Ed Gane, M.D., F.R.A.C.P.

• Associate Professor
• Faculty of Medicine
• University of Auckland
• Consultant Hepatologist
• Liver Unit
• Auckland City Hospital
• Auckland, New Zealand

Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State Diabetic ketoacidosis and hyperosmolar hyperglycemic state are true emergencies 9 arrhythmia treatment purchase lopressor 25 mg on-line,18 prehypertension co to znaczy buy discount lopressor 12.5 mg online,40 pulse pressure healthy range lopressor 100mg line. In patients with type 1 diabetes hypertension zyrtec cheap lopressor amex, ketoacidosis is usually precipitated by the patient omitting insulin prehypertension 39 weeks pregnant order lopressor 50mg without prescription, or an acute illness with subsequent increase in counter-regulatory hormones such as cortisol prehypertension at 24 generic 12.5mg lopressor overnight delivery, catecholamines, glucagon, and growth hormone. Treatment with bicarbonate to correct the acidosis is generally not needed and may be harmful, especially in children. Hourly bedside monitoring of glucose and frequent monitoring (every 2-4 hours) of potassium is essential. A flow sheet is helpful in tracking the fluid and insulin therapies and laboratory parameters in these patients. Metabolic improvement is manifested by an increase in the serum bicarbonate or pH. The insulin infusion should be continued until the urine ketones clear and the anion gap closes. Intramuscular regular insulin or subcutaneous insulin lispro or aspart given every 1 to 2 hours can be utilized rather than an insulin infusion in patients without hypoperfusion. Long-acting insulin should be given 1 to 3 hours prior to discontinuing the insulin infusion. Patients may develop hyperchloremic metabolic acidosis with treatment if they have been given large volumes of normal saline in the course of their treatment. Large ketonemia is usually not seen because residual insulin secretion suppresses lipolysis. Blood glucose should be lowered very gradually with hypotonic fluids and low-dose insulin infusions (1-2 units/h). Hospitalization for Intercurrent Medical Illness Patients on oral agents may need transient therapy with insulin to achieve adequate glycemic control during a hospitalization41,42,44. It is prudent to stop metformin in all patients who arrive in acute care settings as contraindications to metformin are prevalent in hospitalized patients. In patients requiring insulin, patients should receive scheduled doses of insulin with additional short-acting insulin. Approximately one third of patients who develop hyperglycemia during a hospitalization will have newly diagnosed diabetes and another one third will likely have prediabetes. Obtaining an HbA1C upon admission or prior to discharge can help determine who needs follow-up care. Perioperative Management Patients who require surgery may experience worsening of glycemia similar to those admitted to hospital for a medical illness22. Patients on oral agents may need to be transiently switched to insulin to control blood glucose. In patients requiring insulin, scheduled doses of insulin or continuous insulin infusions are preferred. For patients who can eat soon after surgery, basal insulin continuation is warranted. Patients receiving basal-bolus insulin therapy can continue receiving their usual dose of long acting insulin while holding the premeal bolus doses until the patient eats. However, "tight" perioperative glucose control has not proven to improve outcomes. Metformin should be discontinued temporarily after any major surgery until it is clear that the patient is hemodynamically stable and normal renal function is documented. Pentamidine, commonly used for Pneumocystis Carinii pneumonia infections, is a -cell toxin and may cause some patients to develop hypoglycemia from insulin release followed by hyperglycemia. Megestrol, used as an appetite stimulant, can have glucocorticoid-like effects and cause hyperglycemia in some patients. Stavudine, zidovudine, and didanosine may cause lactemia, especially upon long-term use. It may be advisable to check lactate levels in patients taking this medications prior to metformin use. If lactate levels are greater than 2 times normal, alternative therapy should be considered. DiaPep277 development was halted as data from the full cohort analysis was negative. The "4 lifestyle pillars" for the prevention of type 2 diabetes are to decrease weight, increase aerobic exercise, increase fiber, and decrease fat intake. Patient assigned to the lifestyle arm of the study developed diabetes at a rate of 5% per year compared to an 11% per year rate in the usual care group, a 58% reduction. Interestingly, young and overweight individuals on metformin had a greater reduction in the risk of developing diabetes than normal weight and older study patients. All diabetes medications available for the prevention of diabetes, once discontinued, do not appear to have residual effects on -cell function. Thus patients must continue the medication to "prevent" diabetes, thus raising the question about whether medications are merely early treatment. All commercially available insulin preparations contain only the active insulin peptide. Characteristics that are commonly used to categorize insulin preparations include source, strength, onset, and duration of action. Some insulin preparations, known as insulin analogs, have had amino acids substitutions in the insulin molecule that are designed to impart physiochemical and pharmacokinetic advantages. An insulin analog is a modified human insulin molecule that imparts particular pharmacokinetic advantages. All products are good until expiration date on product if unopened and stored correctly. Insulin is available in several concentrations containing 100 units/mL (U-100), 200 units/mL (U-200), 300 units/mL (U-300), or 500 units/mL (U-500). Concentrated insulins containing more than 100 units/mL are generally reserved for individuals that require larger doses of insulin to control their diabetes. For some patients with type 1 diabetes who require extremely low doses of insulin, U-100 insulin may be diluted in order to accurately measure the necessary insulin doses. Diluents, instructions on dilution, and empty vials can be obtained from the manufacturers. Purity of insulin refers to the amount of proinsulin and other impurities present in the insulin product. Prior to 1980, most insulin products contained impurities (300-10,000 parts per million [ppm]) that sometimes caused local skin reactions as well as systemic antibody production. When given by subcutaneous injection, regular crystalline insulin naturally associates into a hexameric (six insulin molecules) structure when zinc is present. Before absorption through a blood capillary can occur, the hexamer dissociates first into dimers and then monomers. This principle is the premise for additives such as protamine and extra zinc, which strengthen the hexamer interaction, prolonging onset, peak, and duration. Lispro, aspart, and glulisine insulin preparations dissociate more rapidly to monomers due to the substitution of amino acids on the -chain of insulin resulting in a more rapid onset, peak, and duration of action when compared to regular insulin. Lispro (B-28 lysine and B-29 proline human insulin; monomeric) insulin has two amino acids transposed, aspart (B-28 aspartic acid human insulin; monomeric and dimeric) insulin has one amino acid substitution, and glulisine (B-3 lysine and B-29 glutamic acid) has two substitutions. Proteins are insoluble near their isoelectric point and the analog insulin glargine takes advantage of this property to prolong absorption. In the vial, glargine is buffered to a pH of 4, a pH at which it is highly soluble, resulting in a clear colorless solution. When injected into the neutral pH of the body, it rapidly forms microprecipitates that slowly dissolve into dimers and monomers which can then be absorbed. The result is a long-acting insulin product with a duration of action of approximately 24-hours. The long-acting analog insulin detemir, in contrast, attaches a 14-carbon fatty acid at the B-29 position and removes the B-30 amino acid. Once detemir dissociates from albumin at the injection site and enters the blood, it is again binds to albumin, further prolonging its action. Insulin degludec, another long-acting insulin analog, has threonine at position B-30 removed and a 16-carbon fatty acid conjugated to lysine at position B-29 with a glutamic acid spacer. When injected, insulin degludec molecules reorganize from dihexamers to multihexamers that remain in solution at physiologic pH. Slow release of zinc ions from the multihexamers leads to a slow release of insulin degludec monomers. The pharmacokinetics of insulin products given by subcutaneous injection are characterized by their onset, peak, and duration of action (Table 74-8). Absorption of insulin from a subcutaneous depot is dependent on several factors, including source of insulin, concentration of insulin, additives to the insulin preparations (eg, zinc and protamine), blood flow to the area (rubbing of injection area, increased skin temperature, and exercise in muscles near the injection site may enhance absorption), and injection site. U-500 regular insulin has an onset similar to U-100 regular insulin, but a delayed peak and a longer duration of action when compared to U-100 regular insulin. Variability in the absorption and dose due to improper mixing of the suspension by the patient or healthcare provider prior to administration can lead to a labile glucose response. Inhaled insulin has rapid absorption into the blood stream and reaches maximum concentrations in 12 to 15 minutes. Degludec and U-300 insulin glargine appears to have less peak effect compared to U-100 insulin glargine. This may explain the lower insulin dosage requirements and longer duration of activity observed in patients with endstage renal disease. The connection between high insulin levels (hyperinsulinemia), insulin resistance, and cardiovascular events incorrectly leads some clinicians to believe that insulin therapy may cause macrovascular complications. Endogenous hyperinsulinemia in the setting of insulin resistance has been linked to increased cardiovascular events. Nor did basal insulin use in the Outcome Reduction with Initial Glargine Intervention trial increase cardiovascular risk. Moreover, insulin use is associated with an increased risk of hospitalizations in older adults based on public health surveillance data. Patient with neuroglycopenic symptoms may experience confusion, agitation, and eventually a loss of consciousness which may progress to coma. Patients with hypoglycemia unawareness should temporarily raise their glycemic goals and check their blood glucose level prior to any activities that require them to be alert and oriented (eg, driving and certain sports). A glucagon kit should be prescribed and readily available to all patients on insulin who have a history of severe hypoglycemia or at high risk for such events. Family and close friends of the patient should be educated regarding the reconstitution and injection of glucagon. It can take 10 to 15 minutes for the injection to start raising glucose levels and patients often vomit. It is important to position the patient on the side with the head tilted slightly downward to avoid aspiration. The most common pulmonary adverse effect in patients receiving technosphere inhaled insulin was cough and upper respiratory infections. Technosphere insulin use has been associated with a small decline in pulmonary function. Specifically, the forced expiratory volume in 1 second declined by approximately 40 mL in clinical trials. Technosphere insulin patients should have spirometry tests performed at baseline, 6 months, and annually thereafter. If a 20% reduction or greater in forced expiratory volume in 1 second is observed, technosphere insulin should be discontinued. While much less common today in people using insulin, two forms of lipodystrophy still occur. Lipoatrophy, in contrast, is due to insulin antibodies or allergic type-reactions that destroy the fat at the site of injection. Routinely rotating injection sites prevents these problems from developing and, when a lipodystrophy is detected, its use as an injection site should be avoided. Several large studies using administrative data found an association between insulin glargine and cancer. In addition, the prospective, randomized Outcome Reduction with Initial Glargine Intervention trial reported no difference in cancer risk or cardiovascular events with low dose insulin glargine use over approximately 6 years. Detemir theoretically could have albumin binding site interactions, but it occupies a very small percentage of total albumin binding sites. During acute illness or with ketosis or states of relative insulin resistance, the need for higher dosages is common. Dosages vary widely depending on degree of insulin resistance and concomitant antihyperglycemic medication use. U-500 regular insulin is reserved for use in patients with extreme insulin resistance. Extreme caution to avoid errors must be exercised when prescribing and dispensing U-500 regular in a vial. The prescription of U-500 should be written to include both the number of units and the volume (mL). In an individual prescribed 120 units three times a day before meals, this prescription would be written as follows: "U-500 regular insulin inject 120 units (0. If an insulin syringe must be used, the same prescription as described above would be written as follows: "U-500 regular insulin: inject 120 units (24 units as measured by the unit markings of a U-100 syringe) subcutaneously three times daily before meals. For financial reasons, patients may attempt to use insulin preparations longer than the expiration dates. Careful attention must be paid to monitoring for deterioration of glycemic control and signs of clumping, precipitates, and discoloration in the insulin vial or pen cartridge. Biguanides Metformin is the only biguanide available in the United States19,23,53,54.

Diseases

• Congenital insensitivity to pain
• Hypogonadotropic hypogonadism without anosmia, X linked
• Gusher syndrome
• Curth Macklin type ichthyosis hystrix
• Intrauterine infections
• Cystic medial necrosis of aorta
• Opportunistic infections

Effects of butterbur treatment in intermittent allergic rhinitis: A placebo-controlled evaluation blood pressure ear cheap lopressor 50mg mastercard. The etiology of this complex disease originates from multiple causative and contributory factors 13 pulse pressure diastolic purchase cheap lopressor online. Elements of pathogenesis involve defects in epidermal keratinization heart attack sam buy lopressor 50mg overnight delivery, androgen secretion blood pressure yahoo answers safe 50 mg lopressor, sebaceous function hypertension guidelines jnc 7 cheap lopressor 12.5 mg on-line, bacterial growth heart attack heartburn order lopressor 50mg with mastercard, inflammation, and immunity. Minimizing or reversing follicular occlusion will arrest the pathogenic acne cascade and involves combining treatment measures to target all pathogenic elements. Patients should eliminate aggravating factors, maintain a balanced, low-glycemic load diet, and control stress. Cleanse twice daily with mild soap or soapless cleanser, and use only oil-free cosmetics. Comedone extraction in approximately 10% of patients produces immediate cosmetic improvement. First-, second-, and third-line therapies should be appropriate for the severity and staging of the clinical presentation and directed toward control and prevention. Combine the smallest number of agents at the lowest possible dosages to ensure efficacy, safety, avoidance of resistance, and patient adherence. Once control is achieved, maintenance regimens should be simplified to continue with some suppressive therapy. Motivate the patient to continue long-term therapy through empathic and informative counseling. In this chapter, I review the latest developments in understanding acne vulgaris and its treatment. The contents provide an analysis of the physiology of the pilosebaceous unit; the epidemiology, etiology, and pathophysiology of acne; relevant treatment with nondrug measures; and comparisons of pharmacologic agents, including drugs of choice recommended in best-practice guidelines. Options include a variety of alternatives such as retinoids, antimicrobial agents, hormones, and light therapy. Patient assessment, general approaches to individualized therapy plans, and monitoring evaluation strategies are presented. The lifetime prevalence of acne approaches 90%, with the highest incidence in adolescents. Prevalence data available from the European Union, United States, Australia, and New Zealand show that acne affects 80% of individuals between puberty and 30 years of age, depending on the method of lesion counting (50%-95% prevalence range reported for adolescents and 20%-30% prevalence range for ages 20-40). If mild manifestations were excluded and only moderate or severe manifestations were considered, the frequency in epidemiological studies in Western industrialized countries was still 20% to 35%. It is triggered in children by the initiation of androgen production by the adrenal glands and gonads, and it usually subsides after the end of growth. However, to some degree, most patients continue to have symptoms into their mid-20s, and there is evidence that the duration of acne may last into middle age for most women, recorded in 54% of women and 40% of men older than 25 years of age. When untreated, acne usually lasts for several years until it spontaneously remits. After the disease has ended, scars and dyspigmentation are not uncommon permanent negative outcomes. Genetic factors have been recognized; there is a high concordance among identical twins, and there is also a tendency toward severe acne in patients with a positive family history of acne. There are believed to be no gender differences in acne prevalence, although such differences are often reported and may represent social biases. While this hypothesis is based on the observation that primitive societies subsisting on traditional (low glycemic) diets have no acne, the theory awaits validation and acceptance by the dermatologic community. Genetic, racial, hormonal, dietary, and environmental factors have been implicated in its development. Four major etiologic factors are involved in the development of acne: increased sebum production, due to hormonal influences; alteration in the keratinization process and hyperproliferation of ductal epidermis; bacterial colonization of the duct with Propionibacterium acnes; and production of inflammation with release of inflammatory mediators in acne sites. The role of heredity in acne has not been clearly defined; however, there is a significant tendency toward more serious involvement if one or both parents had severe acne during their youth. Environmental factors play a major role in determining the severity and extent of acne and may influence the choice of topical treatments. Heat and humidity may induce comedones; pressure or friction caused by protective devices such as helmets, shoulder pads, or pillows, and excessive scrubbing or washing can exacerbate existing acne by causing microcomedones to rupture. Pressure may cause acne lesions to form in patients who do not have acne vulgaris: this variant is called mechanical acne. Friction, wool, or other rough textured fabrics and occlusive clothing may also be mechanical irritants. Hair styles that are low on the forehead or neck may cause excessive sweating and occlusion, exacerbating acne. In most cases acne is worse in winter and improves during the summer, suggesting a salutary effect of sunlight. The importance of psychologic factors in this prolonged and capricious condition has been repeatedly stressed. Two-thirds of affected teenagers wish that they could speak with their physician their healthcare provider about acne, but only one-third actually do. Emotions, such as intense anger and stress, can exacerbate acne, causing flares or increasing mechanical manipulation: picking, excoriating, or pinching lesions sometimes subconsciously or in sleep. This is probably the result of increased glucocorticoid secretion by the adrenal glands, which appears to potentiate the effects of androgens. In the past, acne was not felt to be influenced by diet, but patients could restrict certain foods they perceived exacerbate acne (chocolate, cola drinks, milk and milk products). A discussion of the issues surrounding dietary influences is elaborated in the Clinical Controversy on Diet box. Diet and Acne the role of dietary influences in acne continues to be disputed in the literature with increasing attention and vigor. Evidentiary studies are currently in progress to elaborate associations between various dietary influences and presentation of acne, following the dismissal of over-interpreted 40-year-old, poorly designed studies that disavowed potential effects of dietary ingestions on acne. Beginning in 2005, a series of studies have linked consumption of dairy products with acne, perhaps due to natural hormonal components and/or other bioactive molecules in milk. The authors suggest that natural hormonal components of milk and/or other bioactive molecules in milk could exacerbate acne. When administered as a dietary supplement on a twice-daily regimen in mild-to-moderate acne vulgaris, it may lead to an overall improvement in acne lesion counts in the majority of affected adolescents and young adults. In a well-designed randomized controlled trial, a significant reduction in acne was seen in patients who eliminated high glycemic index foods. Accompanying changes in physical and endocrinologic parameters suggest that decreases in total energy intake, body weight, and indices of androgenicity and insulin resistance may also be associated with observed improvements in acne. This suggests a possible role of desaturase enzymes in sebaceous lipogenesis and the clinical manifestation of acne; these require further investigation. Independent effects of weight loss versus dietary intervention need to be isolated. Daily consumption of chocolate and sweets was independently and highly associated with acne (odds ratio 2. While still controversial, diet is thought to play a role in the development or progression of acne vulgaris and further studies are ongoing. Investigations reviewing antioxidants from nutritional and topical sources and probiotics, as potential acne-fighting agents are now proceeding in early stages. Increased follicular keratinization Improved understanding of acne development on a molecular level suggests that acne is a disease that involves both innate and adaptive immune systems and inflammatory events. Receptors that regulate sebaceous lipid metabolism work in concert with receptors regulating epidermal growth and differentiation. Acne can be considered as a model of immune-mediated chronic inflammatory skin disease: an innate immune response that is not able to control P. Sebaceous glands increase their size and activity in response to circulating androgens. Most patients with acne do not overproduce androgens (with some exceptions); instead, they have sebaceous glands that are hyperresponsive to androgens. Sebaceous lipids are regulated by peroxisome proliferator-activated receptors, which act in concert with retinoid X receptors to regulate epidermal growth and differentiation as well as lipid metabolism. Sterol response element-binding proteins mediate the increase in sebaceous lipids formation induced by insulin-like growth factor-1. The sebaceous gland also acts as an endocrine organ in response to changes in androgens and other hormones. Oxidized squalene can stimulate hyperproliferative behavior of keratinocytes, and lipoperoxides produce leukotriene B4, a powerful chemoattractant. The infrainfundibulum increases its keratinization of cells with hypercornification and development of the microcomedone, the primary lesion of both noninflammatory and inflammatory acne. In particular androgens, hormones could be a stimulus to pilosebaceous duct hypercornification. Sebum, produced in increasing amounts by the active gland, becomes trapped behind the keratin plug and solidifies, contributing to open or closed comedone formation. Interleukin-1- upregulation contributes to the development of comedones independently of colonization with P. These free fatty acids may trigger the changes that lead to an increase in keratinization and microcomedone formation. The closed comedone is almost completely obstructed to drainage and has a tendency to rupture. Its dark color is not due to dirt but to either oxidized lipid and melanin or to the impacted mass of horny cells. The cylindrically shaped, open comedone is very stable and may persist for a long time as soluble substances and liquid sebum escape more easily. Acne that is characterized by open and closed comedones is termed noninflammatory acne. Acne produces chemotactic factors and promotes the synthesis of tumor factor- and interleukin-1. Both recruitment of polymorphs into the follicle during the inflammatory process and release of P. The pus eventually bursts on the surface with resolution of the inflammation or into the dermis. A time delay of up to 3 years between acne onset and adequate treatment correlates to degree of scarring and emphasizes the need for early therapy. The negative impact of facial acne is one of the primary motivators for patients to seek and to adhere to treatment. In a report of 195 cases, acne impact on health status was worse compared to other chronic diseases. Authors concluded acne is not a minor disease in comparison with other chronic conditions. The conditions most commonly mistaken for acne vulgaris include rosacea, perioral dermatitis, gram-negative folliculitis, and drug-induced acne. Onset is not linked to androgens or endocrine changes; and comedones are not usually present. Aggravating factors include endogenous triggers: ingestion of alcohol, spicy foods, or hot drinks (especially those containing caffeine); smoking; and exogenous triggers: overexposure to sunlight; exposure to temperature extremes, heat and humidity, friction, irritating cosmetics, and steroids. Treatment may include antibiotics, particularly doxycycline (low, antiinflammatory dose) or erythromycin, topical metronidazole, pimecrolimus or azelaic acid as well as agents to reduce erythema (alpha adrenergics). There is a sudden onset of superficial pustules around the nose, chin, and cheeks. Systemic corticosteroids can cause a pustular inflammatory form of acne, especially on the trunk. Acne has also been associated with most of the potent topical steroids, but not with hydrocortisone, which lacks the ability to inhibit protein synthesis. Discontinuation of the steroid results in an initial worsening of appearance due to removal of the anti-inflammatory action of the steroid itself. Caution patients about this reaction, which can be subdued through judicious use of topical hydrocortisone. In addition, halogens can provoke de novo acne lesions in individuals who have increased external exposure often due to occupational contact, or pool or hot tub disinfection; this variant is called chloracne. In addition, certain minor ingredients in cosmetics have been implicated in cosmetic acne, including isopropyl myristate, cocoa butter, and fatty acids. Desired Outcomes (Goals of Treatment) Acne vulgaris is treated as a chronic disease, as it demonstrates typical chronicity characteristics: manifests as either acute outbreaks or slow onset; patterns of recurrence or relapse; a prolonged course; and psychologic and social impact. There are two governing principles: the chronic nature warrants early and aggressive treatment, and maintenance therapy is often needed for optimal outcomes. This must be stressed with the patient to encourage adherence to lengthy treatment regimens, which address management of current symptoms and signs and preventive measures. Basic goals of treatment include alleviation of symptoms by reducing the number and severity of lesions (objective and subjective grading) and improving appearance, slowing progression, limiting duration and recurrence, prevention of long-term disfigurement associated with scarring and hyperpigmentation, and avoidance of psychologic suffering. A significant percentage change in lesion counts is desirable: most patients empirically validate a margin of 10% to 15% reduction in facial lesion counts as appropriate. General Approach to Treatment the most critical treatment target is the microcomedone. Nondrug and pharmacologic treatment and preventive measures should be directed toward cleansing, reducing triggers and combination therapy targeting all four pathogenic mechanisms. Combination therapy is often more effective than single therapy, and may decrease side effects and minimize resistance or tolerance to individual treatments. Family history of persistent acne Topical therapy is the standard of care for mild-to-moderate acne. To reduce new lesion development, they require application to the whole affected area rather than individual spots. Most cause initial skin irritation, which may result in nonadherence or discontinuation. Irritation can be minimized by starting with lower strengths and gradually increasing frequency or dose.

Labeling and effectiveness testing; sunscreen drug products for over-thecounter human use heart attack enrique iglesias generic lopressor 12.5mg otc. Influence of smoking on the efficacy of antimalarials in cutaneous lupus: a meta-analysis of the literature blood pressure medication starts with t cheap lopressor 25mg amex. Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: Report of a Task Force at the 13th International Congress on Antiphospholipid Antibodies heart attack kiss purchase cheap lopressor online. Treat-to-target in systemic lupus erythematosus: Recommendations from an international task force heart attack vol 1 pt 4 trusted lopressor 100mg. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: A systematic review arrhythmia emedicine lopressor 12.5 mg with amex. Routine hydroxychloroquine blood concentration measurement in systemic lupus erythematosus reaches adulthood blood pressure testing order lopressor paypal. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Safety and efficacy of belimumab to treat systemic lupus erythematosus in academic clinical practices. Recent developments in the treatment of patients with systemic lupus erythematosus: Focusing on biologic therapies. Abatacept for lupus nephritis: Alternative definitions of complete response support conflicting conclusions. Incidence and prevention of bladder toxicity from cyclophosphamide in the treatment of rheumatic diseases: a data-driven review. Efficacy and safety of mycophenolate mofetil versus cyclophosphamide for induction therapy of lupus nephritis: A meta-analysis of randomized controlled trials. Maintenance therapy of lupus nephritis with mycophenolate or azathioprine: Systematic review and meta-analysis. Identification of biomarkers that predict response to treatment of lupus nephritis with mycophenolate mofetil or pulse cyclophosphamide. Association between thiopurine S-methyltransferase polymorphisms and azathioprine-induced adverse drug reactions in patients with autoimmune diseases: A meta-analysis. Updated review of complementary and alternative medicine treatments for systemic lupus erythematosus. Side effects unrelated to disease activity and acceptability of highly effective contraceptive methods in women with systemic lupus erythematosus: A randomized, clinical trial. Systemic lupus erythematosus and pregnancy outcomes: An update and review of the literature. Azathioprine during pregnancy in systemic lupus erythematosus patients is not associated with poor fetal outcome. Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but not anticardiolipin antibody, in patients with antiphospholipid antibodies. Treatment of refractory obstetric antiphospholipid syndrome: the state of the art and new trends in the therapeutic management. Advisory Committee on Immunization Practices recommended immunization schedule for adults aged 19 years or older: United States, 2015. European League Against Rheumatism recommendations for monitoring patients with systemic lupus erythematosus in clinical practice and in observational studies. Two theories-the prohapten/hapten concept and the p-i concept-have been proposed to explain how drugs stimulate the immune response. Anaphylaxis is an acute, life-threatening allergic reaction involving multiple organ systems that generally begins within 1 hour but almost always within 2 hours after exposure to the inciting allergen. Anaphylaxis requires prompt treatment to restore respiratory and cardiovascular functions. Epinephrine is the drug of first choice and should be administered to counteract bronchoconstriction and peripheral vasodilation. Factors that influence the likelihood of drug allergy are the chemical composition of the drug, whether the drug contains proteins of nonhuman origin, the route of drug administration, and the sensitivity of the individual as determined by genetics or environmental factors. For some drugs, genetic predisposition to specific human leukocyte antigen alleles has been identified as a risk factor for allergic-mediated skin reactions. Ideally, cephalosporins should be avoided in patients with history of an immediate penicillin allergy but, most studies suggest there is little risk of an allergic response to a cephalosporin even in a person with a positive penicillin skin test result. Similarities in the R1 side chain of the agents should be considered when assessing the risk of cross-reactivity. Fewer than 1% of patients receiving nonionic radiocontrast agents experience some type of adverse reaction. Of the variety of reactions reported, about 90% are nonimmediate and mostly urticarial, with severe immediate reactions occurring as infrequently as 0. Most patients with aspirin sensitivity requiring aspirin for prevention of cardiovascular disease can safely undergo and complete a graded challenge or desensitization. The low crossreactive rate may be explained by differences in the chemical structures and reactive metabolites of the sulfonamide antibiotics and nonantibiotics. The basic principles of management of allergic reactions to drugs or biologic agents include (a) discontinuation of the medication or agent when possible; (b) treatment of the adverse clinical signs and symptoms; and (c) substitution, if necessary, of another agent. The gold standard for evaluating the risk of an immediate allergy to penicillin is the skin test. Skin testing can demonstrate the presence of penicillin-specific immunoglobulin E and predict a relatively high risk of immediate reactions. Skin testing does not predict the risk of delayed reactions or most dermatologic reactions. When an allergenic drug is considered medically necessary, no adequate therapeutic alternative exists, and there is no reliable skin testing method, two options are available to the clinician: induction of drug tolerance (previously known as desensitization) and graded challenge. Drug allergy, as defined by the World Health Organization, is an immunologically mediated drug hypersensitivity reaction. Examples of drug hypersensitivity reactions are isolated urticaria after radiocontrast media, aspirin-induced asthma, opiate-related urticaria, and flushing after vancomycin infusion. Dermatologic reactions represent the most frequently recognized and reported form of drug allergy. Although some reactions are relatively well defined, most are due to mechanisms that are either unknown or poorly understood. This concept is predicated on the assumption that smallmolecular-weight molecules (less than 10 kDa) do not have the ability to serve as antigens on their own. With the exception of polypeptide compounds, most drugs are smaller than 1,000 Da. To become immunogenic, these small compounds must first covalently bind to carrier proteins in plasma or tissue. For some drugs, such as the sulfonamides, the parent compound must be converted to a metabolite before it can combine with the macromolecule. Drugs that are chemically inert and rely on conversion to a metabolite with an antigenic determinant are referred to as prohaptens. Some small-molecular-weight drugs may cause an immune response through a nonhapten pathway. The p-i concept appears most applicable to the initiation of delayed T-cell mediated reactions as opposed to hapten-initiated immediate IgE reactions. Although most immunoglobulin isotypes have been implicated in drug allergy, reactions are usually mediated by IgE and activated T cells. Immunoglobulin E (IgE) bound to basophils or mast cells mediates immediate reactions. IgG or IgM antibodies also may be involved in drug allergy, resulting in destruction of cells and tissues. Basophils and mast cells are instrumental in the development of immediate reactions, whereas eosinophils are recruited in both immediate and nonimmediate reactions. Platelets and vascular endothelial cells are important because they also can release a number of inflammatory mediators. Mediators of Allergic Reactions the release of a number of preformed, pharmacologically active chemical mediators (eg, histamine, heparin, proteases such as tryptase and chymase, and a variety of other enzymes) is triggered when antigens cross-link IgE molecules on the surface of circulating basophils and tissue mast cells. Histamine is a low-molecular-weight amine compound formed by decarboxylation of histidine and is stored in basophil and mast cell granules. The tissue effects of histamine are evident within 1 to 2 minutes, but it is rapidly metabolized within 10 to 15 minutes. The major effects of histamine on target tissues include increased capillary permeability, contraction of bronchial and vascular smooth muscle, and hypersecretion of mucous glands. Four classes of histamine receptors (H1-H4) are present in varying degrees in organs and tissues. H1 receptors are most prominent in blood vessels and bronchial and intestinal smooth muscle. Platelet-activating factor is a glyceride-derived substance that is released by mast cells, alveolar macrophages, neutrophils, platelets, and other cells but not by basophils. It has potent bronchoconstrictor effects and causes platelet aggregation and lysis. Thromboxanes cause platelet aggregation and are important regulators of coagulation. The complement system consists of about 30 plasma proteins and is involved in allergy through a variety of immunologic responses, including enhancement of phagocytosis (opsonization of target cells), cell lysis, and generation of anaphylatoxins C3a, C4a, and C5a, which can cause non-IgEmediated activation of mast cells and release of inflammatory mediators. The Coombs and Gell classification was developed before our understanding of the varied roles of T cells in the immune response. As such, the original classification system has been adapted to better represent our current understanding of drug allergy (see Table e88-1). Immediate reactions typically occur within 1 hour of first re-exposure to an immunogenic drug and manifest as angioedema, bronchospasm, anaphylaxis or anaphylactic shock. As noted by the expert panel, this classification system has limitations because route of drug administration and the presence of immune co-factors (eg, viruses, drug interactions affecting drug metabolism) can influence the onset or progression of the immune reaction. On repeat exposure to the drug, B memory cells allow for early recognition of the immunogen. Two or more IgE molecules on the basophil or mast cell surface bind to one multivalent antigen molecule (referred to as cross-linking), initiating cellular activation. Generation of a type I reaction results in an immediate reaction that may be limited to single organs, typically in the nasal mucosa (rhinitis), respiratory tract (acute asthma), skin (urticaria), or gastrointestinal tract, or they can involve multiple organs simultaneously, termed anaphylaxis. First, the drug binds to the cell as a hapten (eg, the platelet or red blood cell). Antibodies (IgG or IgM) are produced that are specific for the bound drug or for a component of the cell surface altered by the drug. Cell destruction may be mediated by complement or by phagocytic cells that have antibody Fc receptors on their surfaces. Activation of complement near the cell surface can result in loss of cell membrane integrity and cell death. Alternatively, neutrophils, monocytes, or macrophages may bind to an antibody-coated cell through IgG Fc receptors on their cell surfaces, resulting in phagocytosis of the target cell. The process of enhancement of phagocytosis by antibody binding to cell surfaces or other particles is referred to as opsonization. In addition, cell-bound IgG may direct the nonphagocytic action of T cells or natural killer cells, which results in cell destruction by a process called antibody-dependent cellular cytotoxicity. This process can proceed in a nonspecific fashion as T cells bind to the target cell through IgG Fc receptors on the T-cell surface. This process may be initiated by drugs such as penicillin, quinidine, quinine, phenacetin, cephalosporins, and sulfonamides. The complexes form with drug immunogen and antibody in varying ratios and may deposit in tissues, resulting in local or disseminated inflammatory reactions. These substances cause the influx of neutrophils and result in the release of a number of toxic substances from the neutrophil (eg, proteinases, collagenases, kinin-generating enzymes, and reactive oxygen and nitrogen substances), which can cause local tissue destruction. Platelet aggregation may occur as a result of immune-complex formation, resulting in the formation of microthrombi and the release of vasoactive mediators. Also, insoluble complexes may be phagocytized by macrophages and activate these cells. In this model, a high level of preformed specific IgG antibody combines with antigen to produce a localized edematous, erythematous reaction within 5 to 8 hours. On exposure to the antigen, the immune response is mediated by a specific subtype of T cell that orchestrates an inflammatory response through the secretion of cytokines and the recruitment of effector cells. These reactions are associated with a wide variety of adverse effects and they also may be useful for diagnostic purposes. After intradermal injection, these antigens produce a local reaction (erythema and induration) within 48 to 72 hours. Other Allergic Reactions Not all drug allergies can be classified with the system described by Coombs and Gell because the precise immune drug mechanism may not be known. In some cases, hepatic drug reactions (cholestatic or hepatocellular) and pulmonary reactions (eg, nitrofurantoin-associated interstitial pneumonitis) have been described as immune events. Perhaps most common are the delayed dermatologic reactions that occur with a variety of drugs (especially penicillins and sulfonamides). These reactions may be evident as fixed drug eruptions; macropapular, morbilliform, or erythematous rashes; exfoliative dermatitis; photosensitivity reactions; or eczema. These reactions also may manifest as late onset pruritus, urticaria, and angioedema.

It has long been recognized that the lower the absolute neutrophil count arrhythmia greenville sc order cheap lopressor, the greater the risk of infection prehypertension yahoo order lopressor 50mg otc. Drugs (eg arrhythmia ketosis buy cheap lopressor 25mg, chemotherapy) and diseases (eg pulse pressure usmle buy line lopressor, collagen vascular disorders) may lower the neutrophil count and make the patient more susceptible to infections heart attack definition discount lopressor 25 mg otc. Functional analysis of these cell types is rarely done in routine clinical practice heart attack 720p purchase cheapest lopressor. Patients with suspected functional deficits in these cell types are generally referred to tertiary medical centers for evaluation and treatment. Lymphocyte populations with different functions or in various stages of activation can be enumerated based on their cell surface markers. Hundreds of monoclonal antibodies have been designed to recognize these cell surface markers. For flow cytometry, the cell suspension is put under pressure such that the cells flow past a laser in a stream of single cells. The laser will excite the fluorescently labeled antibodies bound to the lymphocytes. A light detector is able to count the labeled cell as the fluorescent tag emits light and determines the size of the cell based on its light scatter characteristics. Although no single test can predict the function of the immune system, available tests can measure the viability of certain cell lines and communication between cells. Historically, the most common in vivo assay of lymphocyte function is the delayed hypersensitivity skin test. This test specifically evaluates the presence of delayed-type hypersensitivity or the presence of memory T lymphocytes. Specifically, a small amount of antigen, of which the patient is known to have been previously exposed, is administered. Under normal immunologic host conditions, exposure to this amount of antigen in the skin should produce lymphocytic infiltrate into the area within a few hours; followed by additional lymphocyte recruitment and phagocytes (eg, macrophages and neutrophils) translocation. A delayed-type hypersensitivity reaction is a test of cell-mediated immunity used to assess immunocompetency. The most common method to assess delayed-type hypersensitivity is to administer intradermally a panel of recall antigens. Commonly used antigens include Candida albicans, mumps, Trichophyton, tetanus toxoid, and purified protein derivative of tuberculin. A reaction is considered positive if the diameter of induration is 2 mm or greater. Most immunocompetent individuals will show a positive reaction to at least one of these antigens. Global assessment of the in vivo immunologic response is also used commonly in solid organ transplantation during the diagnosis and assessment of acute rejection. For example, pathologists can detect cellular rejection on gross tissue biopsy by counting the number of lymphocytes present in the tissue and correlating their presence with other clinical findings, such as increasing serum creatinine in kidney transplant. In vivo assessment of B-lymphocyte function involves immunizing the patient with a protein (eg, tetanus toxoid) and a polysaccharide (eg, pneumococcal polysaccharide vaccine) antigen to elicit and measure antibody responses after immunization. This test measures B-lymphocyte responsiveness to the inoculated antigens but is reserved for patients who are suspected to have impaired B-lymphocyte function. The cells are exposed to nonspecific mitogens, such as pokeweed mitogen, phytohemagglutinin, or concanavalin A. Normally in the presence of the mitogens, lymphocytes will be stimulated to proliferate. The level of radioactivity of the cells can be measured on a -scintillation counter and is proportional to the degree of proliferation. The host lymphocytes are irradiated prior to the incubation so that they cannot proliferate. The degree of uptake correlates to the level of proliferation of donor lymphocytes. If the cells are mismatched, proliferation will be noted with the level of proliferation predictive of the potential extent of graftversus-host disease. This assay is one of the first functional assays aimed at assessing individual patient response to immunosuppressive therapy and may allow for tailoring of immunosuppression. Since Tregs control autoimmune reactions, the presence of these cells in an allograft may indicate a level of "tolerance" to the donor tissue. Tolerance, basically, is a state in which the body knows that foreign tissue (eg, kidney transplant) exists but does not attack it. Although these evaluations are not commonly performed, they may be helpful in some specific diseases and will likely be the way in which we monitor and detect immunologic events in the future. The most common evaluation of immunoglobulins is measurement of individual isotypes by immunoturbidity or immunonephelometry techniques. The -globulin fraction contains the five isotypes of immunoglobulin (IgG, IgA, IgM, IgE, and IgD). Total immunoglobulin or -globulin concentrations cannot be used to measure antigen-specific antibodies or specific isotypes, although they can be measured with other laboratory tests. In a patient suspected of having humoral immune deficiency or B-lymphocyte failure (primary and secondary hypogammaglobulinemia), specific immunoglobulin isotypes in the plasma should be measured. The most common reason to measure antigen-specific antibody is to determine whether or not a patient has been exposed to an infectious agent. Generally, IgM antibodies directed against the pathogen indicate an active or recent infection while IgG antibodies directed against the pathogen indicate prior exposure. This observation correlates with our understanding of B-lymphocyte responses in which plasma cells produce IgM initially in response to an infection, but later switches to IgG. Therefore, IgM antibodies will be present during an active infection and shortly after recovery from the infection. IgG concentrations will increase at the end of the primary exposure, but predominate after a second exposure. IgG predominates after a second exposure because memory B lymphocytes predominately secrete IgG in the serum. Other uses of antigen-specific antibody include determining if a patient has had exposure and is likely to be protected from infection (eg, hepatitis A virus) or to determine adequate response to vaccination (eg, hepatitis B vaccine). Measurement of antihuman IgG antibodies is used pre- and postsolid organ transplant to detect and potentially predict allograft compatibility and treat antibody-mediated rejection. Because the presence of antigen-specific IgE is related to clinical allergy, measurement of these antibodies can be helpful in diagnosing allergies and determining offending substances, but the circulating levels are so low they do not normally lead to interpretable results. Traditionally allergen-specific IgE was measured by radio-allergosorbent methodology. Contemporary laboratories have largely abandoned the use of radioisotope labels in immunoassays, and instead make use of enzymes labeled Anti IgE antibody as conjugate, with use of appropriate substrate for chemiluminescent, fluorescent, or colorimetric detection. After incubation and several washings, an enzyme-labeled antibody to IgE is added to bind to any IgE antibody bound to the antigen. After further washings, the enzyme-antibody conjugate bound to IgE, which is bound to the antigen on the bead or disk, is measured by an appropriate substrate, which generates the measurement signal, which is quantified. Antigen skin testing is the preferred method to determine the presence of allergen-specific IgE. When it is produced, IgE binds to high-affinity IgE Fc receptors on basophils or mast cells. Contact of an allergen with the specific IgE on the basophil or mast cell surface causes activation of these cells and the release of inflammatory mediators (eg, histamine). When it occurs in a confined area, such as the skin, erythema, and induration are observed within a few minutes of allergen injection. This is the principle used for detection of penicillin allergy and environmental or food allergies. A positive skin reaction (5 mm of induration) within 15 to 20 minutes indicates the presence of allergen-specific IgE. The four subclasses of IgG: IgG1, IgG2, IgG3, and IgG4 make up 65%, 20%, 10%, and 5% of total plasma IgG, respectively. Concentrations of the subclasses are often measured in patients with suspected primary and secondary hypogammaglobulinemia. Complement System the complement system consists of a group of over 30 different proteins involved in lysing and opsonizing invading pathogens as well as serving as chemotactic factors. Numbers following the letter C (eg, C1 and C2) name the various proteins of the complement system. Assessment of the complement system is important in patients suspected of having humoral immune deficiencies (ie, recurrent infections). This test is based on the premise that complement is needed for a rabbit anti-sheep antibody to lyse sheep red blood cells. Each laboratory standardizes the test so normal ranges vary, but a standard curve is developed by adding titrated amounts of sera and measuring the amount of hemolysis. The hemolysis is determined with a spectrophotometer to measure the amount of hemoglobin released. Many laboratories assess total complement activity with semiquantitative enzyme immunoassay methods based on enzyme-conjugated monoclonal antibodies that bind to newly expressed antigens of the terminal complement proteins or methodology based on lysis of antibody sensitized dinitrophenyl-labeled liposomes with trapped glucose-6-dehydrogenase. These tests do not provide an indication of the function of any specific complement component but is used as a screening test for any complement system defects. If a defect is found, individual complement proteins can then be evaluated by either functional or immunochemical methods. These states of apparent low complement concentrations are generally due to high rates of complement utilization or consumption that cannot be compensated for by increased complement synthesis. The presence of donor-specific antibodies is correlated with evidence of antibody-mediated rejection on tissue samples. This is characterized by the presence of complement split products, namely C4d, which is present after complement-dependent antibody-mediated rejection. C4d covalently binds to the allograft tissue and can be stained for biopsy samples. Unfortunately, unless biopsy findings can be correlated with a clinical finding consistent with rejection, the presence of C4d and its prognosis on long-term allograft function are unknown. Cytokines Disease states involving the loss or upregulation of cytokines are sometimes overlooked as diseases of the immune system. However, as we have just reviewed, cytokines are essential components of both the innate and adaptive immune systems and provide the communication linking them together. Methods to detect and measure cytokines in biological samples have been developed. For nearly all the currently identified cytokines, commercial kits are available to measure endogenous and exogenously administered cytokines. To measure the concentration of antibodies to a particular antigen, the antigen is coated onto a solid phase, such as a microtiter plate or beads. If the purpose of the assay is to measure the concentration of antigen in solution, an antibody to the antigen is coated on the solid phase. The intensity of the color as measured spectrophotometrically is proportional to the concentration of the antibody in the biologic fluid. We are still at the very early stages of interpreting the clinical relevance of endogenous cytokine concentrations. Therefore, measurement of cytokine concentrations may be important in the evaluation of other systems as well as the immune system. Administration of cytokines in clinical practice may change not only the concentration of that particular cytokine, but also the resultant concentration of other cytokines. In the future, tissue concentrations as well as blood concentrations may be measured. Soluble Receptors and Receptor Antagonists the inflammatory response is highly regulated. The activity of cytokines, their receptors, and their antagonists are in a delicate balance. Although cytokine receptors are typically thought of as being found on the target cell, soluble cytokine receptors can modulate the activity of cytokines in at least two ways: (a) acting as antiinflammatory agents by binding cytokines with high affinity, but without biological activity58; and (b) augmenting cytokine activity by prolonging the cytokines plasma half-life and even maintaining agonist activity on cells that do not inherently respond to the cytokine. One example is the administration of recombinant activated protein C (drotrecogin alfa) to patients in septic shock. Unfortunately, protein C also possesses anticoagulant and fibrinolytic properties, leading to a significantly increased risk of bleeding. As a result, no survival benefit was observed when drotrecogin alfa was given to patients in septic shock. Many of our newer biological agents directed at immune pathways are derived from animals, and are subsequently humanized via various genetic engineering techniques to increase their biological effectiveness and decrease their antigenicity. Despite these efforts, these agents can serve as antigens and elicit an immune response, which may have a variety of consequences. Based on the few examples presented here, one can understand why manipulation of the immune system must be carefully assessed and appropriate patient instruction given. Immunosuppression Immunosuppression was first developed and used to allow transplantation of foreign tissues or to treat malignancies of the immune system. These medications are usually very expensive and associated with potentially serious adverse effects. Immunosuppressants block critical steps of the immune response, and patients must be counseled on their risk of infection and the plan to monitor effectiveness of the immunosuppressant. Several key concepts and questions can be used to help clinicians discern the potential benefits and harms of administering any immunosuppressant. Immunopotentiation In an attempt to restore normal immune system function or to activate the immune system, immunopotentiators are often used. The best example of immunopotentiation of the immune system is the practice of immunizations.

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