David J.Moliterno, MD

• Professor and Vice-Chairman of Medicine
• Chief, Cardiovascular Medicine
• Jefferson Morris Gill Professor of Cardiology
• Gill Heart Institute and
• Division of Cardiovascular Medicine
• University of Kentucky
• Lexington, Kentucky

However menstrual emotions 25mg clomiphene, most studies test for only a few drugs or drug classes menopause depression treatment buy clomiphene online pills, and the repeated reporting of the same drugs may be a function of limited testing breast cancer awareness bracelets effective clomiphene 100mg. Before "driving under the influence of drugs" testing is as readily accepted by the courts as ethanol testing menstrual hormone cycle purchase clomiphene in united states online, many legal and scientific problems concerning drug concentrations and driving impairment must be resolved (Consensus Report pregnancy nightmares generic clomiphene 25 mg on-line, 1985) women's health clinic st louis cheap clomiphene 50mg on-line. The ability of analytical methodology to routinely quantify minute concentrations of drug in blood must be established. Also, drug-induced driving impairment at specific blood concentrations in controlled tests and/ or actual highway experience must be demonstrated. As a general rule of evidence, a witness may testify only to facts known to him or her. The witness may offer opinions solely on the basis of what he or she has observed (Moenssens et al. An expert witness may provide two types of testimony: objective testimony and "opinion. When a toxicologist testifies as to the interpretation of his or her analytical results or those of others, that toxicologist is offering an "opinion. Before a court permits opinion testimony, the witness must be "qualified" as an expert in his or her particular field. During direct examination, an expert witness has the opportunity to explain to the jury the scientific bases of his or her opinions. Regardless of which side has called the toxicologist to court, the toxicologist should testify with scientific objectivity. The jury, not the expert witness, determines the guilt or innocence of the defendant. During this cross-examination, the witness is challenged as to his or her findings and/or opinions. The toxicologist will be asked to defend his or her analytical methods, results, and opinions. The best way to prepare for such challenges before testimony is to anticipate the questions the opposing attorney may ask. After cross-examination, the attorney who called the witness may ask additional questions to clarify any issues raised during cross-examination. This allows the expert to explain apparent discrepancies in his or her testimony raised by the opposing attorney. Often, an expert witness is asked to answer a special type of question, the "hypothetical question. The expert is then asked for his or her conclusion or opinion based solely on this hypothetical situation. The witness should be sure he or she understands all the facts and implications in the question. As an aid in the diagnosis and treatment of toxic incidents, as well as in monitoring the effectiveness of treatment regimens, it is useful to clearly identify the nature of the toxic exposure and measure the amount of the toxic substance that has been absorbed. Frequently, this information, together with the clinical state of the patient, permits a clinician to relate the signs and symptoms observed to the anticipated effects of the toxic agent. This may permit a clinical judgment as to whether the treatment must be vigorous and aggressive or whether simple observation and symptomatic treatment of the patient are sufficient. A cardinal rule in the treatment of poisoning cases is to remove any unabsorbed material, limit the absorption of additional poison, and hasten its elimination. The clinical toxicology laboratory serves an additional purpose in this phase of the treatment by monitoring the amount of the chemical remaining in circulation or measuring what is excreted. In addition, the laboratory can provide the data needed to permit estimations of the total dosage or the effectiveness of treatment by changes in known pharmacokinetic parameters of the drug or other chemical ingested. Although the instrumentation and the methodology used in a clinical toxicology laboratory are similar to those utilized by a forensic toxicologist, a major difference between these two applications is responsiveness. In emergency toxicology testing, results must be communicated to the clinician within hours to be meaningful for therapy. A forensic toxicologist may carefully choose the best method for a particular test and conduct replicate procedures to assure maximum accuracy. A clinical laboratory cannot afford this luxury and may sacrifice accuracy for a rapid turnaround time. Additionally, because it is impossible to predict when toxicological emergencies will occur, a clinical laboratory must provide rapid testing 24 hours a day, every day of the year. Primary examples of the usefulness of emergency toxicology testing are the rapid quantitative determination of acetaminophen, salicylate, alcohols, and glycol serum concentrations in instances of suspected overdose. In addition, continuous monitoring of serum values permits an accurate pharmacokinetic calculation of the ingested dose (Melethil et al. Similarly, salicylate serum values related to the time after ingestion may indicate an overdose, providing a prognosis for possible delayed severe metabolic acidosis and the need for lifesaving dialysis treatment. Continuous monitoring of serum salicylate values permits an accurate assessment of the efficacy of dialysis. Although relatively few fatal intoxications occur with ethanol alone, serum values are important in the assessment of behavioral, physiologic, and neurological function, particularly in trauma cases where the patient is unable to communicate and surgery with the administration of anesthetic or analgesic drugs is indicated. Intoxications from accidental or deliberate ingestion of other alcohols or glycols-such as methanol from windshield deicer or paint thinner, isopropanol from rubbing alcohol, and ethylene glycol from antifreeze-are often encountered in emergency departments. Following ingestion of methanol or ethylene glycol, patients often present with similar neurological symptoms and severe metabolic acidosis due to the formation of toxic aldehyde and acid metabolites. A rapid quantitative serum determination for these intoxicants will indicate the severity of intoxication and the possible need for dialysis therapy. Alcohol infusion, in order to saturate the enzyme alcohol dehydrogenase, blocks the conversion of methanol and ethylene glycol to their toxic metabolites. To provide effective service to the emergency department, laboratories should have available chromatographic methods for the rapid separation and detection of alcohols and glycols (Edinboro et al. The utilization of the analytical capabilities of a clinical toxicology laboratory has increased enormously in recent years. Typically, the laboratory performs testing not only for the emergency department but also for a wide variety of other medical departments, as drugs and toxic chemicals may be a consideration in diagnosis. Urine is analyzed from substance abuse treatment facilities to monitor the administration of methadone or other therapeutic agents and/ or to assure that patients do not continue to abuse drugs. Similarly, psychiatrists, neurologists, and physicians treating patients for chronic pain need to know whether patients are self-administering drugs before such patients undergo psychiatric or neurological examinations. Analysis for drugs of abuse in meconium and urine obtained from neonates is used to corroborate the diagnosis of withdrawal symptoms in newborns and document fetal exposure to controlled substances. Toxic metal determinations, such as blood lead concentration, are often performed to assess possible toxic metal exposure or severity of toxicity. The rate of this conversion is a sensitive indicator of hepatic dysfunction and is often used to assess hepatic viability in donor livers prior to transplantation. A dosage amount was selected and administered at appropriate intervals based on what the clinician had learned was generally tolerated by most patients. If the drug seemed ineffective, the dose was increased; if toxicity developed, the dose was decreased or the frequency of dosing was altered. Establishing an effective dosage regimen was particularly difficult in children and the elderly. The factors responsible for individual variability in responses to drug therapy include the rate and extent of drug absorption, distribution, and binding in body tissues and fluids, rate of metabolism and excretion, pathological conditions, and interaction with other drugs (Blaschke et al. Monitoring of the plasma or serum concentration at regular intervals will detect deviations from the average serum concentration, which, in turn, may suggest that one or more of these variables need to be identified and corrected. With multiple administrations of a given drug at regular intervals, plasma drug concentrations will gradually increase and eventually reach a plateau over the course of therapy. The plateau is referred to as a steady-state condition, whereas the amount of drug absorbed is in equilibrium to the amount of drug eliminated. Serum ethylene glycol and ethanol concentrations monitored during dialysis and ethanol infusion therapy. For drugs that have a defined correlation between serum concentrations and undesired toxic effects, the lowest serum concentration immediately prior to dosing (trough) and the highest expected serum concentration (peak) are monitored to assure efficacy and minimize toxicity. Because the drug being administered is known, qualitative characterization of the analyte generally is not required. Frequently, the methodology applied is important, particularly in regard to its selectivity. For example, methods that measure the parent drug and its metabolites are not ideal unless the individual analytes can be quantified separately. Depending on the drug, metabolites may or may not be active to a different degree than the parent drug. This metabolite has antiarrhythmic activity of almost equal potency to that of the parent drug procainamide. Because absolute characterization of the analyte is not necessary for many drugs, immunoassay procedures are commonly used. This is particularly true of drugs with extremely low serum concentrations, such as cardiac glycosides, and drugs that are difficult to extract because of a high degree of polarity, such as the aminoglycoside antibiotics. In these cases, serum can be conveniently assayed directly by using commercially available kits for immunoassays. The chromatographic methods in which an appropriate internal standard is added are favored when more than one analyte is to be quantified or if metabolites with structures similar to those of the parent drugs must be distinguished. Because the nature of drugs is varied, many different analytical techniques may be applied, including atomic absorption spectrophotometry for measuring lithium used to treat manic disorders. Virtually all the tools of the analyst may be used for specific applications of analytical toxicology. Many new analytical tools have been applied to toxicological problems in almost all areas of the field, and the technology continues to open new areas of research. Forensic toxicologists continue to be concerned about conducting unequivocal identification of toxic substances in such a manner that the results can withstand a legal challenge. As these challenges are met, analytical toxicologists will continue to play a substantial role in the expansion of the discipline of toxicology. An overview of gamma-hydroxybutyric acid: pharmacodynamics, pharmacokinetics, toxic effects, addiction, analytical method, and interpretation of results. Postmortem tricyclic antidepressant concentrations: assessing cause of death using parent drug to metabolite ratio. Interpretation of drug concentrations in an alternative matrix: the case of meprobamate in vitreous humor. Hair as a biological indicator of drug use, drug abuse or chronic exposure to environmental toxicants. Artifact formation during chloroform extraction of drugs and metabolites with amine substitutes. Synthetic cathinones: chemistry, pharmacology and toxicology of a new class of designer drugs of abuse marketed as "bath salts" or "plant food". Detection of antidepressant and antipsychotic drugs in postmortem human scalp hair. The effects of adulterants and selected ingested compounds on drugs-of-abuse testing in urine. Mandatory guidelines for federal workplace drug testing: final guidelines-notice. Determination of ethylene glycol in serum utilizing direct injection on a wide-bore capillary column. Determination of chromate adulteration of human urine by automated colorimetric and capillary ion electrophoretic analyses. Alcohol and the Impaired Driver: A Manual on the Medicolegal Aspects of Chemical Tests for Intoxication. Resolution of methamphetamine stereoisomers in urine drug testing: urinary excretion of R(-)-methamphetamine following use of nasal inhalers. Preliminary observations of the effects of amitriptyline in decomposing tissue on the development of Parasarcophaga ruficornis (Diptera: Sarcophagidae) and implications of this effect to estimation of postmortem interval. Commonly practiced quality control and quality assurance procedures for gas chromatography mass spectrometry analysis in forensic urine drug-testing laboratories. A pyrolysis product, anhydroecgonine methyl ester (methylecgonidine), is in the urine of cocaine smokers. Interfering compounds and artifacts in the identification of drugs in autopsy material. Analytical and Practical Aspects of Drug Testing in Hair [International Science and Forensic Investigation]. Detection of paraquat in oral fluid, plasma, and urine by capillary electrophoresis for diagnosis of acute poisoning. Papain adulteration in 11-nor-delta9-tetrahydrocannabinol-9-carboxylic acid-positive urine samples. Recommendations for toxicological investigation of drug-facilitated sexual assaults. The role of variations in growth rate and sample collection on interpreting results of segmental analyses of hair. Potassium nitrite reaction with 11-nordelta-9-tetrahydrocannabinol-9-carboxylic acid in urine in relation to drug screening analysis. Determination of morphine in the hair of heroin addicts by high performance liquid chromatography with fluorometric detection. Ethanol, marijuana, and other drug use in 600 drivers killed in single-vehicle crashes in North Carolina. Estimation of the amount of drug absorbed in acetaminophen poisoning: a case report. Studies on the structure-activity relationships for the metabolism of polybrominated biphenyls by rat liver microsomes. Detection of a metabolite of -benzylN-methylphenylamine synthesis in a mixed drug fatality involving methamphetamine. Deaths involving fentanyl, fentanyl analogs, and U-47700-10 States, JulyDecember 2016.

These are common vital sign findings when there is an acute decrease in the PaO level womens health 2014 beauty awards buy clomiphene discount. In addition to asthma women's health center hudson ny cheap clomiphene online, other common respiratory disorders that cause acute alveolar hyperventilation with hypoxemia include pneumonia pregnancy x medications clomiphene 25mg online, postoperative atelectasis menstruation 2 days only discount clomiphene 50 mg line, pulmonary edema breast cancer lumpectomy buy clomiphene 50mg with mastercard, pneumothorax women's health center wv purchase discount clomiphene online, pleural effusion, and acute respiratory distress syndrome. Even though this patient appears short of breath, oxygen therapy is not really indicated (although it would not hurt the patient). Her agitation and appearance of respiratory distress are most likely caused by pain. Chronic alveolar hyperventilation is also seen in patients during the early stages of chronic pulmonary disease, chronic heart failure, and in people who reside in areas of high altitudes. This is due to water and chloride ion shifts that occur between the intercellular and extracellular spaces when the renal system works to compensate for a decreased blood pH. According to the law of electroneutrality, the total number of plasma positively charged ions (cations) must equal the total number of plasma negatively charged ions (anions) in the body fluids. To determine the anion gap, the most commonly measured cations are sodium (Na1) ions. An elevated anion gap is most commonly caused by the accumulation of fixed acids. Whenever an acute hypoxemia is present, the presence of lactic acids should be suspected. When blood insulin is low in the patient with diabetes, serum glucose cannot easily enter the tissue cells for metabolism. This condition activates alternate metabolic processes that produce ketones as metabolites. The excessive ingestion of aspirin leads to an increased level of salicylic acids in the blood and metabolic acidosis. Metabolic acidosis caused by salicylate intoxication causes the anion gap to increase. Metabolic acidosis caused by severe diarrhea is associated with a normal anion gap. Nonvolatile acids (also called fixed acids or metabolic acids) are produced from sources other than carbon dioxide-for example, ketone acids, which are commonly associated with diabetes or starvation. The lungs do not excrete nonvolatile acids; only the renal system can excrete fixed acids. Ketoacidosis is commonly seen in the diabetic patient who is not eating properly or not taking his or her insulin at regular intervals. In this case, it is also interesting to note that the patient is not hyperventilating because of a low arterial oxygenation level. A greater than normal PaO -even as high as 115 to 120 mm Hg-is not unusual in the patient with ketoacidosis-even on room air! Other causes of metabolic acidosis include lactic acidosis (caused by inadequate oxygen for tissue metabolism), renal failure, salicylate intoxication (aspirin overdose), and uncontrolled diarrhea. Once the patient is adequately oxygenated, the metabolic acidosis (caused by lactic acids) usually dissipates rapidly. For example, a metabolic acidosis caused by lactic acids justifies the need for oxygen therapy (to reverse the accumulation of the lactic acids) or one caused by ketone acids justifies the need for insulin (to reverse the accumulation of the ketone acids). To summarize, when metabolic acidosis is accompanied by an increased anion gap, the most likely cause of the acidosis is fixed acids. Metabolic Acidosis with Respiratory Compensation Under normal conditions, the immediate compensatory response to metabolic acidosis is an increased ventilatory rate (respiratory compensation). He has a long history of asthma and has been hospitalized for exacerbation of asthma three different times over the past 4 years. In fact, during his last hospital stay, he was on a mechanical ventilator for 48 hours. In this case, the patient needs to be immediately intubated, placed on a mechanical ventilator, and started on a regimen of first-line defense bronchodilator therapy and oxygen therapy. While the mechanical ventilator is being set up, the respiratory therapist should aggressively ventilate the patient with 100 percent oxygen via a bag and mask. The respiratory therapist should always be on the lookout for lactic acidosis when the PaO is severely low. Whenever the potassium level is low, the kidneys attempt to conserve potassium by excreting hydrogen ions. In addition, as the potassium level in the blood decreases, intracellular potassium moves into the extracellular space in an effort to offset the reduced potassium level in the blood serum. As the potassium (K1) cation leaves the cell, however, a hydrogen cation (H1) enters the cell. Patients with hypokalemia frequently demonstrate the clinical triad of (1) metabolic alkalosis, (2) muscular weakness, and (3) cardiac dysrhythmia. When the chloride ion (Cl2) concentration decreases, bicarbonate ions increase in an attempt to maintain a normal cation balance in the blood serum. Large doses of sodium-retaining corticosteroids can cause the kidneys to accelerate the excretion of hydrogen ions and potassium. Excessive excretion of either one or both of these ions will cause metabolic alkalosis. If an excessive amount of sodium bicarbonate is administered, metabolic alkalosis will occur. Although it is not as directly lifethreatening as metabolic acidosis, metabolic alkalosis is potentially dangerous. Cardiac arrhythmias associated with hypokalemia include premature atrial and ventricular contractions, atrial and ventricular tachycardia, and ventricular fibrillation. Potassium plays an important role in normal cardiac function and skeletal and smooth muscle contraction. Hypokalemia and metabolic alkalosis are common causes of muscle weakness and difficult weaning from mechanical ventilation. The student should recall that alkalosis (increased pH) shifts the oxyhemoglobin curve to the left, making it more difficult for the hemoglobin to release oxygen to the tissues. Other causes of metabolic alkalosis include hypochloremia, gastric suction or vomiting, excessive administration of corticosteroids and sodium bicarbonate, diuretic therapy, and hypovolemia. At this time, the mechanical ventilator is set as follows: rate-12 breaths/min, tidal volume-0. For unrelated respiratory problems, she is receiving diuretic therapy, corticosteroids, and potassium to treat her hypokalemia. The attending physician should be notified to correct the metabolic alkalosis problems caused by the diuretic therapy, corticosteroids, and hypokalemia. This can easily be accomplished by either decreasing the tidal volume or decreasing the respiratory rate on the ventilator. Metabolic alkalosis is treated by correcting the underlying electrolyte problem. Because of this, the patient was frequently suctioned orally to prevent aspiration. Although he was still unconscious, he (continued) 344 Section one the Cardiopulmonary System-The Essentials Clinical Application Case 1 (continued) was breathing on his own through a non-rebreathing oxygen mask. A medical student assigned to the emergency department stated that it appeared that the patient was being over-oxygenated-because his skin appeared cherry red-and that perhaps the oxygen mask should be removed. The patient was transferred to the intensive care unit, where he continued to be monitored closely. Although the patient never required mechanical ventilation, he continued to receive high concentrations of oxygen for the first 48 hours. By the end of the third day he was breathing room air and was conscious and able to talk with his family and the medical staff. His vital signs were blood pressure-117/77 mm Hg, heart rate-68 beats/min, and respirations-12 breaths/min. In addition, any oxygen that was being carried by the hemoglobin was unable to detach itself easily from the hemoglobin. The "cherry red" skin color noted by the medical student was a classic sign of carbon monoxide poisoning and not a sign of good skin color and oxygenation. His physician ordered a full diagnostic evaluation of the patient, which included a complete pulmonary function study and stress test. In fact, he jokingly stated that whenever he would start to feel as if he should start to exercise, he would quickly sit down and the feeling would go away. The patient was about 35 pounds overweight and, during the stress test, appeared moderately ashen and diaphoretic. When the patient collapsed, a "Code Blue" was called and cardiopulmonary resuscitation was started immediately. When the Code Blue Team arrived, the patient had an oral airway in place and was being manually ventilated, with room air only, using a face mask and bag. Immediately after the patient was intubated, breath sounds could be heard bilaterally. While waiting for the arterial blood gas analysis results, epinephrine and norepinephrine were administered. Two hours later, it was determined that the patient would not require mechanical ventilation and he was extubated. Fortunately, this was discovered when the first arterial blood gas values were seen. In this case, therefore, the treatment of choice was to correct the cause of the respiratory and metabolic acidosis. Because the cause of the respiratory and metabolic acidosis was inadequate ventilation, the treatment of choice was aggressive ventilation. Finally, as shown by the second arterial blood gas analysis, the arterial blood gases were rapidly corrected after intubation. Metabolic acidosis caused by fixed acids is present when the anion gap is greater than A. The increased blood pressure, heart rate, and respiratory rate seen in the emergency. Explain how the ventilationperfusion ratio progressively changes from the upper to the lower lung regions in the normal upright lung. Describe how an increased and decreased ventilationperfusion ratio affects alveolar gases. Describe how the ventilationperfusion ratio affects endcapillary gases and the pH level. Ventilation-Perfusion Ratio Ideally, each alveolus in the lungs should receive the same amount of ventilation and pulmonary capillary blood flow. Overall, alveolar ventilation is normally about 4 L/min and pulmonary capillary blood flow is about 5 L/min, making the average overall ratio of ventilation to blood In the normal individual in the upright position, the alveoli in the upper portions of the lungs (apices) receive a In the lower regions of the lung, however, alveolar ventilation is moderately increased and blood flow Thus, the V/Q ratio progressively decreases from top to bottom in the upright lung, and the average V/Q ratio is about 0. An increased V/Q ratio can develop from either (1) an increase in ventilation or (2) a decrease in perfusion. Increased V/Q Ratio 1 Refer to how oxygen can be classified as either perfusion or diffusion limited in Chapter 4. In the upright lung, the V/Q ratio progressively decreases from the apex to the base. This case nicely illustrates how an increased ventilation-perfusion ratio can develop as a result of an excessive amount of blood loss. A decreased V/Q ratio can develop from either a decrease in ventilation or an increase in perfusion. The lines in the chart represent all the possible alveolar gas compositions as the V/Q ratio decreases or increases. This case nicely illustrates how an upper airway obstruction can cause a low ventilation-perfusion ratio. The overall pH in the pulmonary veins and, subsequently, in the arterial blood is normally about 7. Under normal circumstances, about 250 mL of oxygen are consumed by the tissues during 1 minute. In fact, capnography is an excellent way to monitor the effectiveness of bronchodilator therapy in the patient experiencing a severe asthmatic episode. This is because bronchospasm produces the classic "shark-fin" wave form on the capnogram as the patient struggles to exhale. As the bronchospasm lessens in response to the bronchodilator therapy, the B-C line moves back to its normal. B to c is the exhalation upstroke where dead space gas mixes with alveolar gas. For example, in disorders that diminish pulmonary perfusion, the affected lung area receives little or no blood flow in relation to ventilation. How Respiratory Disorders Affect the V/Q Ratio Pulmonary emboli Partial or complete obstruction in the pulmonary artery or some of the arterioles. As a result, a larger portion of the pulmonary blood flow will not be physiologically effective in terms of gas exchange and is said to V/Q ratio changes from the upper to lower lung regions in the normal upright lung and (2) how an increased Related topics include the respiratory quotient and respiratory exchange ratio and respiratory disorders that increase the

Immune responses against microbial antigens may cause disease if the reactions are excessive or the microbes are unusually persistent encyclopedia of women's health issues clomiphene 25mg on line. T cell responses against persistent microbes may give rise to severe inflammation menstruation and fatigue generic clomiphene 100mg, sometimes with the formation of granulomas; this is the cause of tissue injury in tuberculosis and some other chronic infections breast cancer 25 years old cheap clomiphene 50 mg on-line. Rarely menstrual acne generic 25mg clomiphene mastercard, antibodies or T cells against a microbe will cross-react with a host tissue menstrual hygiene day buy clomiphene 100mg overnight delivery. Sometimes the mechanisms that an immune response uses to eradicate a pathogenic microbe require killing infected cells women's health group lafayette co buy cheap clomiphene 100mg online, and therefore such responses inevitably injure host tissues. For example, in viral hepatitis, the virus that infects liver cells is not cytopathic, but it is recognized as foreign by the immune system. Most healthy individuals do not react against common, generally harmless environmental substances, but almost 20% of the population is abnormally responsive to one or more of these substances. These individuals produce immunoglobulin E (IgE) antibodies that cause allergic diseases (see Chapter 20). Some individuals become sensitized to environmental antigens and chemicals that contact the skin and develop T cell reactions that lead to cytokine-mediated inflammation, resulting in contact sensitivity. Idiosyncratic immunologic reactions against therapeutic drugs are also a frequent clinical problem. Because the stimuli for these abnormal immune responses are often impossible to eliminate. Therefore, these hypersensitivity diseases tend to be chronic and progressive and pose major therapeutic challenges in clinical medicine. By convention, and especially in clinical situations, the term hypersensitivity refers to harmful immune responses against foreign antigens (environmental antigens, drugs, microbes) and is not used to describe tissue injury in autoimmune diseases. However, in our discussion, we will consider all causes of harmful immune reactions, mainly to emphasize the common pathogenic mechanisms. These mechanisms include some that are predominantly dependent on antibodies and others predominantly dependent on T cells, although a role for both humoral and cell-mediated immunity is often found in many hypersensitivity diseases. In all of these conditions, the mechanisms of tissue injury are the same as those that normally function to eliminate infectious pathogens. These mechanisms include innate and adaptive immune responses involving phagocytes, antibodies, T lymphocytes, mast cells, and various other effector cells, and mediators of inflammation. IgG and IgM antibodies specific for cell surface or extracellular matrix antigens can cause tissue injury by activating the complement system, by recruiting inflammatory cells, and by interfering with normal cellular functions. IgM and IgG antibodies specific for soluble antigens in the blood form complexes with the antigens, and the immune complexes may deposit in blood vessel walls in various tissues, causing inflammation, thrombosis, and tissue injury. In these disorders, tissue injury may be due to T lymphocytes that induce inflammation or directly kill target cells. Antitissue/cell antibodies: Antibodies may bind specifically to extracellular tissue antigens and the recruited leukocytes cause tissue injury, or antibodies may bind to cells (in this example, circulating red cells) and promote depletion of these cells. Immune complexes: Complexes of antibodies and antigens may be formed in the circulation and deposited in the walls of blood vessels, where the complexes induce inflammation. In the discussion that follows, we will use descriptions that identify the pathogenic mechanisms rather than the less informative numerical designations for types of hypersensitivity. This classification is useful because distinct types of pathologic immune responses show different patterns of tissue injury and may vary in their tissue specificity. As a result, the different immunologic mechanisms cause disorders with distinct clinical and pathologic features. However, immunologic diseases in humans are often complex and caused by combinations of humoral and cell-mediated immune responses and multiple effector mechanisms. This complexity is not surprising, given that a single antigen may normally stimulate both humoral and cell-mediated immune responses in which several types of antibodies and effector T cells are produced. Antibodies against cellular or tissue antigens cause diseases that specifically affect the cells or tissues where these antigens are present, so these diseases are often organ-specific and not systemic. By contrast, the manifestations of diseases caused by immune complexes reflect the site of immune complex deposition and are not determined by the cellular source of the antigen. To prove that a disease is caused by antibodies, one would need to demonstrate that the lesions can be induced in a normal animal by the adoptive transfer of immunoglobulin purified from the blood or affected tissues of individuals with the disease. An experiment of nature is occasionally seen in children of mothers suffering from antibody-mediated diseases. These infants may be born with transient manifestations of such diseases because of a transplacental passage of antibodies. However, in clinical situations, the diagnosis of diseases caused by antibodies or immune complexes is usually based on the demonstration of antibodies or immune complexes in the circulation or deposited in tissues, as well as clinicopathologic similarities with experimental diseases that are proved to be antibody mediated by adoptive transfer. A, Antibodies opsonize cells and may activate complement, generating complement products that also opsonize cells, leading to phagocytosis of the cells through phagocyte Fc receptors or C3b receptors. B, Antibodies recruit leukocytes by binding to Fc receptors or by activating complement and thereby releasing by-products that are chemotactic for leukocytes. C, Antibodies specific for cell surface hormone receptors or neurotransmitter receptors interfere with normal physiology. In myasthenia gravis (right panel), autoantibodies specific for the acetylcholine receptor on muscle cells block the action of acetylcholine, leading to paralysis. These opsonized cells are phagocytosed and destroyed by phagocytes that express receptors for the Fc portions of IgG antibodies and receptors for complement proteins. This is the principal mechanism of cell destruction in autoimmune hemolytic anemia and autoimmune thrombocytopenia, in which antibodies specific for red blood cells or platelets, respectively, lead to the opsonization and removal of these cells from the circulation. Antibodies deposited in tissues activate complement, leading to the liberation of breakdown products such as C5a and C3a, which recruit neutrophils and macrophages. These leukocytes express IgG Fc receptors and complement receptors, which bind the antibodies or attached complement proteins. An example of antibody-mediated inflammation and leukocyte activation causing tissue injury is glomerulonephritis. Antibodies that bind to normal cellular receptors or other proteins may interfere with the functions of these receptors or proteins and cause disease without inflammation or tissue damage. Antibodies specific for intrinsic factor, required for vitamin B12 absorption, cause pernicious anemia. Antibodies specific for cytokines are rare but known causes of immunodeficiencies. In a rare sequel to streptococcal infection called rheumatic fever, antibodies produced against the bacteria cross-react with antigens in the heart, deposit in this organ, and cause inflammation and tissue damage. A, Glomerulonephritis induced by an antibody against the glomerular basement membrane (Goodpasture syndrome): the light micrograph shows glomerular inflammation and severe damage, and immunofluorescence shows smooth (linear) deposits of antibody along the basement membrane. B, Glomerulonephritis induced by the deposition of immune complexes (systemic lupus erythematosus): the light micrograph shows neutrophilic inflammation, and the immunofluorescence and electron micrograph show coarse (granular) deposits of antigen-antibody complexes along the basement membrane. Jean Olson, Department of Pathology, University of California, San Francisco, and the electron micrograph is courtesy of Dr. At the time, diphtheria infections were treated with serum from horses that had been immunized with the diphtheria toxin, which is an example of passive immunization against the toxin by the transfer of serum containing antitoxin antibodies. Von Pirquet noted that joint inflammation (arthritis), rash, and fever developed in patients who were injected with the antitoxin-containing horse Immunofluorescence Light microscopy serum. Clinical features of this reaction suggested that it was not due to the infection or a toxic component of the serum itself. The symptoms appeared at least 1 week after the first injection of horse serum and more rapidly with each repeated injection. Von Pirquet concluded that this disease was caused by a host response to some component of the serum. He suggested that the host made antibodies to horse serum proteins; these antibodies Diseases Caused by Antibodies 423 formed complexes with the injected proteins, and the disease was due to the antibodies or immune complexes. The same reaction was also observed in humans receiving serum therapy for tetanus, and it is now more commonly known as serum sickness. This remains a clinical issue today in individuals who receive therapeutic monoclonal antibodies produced in rodents that contain nonhuman sequences or antisera made in animals that are used to treat snakebites or rabies. These antibodies bind to and form complexes with the circulating antigen, and the complexes are initially cleared by macrophages in the liver and spleen. As more and more antigen-antibody complexes are formed, some of them are deposited in vascular beds. In these tissues, the complexes induce neutrophil-rich inflammation by activating the classical pathway of complement and engaging leukocyte Fc receptors. Because the complexes are often deposited in small arteries, renal glomeruli, and the synovia of joints, the most common clinical and pathologic manifestations are vasculitis, nephritis, and arthritis. The clinical symptoms are usually short-lived, and the lesions heal unless the antigen is injected again. A more indolent and prolonged disease, called chronic serum sickness, is produced by multiple injections of antigen, which lead to the formation of smaller complexes that are deposited most often in the kidneys, arteries, and lungs. It is induced by subcutaneous injection of an antigen into a previously immunized animal or an animal that has been given an intravenous injection of antibody specific for the antigen. Circulating antibodies rapidly bind to the injected antigen and form immune complexes that are deposited in the walls of small blood vessels at the injection site. This deposition gives rise to a local cutaneous vasculitis, with thrombosis of the affected vessels, leading to tissue necrosis. The clinical relevance of the Arthus reaction is limited; rarely, a subject receiving a booster dose of a vaccine may develop inflammation at the site of injection because of local accumulation of immune complexes, as in an Arthus reaction. Antigen-antibody complexes are produced during normal immune responses, but they cause disease only when they are produced in excessive amounts, are not efficiently cleared, and become deposited in tissues. Small complexes are often not phagocytosed and tend to be deposited in vessels more than large complexes, which are usually cleared by phagocytes. Complexes containing cationic antigens bind avidly to negatively charged components of the basement membranes of blood vessels and kidney glomeruli. Capillaries in the renal glomeruli and synovia are sites where plasma is ultrafiltered (to form urine and synovial fluid, respectively) by passing at high pressure through specialized basement membranes, and these locations are among the most common sites of immune complex deposition. However, immune complexes may be deposited in small vessels in virtually any tissue. Immune complexes deposited in vessel walls and tissues activate leukocytes and mast cells to secrete cytokines and vasoactive mediators. These mediators may cause more immune complex deposition in vessel walls by increasing vascular permeability and blood flow. Injection of bovine serum albumin into a rabbit leads to the production of specific antibody and the formation of immune complexes. These complexes are deposited in multiple tissues, activate complement (leading to a decrease in serum complement levels), and cause inflammatory lesions, which resolve as the complexes and the remaining antigen are removed and free antibody (not bound to antigen) appears in the circulation. These are the same mechanisms that cause tissue injury in serum sickness, described earlier. Many systemic immunologic diseases in humans are caused by the deposition of immune complexes in blood vessels (Table 19. This is also the mechanism of a disease called poststreptococcal glomerulonephritis, which develops in rare cases after streptococcal infection and is caused by complexes of streptococcal antigen and antibodies depositing in the glomeruli of the kidney. In some forms of glomerulonephritis, immune complexes are not detected in the circulation, leading to the postulate that the antigens are first planted in the kidney and the complexes form locally. The T cells that cause tissue injury may be autoreactive, or they may be specific for foreign protein antigens that are present in or bound to cells or tissues. Diseases Caused by T Lymphocytes 425 intracellular microbes that resist eradication by phagocytes and antibodies. A role for T cells in causing a particular immunologic disease is suspected largely on the basis of the demonstration of T cells in lesions and the detection of increased levels of cytokines in the blood or tissues that may be derived from T cells. Animal models have been very useful for elucidating the pathogenesis of these disorders. Diseases Caused by Cytokine-Mediated Inflammation In immune-mediated inflammation, Th1 and Th17 cells secrete cytokines that recruit and activate leukocytes. Tissue injury results from the products of the recruited and activated neutrophils and macrophages, such as lysosomal enzymes and reactive oxygen species. Cytokines produced by activated lymphocytes and macrophages stimulate more leukocyte recruitment and inflammation, thus propagating the damage (see Chapter 10). Chronic inflammatory reactions often produce fibrosis as a result of the secretion of cytokines and growth factors by the macrophages and T cells.

An inbred strain B mouse will reject a graft from an inbred strain A mouse with first-set kinetics (left panel) menopause vaginal dryness purchase clomiphene 25mg visa. An inbred strain B mouse sensitized by a previous graft from an inbred strain A mouse will reject a second graft from an inbred strain A mouse with second-set kinetics (middle panel) womens health network purchase clomiphene 50 mg with mastercard, demonstrating memory women's health issues in texas discount clomiphene 25mg amex. An inbred strain B mouse injected with lymphocytes from another strain B mouse that has rejected a graft from a strain A mouse will reject a graft from a strain A mouse with second-set kinetics (right panel) women's health clinic newark ohio 50mg clomiphene amex, demonstrating the role of lymphocytes in mediating rejection and memory pregnancy z pack antibiotic cheap clomiphene 25mg overnight delivery. An inbred strain B mouse sensitized by a previous graft from a strain A mouse will reject a graft from a third unrelated strain with first-set kinetics menstrual emotions purchase discount clomiphene online, thus demonstrating another feature of adaptive immunity, specificity (not shown). Such results suggested that the molecules in the grafts that are responsible for eliciting rejection must be poly morphic and their expression is codominant. Polymorphic refers to the fact that these graft antigens differ among the individuals of a species (other than identical twins) or between different inbred strains of animals. Codomi nant expression means that every individual inherits genes encoding these molecules from both parents, and both parental alleles are expressed. George Snell and colleagues produced pairs of congenic strains of inbred mice that were bred to be genetically identical to each other except for genes needed for graft rejection. The relevance of minor histocompatibility antigens in clinical solid organ transplantation is uncertain, mainly because there has been little success in identifying the relevant antigens. Although in humans there is a slightly higher risk of rejection of heart transplants from male donor to female recipient, compared with Adaptive Immune Responses to Allografts 377 gendermatched transplants, given the scarcity of donor hearts, gender matching is not practical. This process is called indirect presentation (or indirect recognition), and it is essentially the same as the recognition of any foreign. Because these complexes are not normally expressed in the thymus or peripheral tissues, they have not participated in negative selection of T cells potentially dangerous to allogeneic grafts. It is likely that these memory cells were gener ated during previous exposure to other foreign. These memory cells not only are expanded populations of antigenspecific cells but also are more rapid and powerful responders than are naive lymphocytes, and thus contribute to the greater strength of the initial alloreactive T cell response to a new graft. Evidence has also been obtained that indirect antigen presentation may contribute to chronic rejection of human allografts. Activation and Effector Functions of Alloreactive T Lymphocytes When lymphocytes recognize alloantigens, they become activated to proliferate, differentiate, and perform effec tor functions that can damage grafts. The activation steps are similar to those we have described for lymphocytes reacting to microbial antigens. Host dendritic cells from the recipient may also migrate into the graft, pick up graft alloantigens, and transport these back to the draining lymph nodes, where they are displayed (the indirect pathway). The effector cells migrate back into the graft and mediate rejection, by mechanisms that are discussed later. B, the alloreactive effector T cells migrate into the allograft, become reactivated by alloantigen, and mediate damage. Costimulation is likely most important to activate naive alloreactive T cells, but even alloreactive memory T cell responses can be enhanced by costimulation. As we will discuss later, blocking of B7 costimulation is a thera peutic strategy to inhibit graft rejection in humans as well. Thus, activation of alloreactive B cells is an example of indirect presentation of alloantigens. We now turn to a consideration of the effector mechanisms responsible for the immunologic rejection of allografts. These different immune effectors cause graft rejection by different mechanisms, and all three effectors may contribute to rejection concurrently. For historical reasons, graft rejection is classified on the basis of histopathologic features and the time course of rejection after transplantation rather than on the basis of immune effector mechanisms. Based on the experi ence of renal transplantation, the histopathologic pat terns are called hyperacute, acute, and chronic. Our discussion of these patterns of rejection will emphasize the underlying immune mecha nisms rather than the pathology or clinical features. Binding of antibody to endothelium acti vates complement, and antibody and complement prod ucts together induce a number of changes in the graft endothelium that promote intravascular thrombosis. Complement activation leads to endothelial cell injury and exposure of subendothelial basement membrane proteins that activate platelets. Both endothelial cells and platelets undergo membrane vesiculation, leading to shedding of lipid particles that promote coagulation. Endothelial cells Activation of Alloreactive B Cells and Production and Functions of Alloantibodies Antibodies against graft antigens, called donor-specific antibodies, also contribute to rejection. A, In hyperacute rejection, preformed antibodies reactive with vascular endothelium activate complement and trigger rapid intravascular thrombosis and necrosis of the vessel wall. B, Hyperacute rejection of a kidney allograft with endothelial damage, platelet and thrombin thrombi, and early neutrophil infiltration in a glomerulus. Hyperacute rejection caused by natural antibodies, specific for a variety of antigens that differ among species, is a major barrier to xenotransplan tation and limits the use of animal organs for human transplantation. Such antibodies generally arise as a result of previous exposure to alloantigens through blood transfusion, previous transplantation, or multiple pregnancies. If the level of these alloreactive antibodies is low, hyperacute rejection may develop slowly, during several days, but the onset is still earlier than that typical for acute rejection. As we will discuss later, patients in need of allografts are routinely screened before grafting for the presence of antibodies that bind to cells of a potential organ donor to avoid hyperacute rejection. Sometimes, if the graft is not rapidly rejected, it survives even in the presence of antigraft antibody. One possible mechanism of this resistance to hyperacute rejection is increased expression of comple ment regulatory proteins on graft endothelial cells, a beneficial adaptation of the tissue called accommodation. Acute Rejection Acute rejection is a process of injury to the graft parenchyma and blood vessels mediated by alloreactive T cells and antibodies. Before modern immunosuppression, acute rejection would often begin several days to a few weeks after transplantation. The time of onset of acute rejection reflects the time needed to generate alloreactive effector T cells and antibodies in response to the graft. In current clinical practice, episodes of acute rejection may occur at much later times, even years after transplanta tion, if immunosuppression is reduced for any number of reasons. Although the patterns of acute rejection are divided into cellular (mediated by T cells) and humoral (mediated by antibodies), both typically coexist in an organ undergoing acute rejection. B, Acute cellular rejection of a kidney with inflammatory cells in the connective tissue around the tubules and between epithelial cells of the tubules. C, Inflammation of a blood vessel (vasculitis) in acute cellular rejection, with inflammatory cells damaging endothelium. In kidney allografts, the infiltrates may involve the tubules (called tubulitis), with associated tubular necrosis, and blood vessels (called endotheliitis), with necrosis of the walls of capillaries and small arteries. The binding of the alloantibodies to the endothelial cell surface triggers local complement activation, which causes lysis of the cells, recruitment and activation of neutrophils, and thrombus formation. In addition, alloantibody binding to the endothelial surface may directly alter endothelial function by inducing intracel lular signals that enhance surface expression of proin flammatory and procoagulant molecules. A, Alloreactive antibodies formed after engraftment may contribute to parenchymal and vascular injury. B, Acute antibody-mediated rejection of a kidney allograft with inflammatory cells in peritubular capillaries. C, Complement C4d deposition in capillaries in acute antibody-mediated rejection, revealed by immunohistochemistry as brown staining. Since 1990, 1year survival of kidney allografts has been better than 90%, but the 10year survival has remained approximately 60% despite advances in immunosuppressive therapy. Chronic rejection develops insidiously during months or years and may or may not be preceded by clinically recognized episodes of acute rejection. Chronic rejection of different transplanted organs is associated with distinct pathologic changes. In the kidney and heart, chronic rejection results in vascular occlusion and interstitial fibrosis. Lung transplants undergoing chronic rejection show thickened small airways (called bronchiolitis obliterans), and liver transplants show fibrotic and nonfunctional bile ducts. Graft vasculopathy is frequently seen in failed cardiac and renal allografts and can develop in any vascularized organ transplant within 6 months to a year after transplantation. As the arterial lesions of graft arteriosclerosis progress, blood flow to the graft paren chyma is compromised, and the parenchyma is slowly replaced by nonfunctioning fibrous tissue. The interstitial fibrosis seen in chronic rejection may also be a repair response to parenchymal cell damage caused by repeated bouts of acute antibodymediated or cellular rejection, perioperative ischemia, toxic effects of immunosuppres sive drugs, and even chronic viral infections. Chronic rejection leads to congestive heart failure or arrhythmias in cardiac transplant patients or loss of glomerular and tubular function and renal failure in kidney transplant patients. The strategies used in clinical practice and in experimental models to avoid or to delay rejection are general immunosuppression and minimizing the strength of the specific allogeneic reaction. An important goal of transplantation research is to find ways of inducing donorspecific tolerance, which would allow grafts to survive without nonspecific immunosuppression. A, In chronic rejection with graft arteriosclerosis, injury to the vessel wall leads to intimal smooth muscle cell proliferation and luminal occlusion. This lesion may be caused by a chronic inflammatory reaction to alloantigens in the vessel wall. The vascular lumen is replaced by an accumulation of smooth muscle cells and connective tissue in the vessel intima. C, Fibrosis and loss of tubules in a kidney with chronic rejection (lower left) adjacent to relatively normal kidney (upper right). The blue area shows fibrosis, and an artery with graft arteriosclerosis is present (bottom right). The greatest barrier to transplantation as a therapeutic option for organ failure is availability of organs. Currently in the United States, there are approximately 120,00 people in need of a lifesaving organ transplant, but there are only approximately 10,000 donors. Living donors can donate one kidney, a lobe of a lung, and parts of liver, pancreas, or intestine, because they can remain healthy after these types of donations. Living donors may be genetically related to the recipient, including siblings, parents, children (over 18 years of age), aunts, uncles, cousins, nieces, and nephews. As we have discussed, immunologic graft rejection is targeted at allogeneic proteins encoded by polymorphic alleles in the recipient not shared by the donor. Deceased donors, called cadaveric donors, are sources of any transplantable organ and the only source of organs that could not be removed from a living donor, such as hearts. Most deceased donors are brain dead, with com plete and irreversible loss of all higher brain function, but whose other organs can be kept alive in the body by cardiorespiratory life support, until just prior to organ harvest. Less frequently, organs are retrieved from people after very recent but irreversible cessation of circulation and respiration, such as after trauma. The survival of grafts from deceased donors is on average lower than from either related or unrelated living donors because there is more ischemic damage to organs removed after death of the donor. Furthermore, most deceased donors are unrelated to the recipients, and grafts from unrelated donors usually express more antigens that differ from the recipient and can simulate stronger rejection responses than those from living donors. Several clinical laboratory tests are routinely performed to reduce the risk for immunologic rejection of allografts. If the patient expresses either blood group antigen, the serum specific for that antigen will agglutinate the red blood cells. Zeroantigen mismatches predict the best survival of living related donor grafts, and grafts with oneantigen mismatches do slightly worse. In the case of heart and liver transplantation, organ preservation is more difficult, and potential recipients are often in critical condition. Each allele defined by sequence has at least a fourdigit number, but Prevention and Treatment of Allograft Rejection 387 some alleles require six or eight digits for precise defini tion. The first two digits usually correspond to the older serologically defined allotype, and the third and fourth digits indicate the subtypes. Alleles with differences in the first four digits encode proteins with different amino acids. The presence of these anti bodies, which may be produced as a result of previous pregnancies, transfusions, or transplantation, increases risk for hyperacute or acute vascular rejection. Complementmediated cytotoxicity tests or flow cyto metric assays can then be used to determine if antibodies in the recipient serum have bound to the donor cells. This would be a positive cross match, which indicates that the donor is not suitable for that recipient. Immunosuppression to Prevent or to Treat Allograft Rejection Immunosuppressive drugs that inhibit or kill T lymphocytes are the principal agents used to treat or prevent graft rejection. Each major category of drugs used to prevent or to treat allograft rejection is shown along with the molecular targets of the drugs. The complex of cyclosporine and cyclophilin binds to and inhibits the enzymatic activity of the calcium/calmodulin activated serine/threonine phosphatase calcineurin (see Chapter 7). The introduction of cyclosporine into clinical practice ushered in the modern era of transplantation.

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