist is documenting his findings blindly to reduce the observer-expectancy effect induced by observer bias.<br/>
'''Educational Objective:''' An example of observer bias is when the researcher is aware beforehand of what to expect and is unconsciously influenced by his knowledge. Blind experimentation reduces observer bias.<br/>
'''References:''' First Aid 2014 page 55 +
While facing situations of non-adherence, physicians must be very careful about their approach. Discussing the non-adherence in a non-judgmental tone prevents offending the patient or breaking his/her trust, which further worsens non-adherence. Accordingly, the physician must attempt to understand the patient's concerns in order to address them objectively and effectively. It is important to ask about the reasons and barriers that may be preventing the patients adherence to medications. It is important not to ask directed or closed-ended questions that tend to be judgmental by jumping to personal conclusions about the situation.<br/>
'''Educational Objective:''' Identifying the patient's concerns and reasons for discontinuing medications is the best initial approach in cases of non-adherence.<br/>
'''References:''' Delamater A. Improving Patient Adherence. Clinical Diabetes. 2006;24(2):71.<br>
First Aid 2014 page 61 +
Regardless of how benign or how serious a medical error is, disclosure of that error and a clear explanation of the circumstances that led to it is an ethical obligation. The physician must also be clear about the severity of the error and what consequences may arise from it. In the case of an adult patient (above 18 years of age), the physician must only share the information with the patient himself; involvement of a third party is considered a breach to the patient's confidentiality. In some cases, the hospital may offer reimbursement to the patient; however, the physician is never to offer monetary compensation to the patient.<br/>
'''Educational Objective:''' A physician must always inform the patient when a medical error is made.<br/>
'''References:''' Association AM. Code of Medical Ethics, 2014-2015. Amer Medical Assn; 2014. +
Hereditary spherocytosis (HS) is an autosomal dominant genetic disorder characterized by round, deformed red blood cells (RBC) due to red cell membrane defect. The RBC loses its biconcave shape and takes on a spherical shape that predisposes it to rupture and splenic sequestration. These RBC abnormalities are responsible for the clinical manifestations of the disease: anemia and jaundice secondary to the hemolysis, and splenomegaly secondary to sequestration of RBCs in the spleen. Blood work-up typically reveals low hemoglobin with elevated MCHC, and elevated levels of unconjugated bilirubin. Diagnosis of HS is by peripheral smear that shows the pathognomonic spherical RBCs. For most patients with HS, splenectomy is curative. Because HS is an autosomal dominant disorder, patients usually have a positive family history of the disease. In these patients, elevated bilirubin due to hemolysis predisposes to gallbladder stones that increase the risk of cholecystitis. As such, patients may present with a very positive family history of cholecystectomies.<br/>
'''Educational Objective:''' Young patients presenting with jaundice, splenomegaly, and anemia with a positive family history for cholecystectomies should raise the suspicion for hereditary spherocytosis.<br/>
'''References:''' Shah S, Vega R. Hereditary spherocytosis. Pediatr Rev. 2004;25(5):168-72. +
Contraction of muscle cells requires 2 co-factors: adenosine triphosphate (ATP) and calcium (Ca). While ATP provides the energy necessary for the contraction to occur, Ca is required to block the binding of myosin to actin. Physiologically, troponin is responsible for exposing the actin-myosin binding sites by shifting the position of tropomyosin away from the myosin-binding sites on actin.
As binding sites are uncovered, myosin can bind to actin. The process of "cross-bridge" cycling thus begins. Cycling releases energy from ATP in the form of adenosine diphosphate (ADP) and phosphate. In the absence of ATP, however, this energy-dependent cycling process may not occur. As such, the absence of ATP marks a phenomenon called "rigor mortis", where the muscles are continuously contracted due to the sustained actin-myosin binding.<br/>
'''Educational Objective:''' Tropomyosin plays a role in covering the myosin-binding sites on actin.<br/>
'''References:''' Krans JL. The sliding filament theory of muscle contraction. Nature Education. 2010; 3(9):66 +
In contrast to skeletal troponin, cardiac troponin contains more amino acids. There are approximately 33 additional amino acids found in cardiac troponin. The extra number of amino acids are located at the N-terminus. These additional amino acids are most significant for the presence of 2 adjacent serine residues that are phosphorylated by protein kinase A when cardiac cells are stimulated by beta-agonists.<br/>
'''Educational Objective:''' Cardiac troponin contains 33 additional amino acids compared to skeletal troponin. These additional amino acids are most significant for the presence of 2 adjacent serine residues that are phosphorylated by protein kinase A when cardiac cells are stimulated by beta-agonists.<br/>
'''References:''' Zhang R, Zhao J, Mandveno A, Potter J. Cardiac troponin I phosphorylation increases the rate of cardiac muscle relaxation. 1995;76:1028-1035.<br>
First Aid 2014 page 217 +
Approximately 80% of patients with idiopathic membranous glomerulopathy (MGN or membranous nephropathy) present with nephrotic syndrome. A minority of patients have sub-nephrotic-range proteinuria at presentation. Patients may also have microscopic hematuria. The finding of gross hematuria, on the other hand, is unlikely in MGN, and generally suggests the need to search for alternative diagnoses. However, gross hematuria has nonetheless been described in MGN. Kidney biopsy is the gold standard for the diagnosis of MGN. On light microscopy, kidney biopsy typically demonstrates capillary wall thickening with normal cellularity. Immunofluorescence is remarkable for IgG and C3 deposits along the capillary walls. Electron microscopy shows exclusively subepithelial deposits between podocyte foot processes. IgG subtypes present on immunofluorescence may be helpful in differentiating idiopathic vs. secondary causes of MGN. In primary idiopathic MGN, the IgG4 subtype of IgG is most commonly observed, comprising approximately 80% of all idiopathic cases. However, this is not true for secondary causes of MGN. Although other features on renal biopsy are common between the 2 forms, IgG1, 2, and 3 are more commonly observed in secondary MGN. Furthermore, the location of the deposits may also provide clues to the diagnosis. While deposits in primary MGN are exclusively observed in the subepithelial region, deposits in secondary MGN may involve both the subepithelial and subendothelial regions of the capillary wall.<br/>
'''Educational Objective:''' IgG subclass on immunofluorescence may differentiate primary vs. secondary membranous nephropathy. IgG4 is associated with primary membranous nephropathy, whereas IgG1, 2, and 3 are more commonly associated with secondary membranous nephropathy.<br/>
'''References:''' Jennette JC, Iskandar SS, Dalldorf FG. Pathologic differentiation between lupus and nonlupus membranous glomerulopathy. Kidney Int. 1983; 24(3):377-85.<br>Ohtani H, Wakui H, Komatsuda A, et al. Distribution of glomerular IgG subclass deposits in malignancy-associated membranous nephropathy. Nephrol Dial Transplant. 2004; 19(3):574-9.<br>
Polanco N, Gutierrez E, Covarsi A, et al. Spontaneous remission of nephrotic syndrome in idiopathic membranous nephropathy. J Am Soc Nephrol. 2010; 21(4):697-704.<br>Menon S, Valentini RP. Membranous nephropathy in children: clinical presentation and therapeutic approach. Pediatr Nephrol. 2010; 25(8):1419-28.<br>
First Aid 2014 page 536
The patient presents with clinical and radiological features typical of osteoid osteoma. The disease is often diagnosed based on findings during history-taking and physical examination when a high index of suspicion is present. Typically, patients are adolescent males, presenting with a painful lesion in the proximal femoral area (most common), the tibia, the spine, or even the hands. One classical finding is the reported dramatic relief to aspirin and other NSAIDs, which sometimes may be diagnostic of the disease, but pathological findings may still be necessary. Imaging of osteoid osteoma usually reveals Osteoid osteoma shows a well-circumscribed neoplasm independent of bone around it with growth of osteoid tissue within it.<br/>
'''Educational Objective:''' Osteoid osteoma is a neoplasm of the bone, most commonly presenting among adolescent males as a painful lesion in the proximal femur with dramatic relief upon aspirin administration. Imaging of lesions reveals an osteolytic radiopaque zone of dense homogenous bony sclerosis surrounding a central nidus.<br/>
'''References:''' Cohen MD, Harrington TM, Ginsburg WW. Osteoid osteoma: 95 cases and a review of the literature. Seminars in Arthritis and Rheumatism. 1983;12(3):265-281. +
Dermatomyositis is an inflammatory myopathy characterized by symmetric proximal and truncal weakness with or without associated pain. Physical examination is typically remarkable for Gottron papules (violaceous flat-topped papules and plaques in the dorsal aspect of the hand) and characteristic heliotrope rash (periorbital violaceous erythema with periorbital edema). Work-up often demonstrates elevation of muscle biomarkers, such as creatine kinase. Pathologically, dermatomyositis is considered a perimysial inflammation with lymphocytic infiltration that is generally confined to the septa. Dermatomyositis has a bi-modal peak incidence. In adult patients > 50 years of age, the diagnosis of dermatomyositis prompts the investigation of a malignancy due to frequent association. This is not true, however, for those diagnosed at young age.<br/>
'''Educational Objective:''' Dermatomyositis is characterized by perimysial inflammation.<br/>
'''References:''' Khan S, Christopher-Stine L. Polymyositis, dermatomyositis, and autoimmune necrotizing myopathy: clinical features. Rheum Dis Clin N Am. 2011; 37:143-158.<br
Dalakas M. Polymyositis, dermatomyositis, and inclusion-body myositis. N Engl J Med. 1991; 325:1487-1498.<br>
First Aid 2014 page 429. +
Gout is the most common inflammatory arthritis in men. It is characterized by the deposition of monosodium urate (MSU) crystals and is associated with hyperuricemia (overproduction of urate or underexcretion of urate by the kidneys). Blood concentration of uric acid is typically higher than 6.8 mg/dL in gout. Beyond this concentration, uric acid is not soluble anymore in physiologic condition. Gout has 2 phases: The first phase is characterized by episodic attacks, each lasting 1-2 weeks. The second phase occurs secondary to an untreated initial phase, whereby patients progress to chronic tophaceous gout with polyarticular attacks. While patients remain asymptomatic between attacks in the first phase, they are symptomatic between attacks in the second phase. Alcohol may induce hyperuricemia, and hyperuricemia has often been used as a marker of alcohol intake. Among alcohol beverages, beer is the most strongly associated with recurrence of gouty attacks; probably due to its high content of guanosine, which is a highly absorbable purine when compared with other nucleosides. Intake of two or more beers per day is associated with a two-fold increased risk of development of gout.<br/>
'''Educational Objective:''' Gout is characterized by the deposition of monosodium urate (MSU) crystals and is associated with hyperuricemia (overproduction of urate or underexcretion of urate by the kidneys). Beer intake is associated with the development of gout.<br/>
'''References:''' Choi HK, Atkinson K, Karlson EW. et al. Alcohol intake and risk of incident gout in men: a prospective study. The Lancet. 2004;363:1277-81.<br>
Neogi T. Gout. N Engl J Med. 2011; 364:443-452.<br>
First Aid 2014 page 425 +
Ewing's sarcoma is the second most common bone tumor in children and adolescents. It is a malignant condition that is typically located in the diaphysis of the long bones. Ewing's sarcoma is part of Ewing's sarcoma family of tumors (ESFT), which includes several tumors: Ewing's sarcoma, Askin tumor, and peripheral primitive neuroectodermal tumor. Ewing's sarcoma has a high rate of rapid metastasis, but chemotherapy has greatly contributed to the survival of patients with Ewing's sarcoma. Before chemotherapy, only 10% of patients survived, but now the majority of patients with primary local tumors survive. Ewing's sarcoma is optimally diagnosed by biopsy of the mass, which typically demonstrates small round blue "onion" cells. Molecular findings in Ewing's sarcoma typically show a t(11,22) chromosomal translocation, which results in the formation of ''EWS-FL11'' fusion gene. Normally, the ''EWS'' gene (chromosome 22) encodes an RNA-binding proteins, whereas ''FL11'' gene (chromosome 11) encodes a protein with a DNA-binding domain.<br/>
'''Educational Objective:''' Ewing's sarcoma is characterized by a t(11,22) chromosomal translocation that results in the formation of a ''EWS-FL11'' fusion gene.<br/>
'''References:''' Balamuth N, Womer RB. Ewing's sarcoma. Lancet Oncol. 2011; 11:184-92.<br>
Image Attribution: Ewing sarcoma - PAS - very high mag.jpg by user:Nephron on commons.wikimedia.org under the terms of the GNU Free Documentation License v1.2 licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license. Retrieved on 6-March-2015.<br>
First Aid 2014 page 422 +
Following cardiac catheterization and stent placement, patients are usually prescribed dual antiplatelet therapy (DAPT). With drug-eluting stents (DES), patients are usually prescribed clopidogrel ideally for 12 months along with life-long aspirin therapy. In contrast, patients who receive bare metal stents receive a shorter duration of dual antiplatelet therapy, where clopidogrel administration is limited to only one month (while aspirin is still continued for life). While drug-eluting stents are associated with a reduced risk of stent thrombosis, the limited duration of dual antiplatelet therapy with bare metal stents may be beneficial among patients who are at very high risk of bleeding, such as those alreay receiving other forms of anticoagulation for other diseases (e.g. patients with atrial fibrillation who are already receiving warfarin therapy). Accordingly, limited antiplatelet therapy with clopidogrel is associated with a reduced risk of bleeding among these patients. To date, aspirin is indicated in all patients for the secondary prevention of acute coronary syndromes (ACS), which includes STEMI, NSTEMI, and unstable angina. Aspirin is an irreversible inhibitor of cyclooxygenase (COX1 and COX2) that acts by the process of covalent acetylation. It reduces thromboxane A2 synthesis and prolongs bleeding time, without affecting the prothrombin time (PT) or partial thromboplastin time (PTT). Platelet dysfunction with aspirin therapy is described as functional, i.e. there is no actual decrease in the numbers of platelet count, but patients have a reduced platelet function and are thus at high risk of bleeding. Recently and with the introduction of novel oral factor Xa anticoagulants (NOACs), a novel "dual pathway" approach (thrombin inhibition by factor Xa inhibitors along with platelet inhibition) is currently being evaluated for the secondary prevention of ACS and may replace the traditional "dual antiplatelet" approach (aspirin plus thienopyridine).<br/>
'''Educational Objective:''' Patients receiving aspirin typically have a prolonged bleeding time with normal PT, PTT, and platelet counts. Aspirin is associated with platelet dysfunction without affecting the actual platelet count.<br/>
'''References:''' First Aid 2014 page 439
The patient is presenting with signs and symptoms consistent with gout. Given his alcohol history, the location and asymmetric nature of the joint pain (left great toe), and elevated concentrations of uric acid and CRP, the diagnosis of gouty attack is very likely. Febuxostat is a new non-purine, xanthine oxidase inhibitor that is more potent than allopurinol. In comparison, allopurinol is a xanthine oxidase inhibitor that contains a purine ring. Xanthine oxidase is an enzyme that metabolizes 2 consecutive reactions in the pathway of uric acid degradation. Xanthine oxidase inhibition results in a reduced rate of hypoxanthine conversion to xanthine and similarly, xanthine conversion to plasma uric acid.<br/>
'''Educational Objective:''' Febuxostat is a potent non-purine xanthine oxidase inhibitor indicated for the management of gout.<br/>
'''References:''' Edwards L. Febuxostat: a new treatment for hyperuricaemia in gout. Rheumatology. 2009; 48(2):ii15-ii19.<br>
First Aid 2014 page 441 +
The patient is presenting with signs and symptoms consistent with exercise-induced asthma. Antileukotrienes, such as montelukast and zafirlukast, are leukotriene receptor antagonists that have demonstrated efficacy among patients with exercise-induced asthma and aspirin-induced asthma.<br/>
'''Educational Objective:''' Leukotriene receptor inhibitors, such as montelukast and zafirlukast, are indicated in exercise-induced asthma and aspirin-induced asthma.<br/>
'''References:''' First Aid 2014 page 614 +
The patient is undergoing the methacholine challenge test that helps in the diagnosis of asthma. Methacholine is a crystalline powder that is stored at cold temperatures before use. As described in the vignette, it is mixed with saline containing 0.4% phenol using a sterile technique. Methacholine is a synthetic derivative of acetylcholine that is metabolized much slower than acetylcholine by cholinesterase. Its effect can nonetheless be blocked or reduced by atropine or other anticholinergic agents with bronchodilating action. Serious adverse events are considered rare during methacholine challenge test, but precaution should still be considered regardless of how rare they are. For safety precautions, oxygen and bronchodilators must always be present nearby in the testing area at all times during the procedure. Bronchodilators may be any of epinephrine, atropine, albuterol, or ipratropium. Contraindications to the methacholine challenge test include severe airflow limitations and cardiovascular conditions (such as history of prior myocardial infarction, recent stroke, uncontrolled hypertension, or aortic aneurysm). Other relative contraindications include moderate airflow limitations, pregnancy or nursing, use of cholinesterase inhibitors, and inability to perform acceptable spirometry.<br/>
'''Educational Objective:''' Either atropine or similar fast-acting bronchodilators (epinephrine, B2 agonists, or ipratropium) along with oxygen supplementation must always be available and ready to prevent serious bronchoconstrictive adverse events during methacholine challenge testing.<br/>
'''References:''' Crapo RO, Casaburi R, Coates AL, et al. Guidelines for methacholine and exercise challenge testing - 1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med. 2000;161(1):309-29.<br>
First Aid 2014 page 614 +
Myasthenia gravis (MG) is an autoimmune disorder characterized by a decrease in the numbers of the acetylcholine receptors at the neuromuscular junction. Physiologically, acetylcholine binds to its cationic receptor, which in turn, is stimulated to open temporarily, and an electrical potential is generated when the receptors open. The electrical potentials in the end-plate normally generate enough power to cause an action potential given the abundance of available receptors. In patients with MG, the decreased available receptors fail to produce sufficient electrical power to generate an action potential. MG manifests with symptoms of neuromuscular fatigue, whereby repeated contractions result in a progressive decrease of transmission of electric signals following repetitive stimulation ("acetylcholine rundown" phenomenon). The quantity of receptor loss is associated with a more severe disease and worse outcomes among patients with MG. The immunopathogenesis of MG is based on the presence of antibodies that target acetylcholine receptors at the post-synaptic neuromuscular junction. However, the amount of acetylcholine receptor antibodies is not associated with the severity of the disease or worse outcomes.<br/>
'''Educational Objective:''' Myasthenia gravis (MG) is an autoimmune disorder characterized by a decrease in the numbers of the acetylcholine receptors at the neuromuscular junction. The concentration of IgG antibodies that target acetylcholine receptors is not associated with the severity of the disease.<br/>
'''References:''' Drachman DB. Myasthenia gravis. N Engl J Med. 1994; 330:1797-1810.<br>
First Aid 2014 page 429 +
Minoxidil is a potent vasodilator indicated for the management of hypertension. Although initially manufactured for its antihypertensive effects, it was then discovered to cause hair growth. Topical minoxidil is currently manufactured and indicated for male pattern baldness. Compliance with the topical agent is difficult because it requires daily application, whereas the sustained benefit is only observed if the drug is applied daily and consistently. Oral minoxidil is still used for severe refractory cases of hypertension; although its use has generally decreased given the availability of other potent and safer drugs and its association with serious cardiac adverse events.<br/>
'''Educational Objective:''' Topical minoxidil may be applied daily to treat male-pattern baldness. In contrast, oral minoxidil is indicated for severe refractory hypertension.<br/>
'''References:''' Storer JS, Brzuskiewicz J, Floyd H, et al. Topical minoxidil for male pattern baldness. Am J Med Sci. 1986;291(5)<br> +