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Lyme disease is a multi-organ disease that involves the skin, nervous system, the heart, and the musculoskeletal system. It is an infectious disease caused by the spirochete ''Borrelia burgdorferi'', whose natural reservoir is mainly mice. ''B. burgdorferi'' is transmitted to humans by ''Ixodes'' tick bite. Characteristically, tick bites are non-painful, and ticks may persist on human skin for several days. For transmission of the infection to occur, the tick needs to bite the skin for at least one day. Lyme disease is a common infection in Europe and Northeast USA during the summer and spring.
Lyme disease may be classified clinically into 3 stages based on chronological progression:
*Early Lyme disease: Characterized by erythema migrans (bull's eye lesion), which is the pathognomonic skin lesion of early Lyme disease. Onset is usually between 3 and 30 days following tick bite. The most common location of erythema migrans is the lower extremities and the trunk. Patients with typical erythema migrans are generally administered empirical doxycycline with no need for further diagnostic work-up.
*Secondary (disseminated) Lyme disease: Characterized by the presence of neurological, cardiac, and rheumatic manifestations that may present anytime within weeks to several months (typically up to 6 months). Neurological manifestations include meningitis, encephalitis, radicular pains, flaccid palsy, and sensory abnormalities. Cardiac manifestations usually appear earlier than neurological manifestations and include atrioventricular blocks, pericarditis, and rarely, pancarditis. Finally, rheumatic manifestations include bone and joint pain with possible edema and effusions of the large joints.
*Tertiary (chronic) Lyme disease: Characterized by chronic symptoms that are usually present several after following an infection that was not adequately treated. Manifestations may include persistent join pain and edema, chronic progressive encephalomyelitis, memory impairment, and chronic peripheral neuropathy. Chronic Lyme disease may be present even when the organism that caused the initial infection has been cleared.
The diagnosis of Lyme disease is made clinically when patients report exposure to ticks and present with typical erythema migrans on physical examination. In contrast, disseminated disease is more difficult to diagnose, and serological testing is necessary with a two-step approach: First, a high-sensitivity ELISA (sensitive) followed by Western blot assay (specific) if ELISA yields positive results. IgM levels typically start to appear 2-4 weeks after infection. Early Lyme disease, early disseminated disease, and Lyme disease with cranial nerve palsy but normal CSF work-up are optimally treated with tetracycline antibiotics (eg doxycyline). Tetracyclines act by blocking entry of aminoacyl tRNAs into the bacterial ribosome, thereby inhibiting protein synthesis. Tetracyclines are contraindicated in children < 8 years of age, pregnant, and lactating women due to its association with teeth discoloration. Instead, these patients should be prescribed amoxicillin, which is the second-line agent for treatment of Lyme disease.<br/>
'''Educational Objective:''' Tetracyclines are antibiotics that act by inhibiting aminoacyl tRNA entry into ribosome. Tetracyclines are the optimal pharmacologic therapy to treat Lyme disease in adult patients.<br/>
'''References:''' Biesiada G, Czepiel J, Lesniak MR, et al. Lyme disease: a review. Arch Med Sci. 2012;8(6):978-82.<br>
First Aid 2014 page 141
The patient in this vignette is suffering from myoclonic epilepsy with ragged red fibers (MERRF). It involves the following characteristics: progressive myoclonic epilepsy, short stature, hearing loss, lactic acidosis, exercise intolerance, and poor night vision. Muscle biopsy of affected patients will demonstrate clumps of diseased mitochondria and appear as ragged red fibers on trichome stain. Because MERRF is a mitochondrial condition, it can only be inherited through the mother. The severity of the patient’s symptoms depends on the proportion of mutated mitochondria the fertilized egg contains. Expressivity refers to the range of symptoms a patient shows. Heteroplasmy is the presence of a mixture of more than one type of an mitochondrial genome within a cell or individual. Some individuals and even particular tissues within certain individuals will differ in the proportion of mitochondria carrying a mutant allele. Thus, the variable phenotype of MERRF can be caused by differing proportions of mutant mitochondria.<br/>
'''Educational Objective:''' The variable phenotype of MERRF can be caused by differing proportions of mutant mitochondria in different patient’s tissues.<br/>
'''References:''' First Aid 2014 page 86 +
Gastrointestinal stromal tumor (GIST) is a rare non-epithelial neoplasm of the GI tract, the mesentary, or the omentum. The majority of GIST tumors are spindle cell tumors that may be either malignant or benign. Most stromal tumors stain positively for C-Kit/CD117 (>90%), CD34, muscle-specific actin, smooth muscle actin, S-100, and desmin. Patients with GIST may be asymptomatic or have non-specific GI symptoms. This patient's symptoms of dull epigastric pain, fatigue, and weight loss, in conjunction with the CT finding of a mass in the stomach, are suggestive of malignancy. Characteristically, the pathogenesis of GIST tumors involves a gain-of-function mutation in the ''KIT'' proto-oncogene, which encodes a transmembrane receptor for stem cell factor that includes a tyrosine kinase component in its intracytoplasmic region.<br/>
'''Educational Objective:''' Gastrointestinal stromal tumor (GIST) is a rare non-epithelial neoplasm of the GI tract, the mesentary, or the omentum. The majority of GIST tumors are spindle cell tumors that may be either malignant or benign. Most stromal tumors stain positively for C-Kit/CD117<br/>
'''References:''' Din OS, Woll PJ. Treatment of gastrointestinal stromal tumor: focus on imatinib mesylate. Ther Clin Risk Manag. 2008;4(1):149-62.<br>
First Aid 2014 page 232 +
Burkitt's lymphoma is an aggressive B-cell non-Hodgkin's lymphoma caused by a translocation that results in the expression of the ''C-MYC'' oncogene, a transcription factor that has a role in the regulation of cell cycle. The tumor has been associated with the translocation t(8;14) among the majority of cases (85%) and translocations t(2;8) or t(8;22) in fewer than 20% of cases. Burkitt's lymphoma is characterized by a high proliferative potential and rapid turnover with a doubling time that is as fast as 24-48 hours. It is considered to be one of the fastest growing tumors. Burkitt's lymphoma is also the first malignancy to be associated with a virus, where EBV has been observed to have a direct causative role in the development of the tumor by immortalising B-cells.
Burkitt's lymphoma is common among children. It is classified into 3 types based on the geographical distribution, its association with infectious agents, and clinical presentation: The sporadic type is the most common type in USA and Europe and is rarely associated with EBV. It usually manifests with an abdominal or pelvic tumor; and patients typically complain of vague abdominal pain, nausea, and early satiety. The endemic type is common in regions with malaria endemicity (e.g. central Africa) and has been associated with EBV in almost all cases. Manifestations of endemic-type Burkitt's lymphoma usually include jaw or periorbital swelling, especially among children between the age 3 to 7 years. Finally, the immunodeficiency-type is common among patients with early HIV infection (CD4 > 200 cells/mm<sup>3</sup>). In this vignette, the patient is most likely diagnosed with endemic-type Burkitt's lymphoma given his age, his recent immigration from Africa, and the location of his tumor involving the jaw.
On histopathological analysis, Burkitt's lymphoma appears as monomorphic, medium-sized cells that have a high rate of turnover. A "starry sky" appearance is observed due to the presence of apoptotic tumor cells within tingible-body-laden macrophages on microscopy. Tumor cells are usually B-cells that express CD10, CD20, and CD79a. EBV RNA may also be expressed and identified on fluorescence in-situ hybridisation (FISH). The prognosis of Burkitt's lymphoma is mainly based on the stage of the tumor at diagnosis. Treatment of localized disease consists of surgical resection and chemotherapy, whereas more advanced cases require chemotherapy only.<br/>
'''Educational Objective:''' Burkitt's lymphoma is an aggressive B-cell non-Hodgkin's lymphoma caused by a translocation that results in the expression of the ''C-MYC'' oncogene, a transcription factor that has a role in the regulation of cell cycle.<br/>
'''References:''' Molyneux EM, Rochford R, Griffin B, et al. Burkitt's lymphoma. Lancet. 2012; 379:1234-44.<br>
First Aid 2014 page 232
Hemophilia A is an an X-linked recessive bleeding disorder caused by a deficiency of clotting factor VIII. Given its mode of inheritance, hemophilia generally affects males only. Factor VIII normally promotes the function of the intrinsic coagulation cascade and enhances thrombin generation and fibrin formation. Factor VIII is bound to von-Willebrand factor (vWF), which protects factor VIII against degradation. Hemophilia A may be clinically classified according to severity into 3 groups:
*Severe: Factor VIII < 1 % of normal. Patients often have spontaneous excessive bleeding.
*Moderate: Factor VIII % ranges between 2 to 5 % of normal. Patients bleed excessively with minor trauma, dental procedures, or surgery.
*Mild: Factor VIII % ranges between 5 to 40 % of normal.
Excessive and prolonged bleeding following circumcision may be the first sign of hemophilia. Other clinical features of hemophilia include hemarthrosis (bleeding within synovial joints), intracranial bleeding, and unexplained bruising when infants start to crawl. Patients typically have an abnormal bleeding profile that demonstrates a prolonged aPTT with normal PT and bleeding time. The diagnosis of hemophilia is made when plasma levels of factors demonstrate severe deficiency. Nonetheless, hemophilia needs to be distinguished from other diseases that might also cause bleeding and factor VIII deficiency, such as Normandy-type (2N) von Willebrand disease that is characterized by bleeding in both males and females due to a binding defect between factor VIII and vWF. Patients with hemophilia are recommended to prophylactically receive recombinant clotting factors. In regions with no capacity to provide prophylactic management to hemophiliacs, on-demand therapy should be administered as soon as possible to prevent major bleeding events and irreversible sequelae. Bleeding can be controlled with infusions of the deficient clotting factor, i.e. factor VIII in hemophilia A and factor IX in hemophilia B. For patients with mild disease, intranasal or intravenous infusion of desmopressin has demonstrated efficacy by increasing the plasma concentration of factor VIII. Accordingly, desmopressin may be administered in hemophilia A but not hemophilia B.<br/>
'''Educational Objective:''' Hemophilia A is an an X-linked recessive bleeding disorder caused by a deficiency of clotting factor VIII.<br/>
'''References:''' Fijnvandraat K, Cnossen MH, Leebeek FW, et al. Diagnosis and management of haemophilia. BMJ. 2012;344:e2707.<br>
First Aid 2014 page 88, 389
Acute exposures to sound pressure levels above 180 dB result in traumatic rupture of the tympanic membrane and conductive hearing loss. The rupture should repair spontaneously unless infection occurs. If the loss persists for more than 3 months, surgical repair is possible.
'''Educational Objective:'''
Acute exposures to sound pressure levels above 180 dB result in traumatic rupture of the tympanic membrane and a temporary conductive hearing loss, which reverses either spontaneously or by surgical repair.<br/>
'''Educational Objective:''' <br/>
'''References:''' +
The vignette describes the classical properties of vasopressin or antidiuretic hormone (ADH). Vasopressin has 2 main functions dictated by their receptors. Type 1 receptors or AVPR1 are found in most organs, particularly in the peripheral vasculature. Activation of AVPR1 results in vasoconstriction in states of reduced plasma volume. In contrast, type 2 receptors or AVPR2 are found on the basolateral membrane of the epithelial cells lining the renal collecting ducts. AVPR2 are activated in response to thirst, reduced plasma volume, and increased osmolarity to stimulate water reabsorption. Vasopressin binding to type 2 receptors activates a cAMP-mediated pathway that triggers the insertion of aquaporins (AQP2) on the luminal surface of the collecting tubules at the level of the kidney. Aquaporins are water channels that only allow water to be reabsorbed resulting in an increased urine concentration. Vasopressin is produced by magnocellular neurosecretory neurons in the supraoptic nucleus on the hypothalamus and are conducted via axonal projection to the posterior pituitary (hence the name neurohypophysis).
This model replicates the syndrome of inappropriate ADH (SIADH) usually caused by pulmonay diseases, CNS disturbances, severe illnesses, and as an adverse effect of certain medications. The most prominent feature of SIADH is hyponatremia.<br/>
'''Educational Objective:''' ADH/Vasopressin causes water reabsorption by binding to its type 2 ADH receptors located at the basolateral aspect of the collecting tubules.<br/>
'''References:''' Verbalis JG. An experimental model of syndrome of inappropriate antidiuretic hormone secretion in the rat. Am J Physiol. 1984;247(4 Pt 1):E540-53.
First Aid 2014 page 311 +
Prednisone is a more potent formulation of the endogenous glucocorticoid cortisol. With chronic administration, patients develop characteristic changes associated with excess glucocorticoids that are collectively known as Cushing's syndrome. Patients classically have symptoms of weight gain, abdominal obesity, and proximal muscle weakness. Physical exam reveals peripheral muscle atrophy, acanthosis nigricans, dorsocervical fat pad (buffalo hump), and purple abdominal skin striae. Patients are at increased risk for osteoporosis.
Glucocorticoids have several functions, most important of which relates to suppression of the immune system. Glucocorticoids cause arrest of all pro-inflammatory pathways leading to a decrease in leukotrienes and prostaglandins, inhibition of histamine release, decrease in eosinophils and lymphocytes, and inhibition of leukocyte adhesion (cause for peripheral neutrophilia). Other functions include maintenance of blood pressure and increase in lipolysis and gluconeogenesis. Glucocorticoids also alter the production of cytokines, causing a decrease in pro-inflammatory molecules such as IL-1, IL-2, IL-6 and an increase in anti-inflammatory or regulatory cytokines, such as IL-10 and TGF-β.<br/>
'''Educational Objective:''' Glucocorticoids cause an increase in anti-inflammatory cytokines such as IL-10 and TGF-β.<br/>
'''References:''' Nakagawa M, Terashima T, D'yachkova Y, Bondy GP, Hogg JC, Van Eeden SF. Glucocorticoid-induced granulocytosis: contribution of marrow release and demargination of intravascular granulocytes. Circulation. 1998;98(21):2307-13.<br>
Hoes JN, Jacobs JW, Verstappen SM, Bijlsma JW, Van der heijden GJ. Adverse events of low- to medium-dose oral glucocorticoids in inflammatory diseases: a meta-analysis. Ann Rheum Dis. 2009;68(12):1833-8.<br>
First Aid 2014 page 332 +
Hyperthyroidism is caused by excessive production or release of T3/T4 from the thyroid gland most often from primary thyroid gland dysfunction and rarely from secondary, central disturbance. Classical symptoms of hyperthyroidism include anxiety, irritability, perspiration, palpitations, tachycardia and possible atrial arrhythmia, hypertension, heat intolerance, warm and moist skin, tremor, lid lag, weight loss, and menstrual abnormalities. Patients with Grave's disease (thyroid gland stimulating TSH receptor antibodies) may also have exophthalmus due to retro-orbital accumulation of glycosaminoglycans, periorbital edema, and pretibial myxedema (mucin accumulation in the dermis).
Thyroid hormones have multiple functions that are executed by binding intra-nuclear receptors. The most important functions are related to an increase in basic metabolic rate including increase in Na<sup>+</sup>/K<sup>+</sup> ATPase activity, glycogenolysis, gluconeogenesis, and lipolysis. T3 increases the expression of β1 receptors on cardiomyocytes. This leads to an increase in contractility, cardiac output, stroke volume, and heart rate.<br/>
'''Educational Objective:''' Thyroid hormones cause an increase in basic metabolic rate including increase in Na<sup>+</sup>/K<sup>+</sup> ATPase activity, glycogenolysis, gluconeogenesis, and lipolysis. T3 increases the expression of β1 receptors on cardiomyocytes. This leads to an increase in contractility, cardiac output, stroke volume, and heart rate.<br/>
'''References:''' Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med. 2001;344(7):501-9.<br>
Yen PM. Physiological and molecular basis of thyroid hormone action. Physiol Rev. 2001;81(3):1097-142. +
Pulmonary tuberculosis (TB) is a global pandemic that commonly affects individuals living in or recently immigrated from developing countries, homeless individuals, healthcare workers, elderly patients, immunocompromised patients, and patients who are administered TNF-alpha inhibitors. Pulmonary TB manifests as a subacute process with worsening, non-productive cough that lasts for more than 3 weeks along with constitutional symptoms, such as fever, gradual weight loss, night sweats, and malaise. In advanced cases, patients develop gradual dyspnea and hemoptysis; but these 2 features are less likely to be initially present. The diagnosis of pulmonary TB is often suspected upon history-taking and physical examination. Chest radiograph typically shows upper lobe zones of infiltration that may be associated with cavitation. Nonetheless, these radiographic findings may not be present in cases of primary TB infection or in immunocompromised patients, as they are more typical of TB reactivation. The diagnosis is then confirmed by direct smear examination of sputum samples, which demonstrate positivity upon acid-fast-bacilli staining (eg. Ziehl-Neelson stain that uses carbol fuchsin and phenol). Other diagnostic modalities include sputum culture, which requires special techniques (ie. Lowenstein-Jensen agar and might take 1-8 weeks before results return). Novel molecular diagnostic techniques, such as PCR, are also available. Unfortunately, not all patients have sputum samples that yield positive results. In these cases, physicians use the combination of clinical features, radiographic findings, and tuberculin-skin testing/interferon-gamma release assay (IGRA) to make the diagnosis.
''M. tuberculosis'' is a unique organism that multiplies within macrophages in pulmonary alveoli. As the organism invades the macrophages, the immune system is activated (coordinated by cell-mediated immunity, which are T-cell lymphocytes that release interferons and lymphokines, and executed by macrophages). When engulfed in macrophages, ''M tuberculosis'' is able to grow intracellularly and evade the phagosome-lysosome complex. Eventually cell lysis occurs, and the organism moves another macrophage. As it grows, ''M. tuberculosis'' is transported into lymph nodes, which become inflamed (primary complexes). Approximately 6 weeks following initial infection, the tuberculin growth stops and caseous necrosis occurs at the time the immunocompetent host develops cell-mediated immunity and delayed-type hypersensitivity. Caseous (cheese) necrosis is a necrosis of the exudative alveolar lesions due to alveolar injury. It develops by the action of the cytotoxic T-cells that kill macrophages infected with ''M. tuberculosis'', resulting in collateral destruction of the surrounding tissue. The destructive process results in a acellular, cheese-like debris in the center of the granuloma which contains dead tubercle bacilli, activated macrophages, CD4 helper T cells and multinucleated giant cells. The cheese-like appearance of caseous necrosis is due to the presence of lipids from the tubercle bacilli within the necrosis. The majority of immunocompetent patients infected with ''M. tuberculosis'' are capable of containing the infection with the help of the host cell-mediated immunity. In these individuals, TB fails to progress and remains latent. Caseous necrosis is also observed with other infections, such as systemic fungal infections (''Histoplasma capsulatum'', ''Coccidioides immitis'', and ''Blastomyces dermatitidis'').<br/>
'''Educational Objective:''' Caseous (cheese) necrosis is a necrosis of the exudative alveolar lesions due to alveolar injury. It develops by the action of the cytotoxic T-cells that kill macrophages infected with ''M. tuberculosis'', resulting in collateral destruction of the surrounding tissue. The destructive process results in a acellular, cheese-like debris in the center of the granuloma which contains dead tubercle bacilli, activated macrophages, CD4 helper T cells and multinucleated giant cells.<br/>
'''References:''' Campbell IA, Bah-Sow O. Pulmonary tuberculosis: diagnosis and treatment. BMJ. 2006;332:1194-7.<br>
Grosset J. ''Mycobacterium tuberculosis'' in the extracellular compartment: an underestimated adversary. Antimicrob Agents Chemother. 2003;47(3):833-6.<br>
First Aid 2014 page 134
Cataract is the progressive and cumulative loss of lens transparency (opacification) that results in vision loss in the affected eye. Cataract is the leading cause of blindness worldwide. It is considered an early complication of diabetes mellitus. The incidence of cataract increases by 2 to 5 times among diabetic patients, and the incidence further increases significantly among diabetics who are diagnosed with diabetes before the age of 40. Patients often complain of light scatter, subjective glare with halos around lights, and vision loss that may affect daily activities such as reading or driving. The pathophysiology of cataracts involves 3 molecular mechanisms: First, non-enzymatic glycation of lens proteins; second, oxidative stress; and third, activation of polyol pathway, which is mediated by the intracellular aldose reductase enzyme, and consequent accumulation of intracellular sorbitol. Excess sorbitol within the fibrils of the lens results in movement of water into the lens fibrils and leads to swelling of the lens fibrils and cataract formation.<br/>
'''Educational Objective:''' The activation of polyol pathway, which is mediated by the intracellular aldose reductase enzyme, and the consequent accumulation of intracellular sorbitol are responsible for the swelling of lens fibrils. This osmotic-induced damage is associated with the development of cataracts among diabetic patients.<br/>
'''References:''' Javadi M, Zarei-Ghanavati S. Cataracts in diabetic patients: a review article. J Ophthalmic Vis Res. 2008;3(1):52-65.<br>
Malone JI, Lowitt S, Cook WR. Nonosmotic diabetic cataracts. Pediatr Res. 1990;27(3):293-6.<br>
Lightman S. Does aldose reductase have a role in the development of the ocular complications of diabetes? Eye. 1993;7:238-241.<br>
First Aid 2014 page 107, 327 +
Primary biliary cirrhosis (PBC) is an autoimmune cholestatic liver disease characterized by the presence of anti-mitochondrial antibodies (AMA). It results in the inflammatory destruction of the intrahepatic bile ducts, fibrosis, and cirrhosis. PBC commonly affects middle-aged women. Diagnosis is often made when 2 out of the following 3 criteria are met: Biochemical evidence of cholestasis (elevated ALP or GGT), presence of disease-specific AMA, or histological feature of PBC. In addition, elevations in IgM levels are often observed in patients and may be helpful in the diagnosis. Patients with PBC (or other autoimmune diseases) are at increased risk of developing other autoimmune diseases. The incidence of rheumatoid arthritis (RA) has been observed to be increased among patients with PBC, and vice versa. Although the pathophysiology for the association is still unclear, studies have suggested several genetic and epigenetic mechanisms for the association of the 2 diseases. Susceptibility loci that involve both HLA and non-HLA regions have been identified and implicated in the pathogenesis of the association between PBC and RA. Development of other autoimmune diseases has also been associated with PBC, including Sjogren's syndrome, systemic sclerosis, and autoimmune thyroiditis.
Most importantly, the patient in the vignette presences with symptoms and signs consistent with RA, such as symmetric morning stiffness and pain of the joints that persist for more than 1 hour and are relieved by movement during the day. Physical examination findings, namely ulnar deviation, boutonniere deformities of the PIP joints, and tender subcutaneous nodules present over the olecranon or the extensor surface of the forearms are characteristic features of RA. Finally, radiographic findings of this patient's joint that demonstrate erosions of the MCP and the PIP joints with sparing of the DIP are classic of RA. Pannus formation of the MCP and PIP joints and Baker cyst, which is a true cyst that is usually present in the popliteal fossa, are also classically observed in RA. Approximately 80% of patients with RA have positive rheumatoid factor (RF), which is an autoantibody against the Fc portion of IgG. RF is a sensitive but non-specific biomarker, given its presence in a number of inflammatory and connective tissue diseases. Clinically, anti-cyclic citrullinated peptide (CCP) antibody is a more specific biomarker that is often used to confirm the diagnosis of RA.<br/>
'''Educational Objective:''' Patients diagnosed with autoimmune diseases are at increased risk of developing other autoimmune diseases. Rheumatoid arthritis (RA) is an autoimmune inflammatory arthritis that is characterized by the presence of symmetric joint pains that typically last more than hour and are relieved by movement. Physical examination findings consistent with RA include ulnar deviation of the fingers, pannus formation, Baker's cyst in the popliteal fossa, and tender subcutaneous nodules over the olecranon or the extensor surfaces of the forearm. The majority of patients with RA have a positive rheumatoid factor (RF), which is an autoantibody against the Fc portion of IgG.<br/>
'''References:''' McInnes IA, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365:2205-2219.<br>
Siegel JL, Luthra H, Donlinger J, et al. Association of primary biliary cirrhosis and rheumatoid arthritis. J Clin Rheumatol. 2003;9(6):340-3.<br>
First Aid 2014 366
Medical ethics are a set of principles that define the ethical practice of modern medicine. There are 4 major principles of medical ethics:<br>
# Beneficence<br>
# Non-maleficence<br>
# Respect for autonomy<br>
# Justice
<br>
'''Beneficence:'''<br>
Physicians must always define the benefit to risk ratio when considering treatment options for patients. All physicians are obligated to provide net benefit to their patients.
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'''Non-Maleficence:'''<br>
Physicians are obligated to do no harm to patients. Similar to the principle of beneficence, all management approaches must have the patient's interest first with no intention to harm. The principles of beneficence and non-maleficence are most pronounced in medical research and population medicine, where clear benefit and harm may not be as evident because the true beneficiary may not be the research subject himself.
<br><br>
'''Respect for Autonomy:'''<br>
Physicians must ensure that the priority of all their decisions is the patient's interest. Adult patients (> 18 years according to US law) who are deemed able to make their own decisions have the right to refuse treatment, regardless of how significant or trivial it may be for their health. A physician's respect for a patient's autonomy, or self-rule, requires that the physician communicates with the patient, discusses all concerns, and answers questions in an evidence-based manner.
<br><br>
'''Justice:'''<br>
Justice refers to the set of principles that dictate the ethics of medicine at a population-based scale. All physicians should act on the basis of fair allocation of resources and adjudication between competing claims. Patients should have the right to have equal access to healthcare. Although healthcare resources are limited, physicians must distribute these resources to efficiently meet the needs of those who require them the most.<br/>
'''Educational Objective:''' Respect for autonomy is a principle of medical ethics. A physician's respect to a patient's autonomy, or self-rule, requires that the physician communicates with the patient, discusses all concerns, and answers questions in an evidence-based manner. Adult patients (> 18 years according to US law) who are deemed able to make their own decisions have the right to refuse to be treated, regardless of how significant or trivial the treatment may be for their health.<br/>
'''References:''' Gillon R. Medical ethics: four principles plus attention to scope. BMJ. 1994;309:184.<br>Luce JM, White DB. A history of ethics and law in the intensive care unit. Crit Care Clin. 2009.25(1):221-237.<br>First Aid 2014 page 59
Defense mechanisms are psychological processes that are utilized to manipulate reality and avoid undesirable emotions. Defense mechanisms may be mature (high adaptive level) or immature (mental inhibitors). While mature defense mechanisms are considered optimal means to deal with stresses, immature defense mechanisms may be mental inhibitors, image-distorting, or disavowal.
<br>Mature defense mechanisms include the following:
* Anticipation: Plan for future stressors by goal-directed worrying processes.
* Altruism: Perform constructive service to others for self-satisfaction.
* Humor: Use comedy to express feelings
* Sublimation: Channel a socially unacceptable behavior to an acceptable one to achieve satisfaction and gratification.
* Suppression: ''Consciously'' block attention to an unresolved issue
<br>In contrast, other non-mature defense mechanisms may be mental inhibitors that prevent the surfacing of threatening or undesirable feelings; they may also be image-distorting processes that regulate self-esteem.
<br>Narcissistic defenses:
* Denial: Avoid painful experiences by totally abolishing sense of reality.
* Distortion: Reshape reality to better fit with one's desires, including sense of delusional superiority, entitlement, or megalomanic beliefs.
* Projection: React to unacceptable inner feelings as though they are external to self.
<br>Immature defenses:
* Acting out: Express unconscious desire through action or aggression
* Blocking: Transiently inhibit a thinking process. Unlike repression, blocking involves feeling of tension upon blocking of thoughts.
* Fixation: Remain at a more childish level of development.
* Hypochondriasis: Exaggerate an illness for evasion and regression.
* Introjection: Internalize object qualities and obliterate the distinction between a subject and an object, including identification with an aggressor.
* Passive-aggression: Express aggression through passivity and masochism.
* Regression: Return to earlier developmental stage to avoid stressors; it is common in children.
* Schizoid fantasy: Daydream and retreat to obtain gratification yet avoid interpersonal intimacy.
* Somatization: Convert of psychological aspects into bodily symptoms.
<br>Neurotic defenses:
* Controlling: Manage and regulate objects to resolve inner stressors.
* Displacement: Shift a feeling from one object to another.
* Externalization: Perceive one's own personality in external objects.
* Inhibition: ''Consciously'' limit ego functions to avoid anxiety that arise from the environment and the superego.
* Intellectualization: Use intellectual strategies to avoid expression.
* Isolation: Separate an idea from the affect that accompanies it.
* Rationalization: Suggest rational thoughts to explain behavior.
* Dissociation: Transiently alter one's character or identity to evade undesired feelings.
* Reaction formation: Convert an unacceptable impulse to its complete opposite, common in obsessional neurosis and may be a permanent feature.
* Repression: ''Unconscious'' withdraw idea from the conscious process. Ideas may either never reach one's conscious (primary repression) or may be expelled form the conscious process once experienced (secondary repression).
* Sexualization: Endow an object with sexual importance.<br/>
'''Educational Objective:''' Projection is a defense mechanism that involves taking one's own unacceptable qualities or feelings and ascribing them to other people. For example, a woman who subconsciously abhors her job, might believe that her boss loathes her.<br/>
'''References:''' Vaillant GE. Ego mechanisms of defense and personality psychopathology. J Abnorm Psychol. 1994;103(1):44-50.<br>
First Aid 2014 page 500
Chediak-Higashi syndrome (CHS) is a rare, autosomal recessive immunodeficiency disorder characterized by bleeding tendency, recurrent pyogenic bacterial infections, partial albinism, and progressive neurologic dysfunction. The classical pathologic feature of CHS is enlarged lysosomes or lysosome-related organelles in all cell types. These abnormal and dysfunctional lysosomes form as a result of abberant degranulation and fusion the phagosome and the maturing lysosome. The disorder is caused by a mutation in the CHS1/LYST gene. The disease is extrememly rare with around 500 cases reported worldwide. The most documented presentation, and indication for work-up, is recurrent pyogenic infections in a patient with partial albinism. The disorder may also present with an ‘accelerated phase’, a lymphoproliferative disorder characterized a lymphocytic infiltration of the major organs of the body. Patients with CHS are treated with prophylactic antibiotics as soon as the diagnosis is made. The only successful treatment for CHS is allogenic bone marrow transplantation.
To remember the characteristic presentation of CHS, remember the '''4 P''''s: '''P'''artial albinism, '''P'''yogenic infections, '''P'''latelet dysfunction, and '''P'''eripheral neuropathy.<br/>
'''Educational Objective:''' Chediak-Higashi syndrome is a rare, autosomal recessive immunodeficiency disorder caused by a defect in lysosomal degranulation and phagolysosome formation. It presents with partial albinism, peripheral neuropathy, bleeding tendency, and pyogenic sinopulmonary infections. Other findings include lymphadenopathy, hepatosplenomegaly, and mucosal ulcerations.<br/>
'''References:''' Kaplan J, De Domenico I, Ward DM. Chediak-Higashi syndrome. Curr Opin Hematol. Jan 2008;15(1):22-9. +
Diphtheria is an acute infectious disease caused by ''Corynebacterium diphtheriae''. ''C. diphtheriae'' is an exotoxin-producing, club-shaped, urease-negative, catalase-positive, gram-positive bacteria that is usually transmitted by direct contract or by aerosol. The most common manifestations of ''C. diphtheriae'' infection include an upper respiratory tract infection that often involves the posterior oral and the proximal pharyngeal regions, resulting in significant edema and formation of "pseudomembranes" (coalescence of the bacteria on the mucosal membranes and the outpouring of fibrinosuppurative exudates). The "pseudomembrane" is often described as dirty-looking and firmly attached to the mucosa, causing mucosal bleeding when scraped off the pharynx or palates. It is usually white-grey early in the disease and becomes necrotic green-black as the infection progresses. The bacteria contains diphtheria exotoxin, which acts by inhibiting the cellular protein synthesis by stimulation of adenosine diphosphate (ADP) ribosylation and inactivation of protein synthesis elongation factor 2. The toxigenicity of ''C. diphtheriae'' is derived from ''tox'' genes, three structural genes found in lysogenic corynebacteriophages that are eventually inserted into the bacterial genome. The bacteria regulates the expression of these genes in an iron-dependent manner (increased toxin production in low iron concentrations). Following excretion from the bacteria, these toxins undergo cleavage into 2 chains (A and B) held by a disulfide bond.
Systemic manifestations of ''C. diphtheriae'' infection may also occur due to the absorption of diphtheria exotoxin into the blood. Cervical lymph nodes may become enlarged and hemorrhagic with a "bull neck" appearance. Potentially fatal complications include myocarditis and neuropathy. Cardiac failure develops due to myocardial distortions, granular degeneration with loss of striations, and cardiac conduction abnormalities. Patients with diphtheria and cardiac complications may eventually die of myocardiosclerosis within 1-2 weeks of disease progression. On autopsy, the heart will appear dilated and pale with a "streaky" appearance. Neuropathy first manifests with food regurgitation through the nose due to paralysis of the soft palate and the posterior pharyngeal wall. If left untreated, other cranial and peripheral motor and sensory neuropathies develop at a later stage.
The diagnosis of diphtheria should be considered upon high clinical suspicion among young patients (usually < 5 years of age) with consistent manifestations (sore throat, drooling, and leaning forward on the hands or "tripod positioning" in attempt to breathe) and findings on physical examination (fever, cervical lymphadenopathy, pharyngeal edema, and pseudomembranes that bleed when scraped in the palate and the pharynx). Suspicion is confirmed with gram stain and culture from the throat, nose, secretions of the respiratory tract, or parts of the pseudomembranes. Gram stain may rapidly aid in the diagnosis, often demonstrating gram-positive rods with a "Chinese character" distribution. Metachromatic (red and blue) granules are observed on Loffler's media, whereas brown/black colonies with halo formation are observed on tellurite agar. Elek test (''in vitro'' immunodiffusion technique) is a blood test that may be used to evaluate the toxigenicity of the infectious ''C. diphtheriae'' strain. Once diphtheria is suspected, management includes early isolation, empirical administration of anti-toxin and intravenous antibiotics (erythromycin or penicillin G), and careful monitoring for respiratory, cardiac, or neurological complications. With the introduction of toxoid vaccines against ''C. diphtheriae'' infection, the incidence of diphtheria has greatly been reduced; and diphtheria respiratory infection noawadays is rarely described in developed countries. However, cutaneous diphtheria is still a common source of wound and umbilical infections, often showing single/multiple, curved, punched-out ulcers with elevated margins.<br/>
'''Educational Objective:''' ''C. diphtheriae'' exotoxin acts by inhibiting the cellular protein synthesis by stimulation of adenosine diphosphate (ADP) ribosylation and inactivation of protein synthesis elongation factor 2.<br/>
'''References:''' Hadfield TL, McEvoy P, Polotsky Y, et al. The pathology of diphtheria. J Infect Dis. 2000;181 Suppl 1:S116-20.<br>
Clarridge JE, Popovic T, Inzana TJ. Diphtheria and other corynebacterial and coryneform infections. In: Topley and Wilson's Microbiology and Microbial Infections, Hausler WJ, Sussman M (Eds), Oxford University Press, New York City 1998. Vol 3, p.347.<br>
Kneen R, Pham NG, Solomon T, et al. Penicillin vs. erythromycin in the treatment of diphtheria. Clin Infect Dis. 1998;27(4):845.<br>
Shen Y, Zhukovskaya NL, Zimmer MI, et al. Selective inhibition of anthrax edema factor by adefovir, a drug for chronic hepatitis B virus infection. Proc Natl Acad Sci USA. 2004;101(9):3242-7.<br>
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Facial erysipelas is a clinical diagnosis characterized by an acute-onset of fever, facial pain, erythema, and edema. Patients often complain of a tender skin lesion that has clearly demarcated margins. While patients with uncomplicated erysipelas are treated as out-patients, hospitalization is required for pediatric patients (due to high risk of sepsis) or for adults patients who present with facial involvement or complicated disease. This patient is presenting with symptoms and signs of acute inflammation, which is a transient and early physiological response to the facial erysipelas. During acute inflammation, blood supply and capillary permeability in the involved region significantly increases to facilitate the migration of leukocytes from the blood vessels into the interstitial space of the inflamed tissue. During inflammation, cytokines and chemical mediators are released that result in small vessel changes and leukocytic responses. Clinically, acute inflammation is characterized by 5 important features:
* Rubor (redness)
* Calor (warmth)
* Tumor (swelling)
* Dolor (pain)
* Functio laesa (loss of function)
In acute inflammation, redness and warmth are a result of histamine-mediated vasodilation of arterioles, whereas edema is a result of the increase in histamine-mediated venular permeability. Pain is due to the effect of bradykinin and other pain mediators on nerve endings that have already been sensitized by PGE2. The distinction between the features of acute inflammation and the mechanisms by which they manifest is important.<br/>
'''Educational Objective:''' In inflammation, redness and warmth are a result of histamine-mediated vasodilation of arterioles<br/>
'''References:''' Rankin JA. Biological mediators of acute inflammation. AACN Clin Issues. 2004;15(1):3-17.<br>
MacGlashan D Jr. Histamine: a mediator of inflammation. J Allergy Clin Immunol. 2003;112(4 Suppl):S53-9.<br>
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Myotonic dystrophy subtype 1 (DM1 or MMD1 or Steinert's disease) is a autosomal dominant genetic disorder characterized by progressive distal muscle weakness of the upper and lower extremities. Patients often complain of foot drop or inability to perform physical activities that require intricate use of the hands (use tools or doorknobs). In addition, patients with myotonic dystrophy have frontal balding and unique facial features (temporal wasting and hatchet-appearance) caused by the wasting of the facial muscles and also resulting in ptosis and dysarthria. Patients may exhibit a "warm-up phenomenon", characterized by the improvement in strength of the handgrip myotonia upon repeated contractions (e.g. inability to release hand from doorknob following contraction). On physical examination, percussion myotonia may also be evaluated by percussion of the thenar eminence using a tendon hammer. Patients with myotonic dystophy are at-risk of several complications, including subcapsular cataracts, which eventually develop in almost all patients, cardiac conduction abnormalities (potentially fatal tachyarrhythmias), aspiration pneumonia and diaphragmatic weakness, endocrinopathies, intellectual deficits, cholecystitis and decreased esophageal peristalsis (increased tonicity of gallbladder sphincter and esophageal muscles, respectively), slow gastric emptying, constipation (may be due to pseudo-obstruction), or diarrhea and fecal incontinence.
Myotonic dystophy has 2 subtypes:
* DM1 or MMD1 (Steinert's disease): Autosomal dominant disorder characterized by the presence of unstable CTG trinucleotide repeats (5' CTG 3') in the 3' untranslated region of the ''DMPK'' (myotonic dystrophy protein kinase) gene in chromosome 19q that normally encodes myosin kinase. The number of CTG repeats is directly associated with the clinical manifestations of the disease; normal individuals have less than 37 CTG repeats, asymptomatic patients with a pre-mutation have 37-50 CTG repeats, and patients with clinical myotonic distrophy have > 50 CTG repeats. The disease is characterized by anticipation, whereby children of patients with a pre-mutation (37-50 CTG repeats) may have longer repeats and develop manifestations of the disease.<br>
* DM2 or MMD2 (proximal myotonic myopathy): Autosomal dominant disorder caused by a mutation of ''ZNF9'' (zinc finger protein) gene in chromosome 3q that result in the expansion of CCTG (not CTG) repeats. Unlike DM1, the number of CCTG repeats does not correlate with the clinical manifestations of DM2. Symptoms begin at adulthood, including myotonia, proximal weakness, stiffness, and fatigue. Although it shares similar complications to DM1, DM2 is considered a milder disease. DM2 is not usually tested on USMLE.<br/>
'''Educational Objective:''' Myotonic dystrophy subtype 1 (DM1 or MMD1) is a autosomal dominant genetic disorder characterized by progressive distal muscle weakness of the upper and lower extremities. Patients often complain of foot drop or inability to perform physical activities that require intricate use of the hands (use tools or doorknobs).<br/>
'''References:''' Turner C, Hilton-Jones D. The myotonic dystrophies: diagnosis and management. J Neurol Neurosurg Psychiatry. 2010;81:358-67.<br>
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Down syndrome is the most common chromosomal abnormality that is compatible with life. It is caused by an extra copy of chromosome 21 (trisomy 21). Down syndrome is typically associated with physical growth delays, unique facial dysmorphism, and intellectual disability. Some of the physical characteristics that are associated with Down syndrome include:
* Short neck
* Abnormally small chin
* Flat nasal bridge
* Upslanting of palprebral fissures
* Epicanthic fold (skin folds of the upper eyelid that cover the inner angles of the eyes)
* A protruding, furrowed tongue
* Abnormal teeth and narrow palate
* Low set of small or dysplastic ears
* Short broad hands
* Single palmar fold (simian crease)
* Sandal gap (excessive space between the large toe and second toe, as pictured above)
<br>
Down syndrome is most often caused by meiotic nondisjunction, which occurs during meiosis I. Approximately 2-3% of cases are caused by Robertsonian translocation. On quad screen, Down syndrome is associated with decreased AFP, increased beta-HCG, decreased estriol, and increased inhibin A. Of note non-invasive tests using fetal DNA detected in maternal blood are beginning to replace the quad screen for aneuploidy testing. Down syndrome is associated with the development of several diseases, including cardiac diseases (Endocardial cushion defect, AV canal, VSD, ASD, Tetralogy of Fallot, and PDA), pulmonary diseases (asthma and sleep apnea), GI diseases (Hirschsprung disease, annular pancreas, imperforate anus, esophageal or duodenal atresia, celiac disease, and tracheoesophageal fistula), skin disorders (hyperkeratosis and dermatitis), hypospadias, cryptorchidism, testicular cancer, leukemias, immunodeficiency syndromes, endocrinopathies (type I diabetes mellitus and hypothyroidism), hearing impairment, ocular disorders (Brushfield spots of the iris, refractive errors, strabismus, nystagmus), and Alzheimer's disease at a young age.<br/>
'''Educational Objective:''' Down syndrome is associated an increased risk of leukemia.<br/>
'''References:''' Mullighan CG, Collins-Underwood JR, Phillips LA, et al. Rearrangement of CRLF2 in B-progenitor–and Down syndrome–associated acute lymphoblastic leukemia. Nat Genet. 2009; 41(11):1243-6.<br>
Nikolaev SI, Garieri M, Santoni F, et al. Frequent cases of RAS-mutated Down syndrome acute lymphoblastic leukaemia lack JAK2 mutations. Nat Commun. 2014; 5:4654.<br>
Image: Attribution to "Feet of a boy with Down Syndrome.JPG" uploaded by user:Loranchet licensed under the Creative Commons Attribution 3.0 Unported license. commons.wikimedia.org. Retrieved Jan 9 2015.<br>
First Aid 2014 page 90<br>
Edwards' syndrome is a chromosomal abnormality caused by the presence of all or part of an extra 18th chromosome (trisomy 18). Approximately 80% of patients with Edward's syndrome are female. The majority of fetuses with the syndrome die before birth; those who survive have a median lifespan of approximately 1 to 2 weeks. Fewer than 10% of patients with Edwards' syndrome live beyond 1 year. The physical characteristics of Edwards' syndrome include the following:
* Intellectual disability
* Clenched fingers (shown in the picture above)
* Micrognathia
* Microcephaly
* Prominent occiput
* Low-set, dysmorphic ears
* Cleft lip and/or palate
* Webbing of the toes
* Rocker bottom feet<br/>
'''Educational Objective:''' Edwards' syndrome is a chromosomal abnormality of chromosome 18 (trisomy 18) with severe abnormal facies and symptoms. The majority of patients with Edwards' syndrome die before birth. Among those who survive, the median lifespan of live births is approximately 1 to 2 weeks.<br/>
'''References:''' Image: Attribution to "Overlapping fingers.JPG" uploaded by user:Bobjgalindo licensed under the GNU Free Documentation license. commons.wikimedia.org. Retrieved Jan 9 2015.<br>
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