Professor, Department of Otorhinolaryngology?ead and Neck Surgery
University Descartes-Paris V
H?pital Europ?en Georges Pompidou
Member, Acad?mie Nationale de Chirurgie
Paris, France
Other signs that may result from the anemic state include those caused by heart failure (edema bacteria under a microscope buy 50mg minocin overnight delivery, ascites antibiotics prostatitis discount minocin 50 mg with visa, or pulmonary congestion) antibiotics for uti flucloxacillin 50 mg minocin. The common initial symptoms are pallor antibiotics for uti cefuroxime cheap minocin 50 mg online, jaundice antibiotics keflex 500mg 50 mg minocin otc, dark urine infection control guidelines trusted minocin 50mg, abdominal pain, and fever. The clinical status depends on the rapidity of the hemolysis and the severity of the anemia. In severe cases the patient may appear acutely ill or even moribund, with tachycardia, tachypnea, signs of hypoxia, and even cardiovascular collapse. In severe IgM-induced cold hemagglutinin disease, the skin may have a livedo reticularis pattern and the patient may demonstrate acrocyanosis on exposure to cold. Autoantibodies directed against early erythroid precursors are believed to be responsible for the reticulocytopenia in some patients. Examination of the peripheral blood smear may show spherocytes, polychromasia, nucleated red cells, and erythrophagocytosis. Rosetting of red cells around white cells may be visible in a buffy coat preparation. In severe cases, macroagglutination is visible on the microscope slide or in a capillary tube. Autoimmune hemolysis is also associated with thrombocytopenia and/or leukopenia in a small number of patients. It is also possible to use antibody to human immunoglobulin or complement components as a more specific test reagent. In IgG-induced hemolytic anemia, IgG or IgG plus complement components is found on the surface of erythrocytes. When this phenomenon was originally described, the small amounts of red cell-bound IgG antibody were detected with a complex antiglobulin consumption test. The red cells may be coated with IgG in the presence or absence of detectable complement (warm antibody IgG-mediated autoimmune hemolytic anemia) or with complement protein alone (IgM-induced hemolysis, i. The cold agglutinin titer is the highest dilution of antibody that still agglutinates normal red blood cells in the cold. Most patients with immune hemolysis secondary to cold hemagglutinin disease have cold agglutinin titers greater than 1:1000. If an underlying disease is present, control of this disease often brings the hemolytic anemia under control as well. However, if the patient has significant anemia secondary to hemolysis, therapeutic intervention is in order. Patients with IgG antibody-mediated autoimmune hemolytic anemia or immune thrombocytopenic purpura treated with glucocorticoids often respond within days of initiating therapy in dosages equivalent to 1 to 2 mg of prednisone per kilogram of body weight per day. Glucocorticoids are believed to decrease hemolysis in IgG-induced hemolytic anemia by three major mechanisms. Third, glucocorticoids have been shown in vitro and in vivo to interfere with the macrophage Fcgamma receptors responsible for erythrocyte clearance from the circulation. The effect is to improve erythrocyte survival despite the continued presence of IgG on the erythrocyte surface. This effect of glucocorticoids may be rapid and could be responsible for the rise in hemoglobin noted to occur in some patients after 1 to 4 days of glucocorticoid therapy. Although 4 to 6 weeks of therapy may be required for a response to be evident, in many of these delayed responders further therapy will be needed. Approximately 60 to 80% of patients have an initial response to high-dose glucocorticoids. In many patients with acute autoimmune hemolytic anemia and in a small proportion of patients with chronic autoimmune hemolytic anemia, the steroid dosage can be tapered and stopped with the patient remaining in remission. Some patients have control of their hemolytic process with continued low- to medium-dose steroid therapy. Alternate-day therapy may be less effective in autoimmune hemolytic anemia than in some of the inflammatory autoimmune diseases, and patients should be monitored carefully for exacerbation. For patients who 880 are steroid dependent, the initial and long-term side effects of these drugs must be considered (see Chapter 28). In some patients the presence of a mild hemolytic anemia may be preferable to splenectomy or other treatment options. The initial goal of therapy is to return the patient to normal hematologic values and non-toxic levels of glucocorticoid therapy. However, in some patients, a modified goal of improvement in hemolysis to a clinically asymptomatic state with minimum glucocorticoid side effects is more realistic. Glucocorticoids are not usually effective in cold hemagglutinin disease, probably because these patients generally have large amounts of IgM antierythrocyte antibody and large numbers of C3 molecules deposited on their red cells. Furthermore, macrophage C3b receptors, in contrast to the case with Fcgamma receptors, are less responsive to glucocorticoid therapy. In addition, some of the hemolysis may be intravascular, and glucocorticoids do not inhibit complement-mediated cell lysis. In addition, the few patients described with an IgG cold agglutinin appear to be responsive to both steroids and splenectomy. Patients with cold hemagglutinin disease respond best to the avoidance of cold and control of their underlying disease. The spleen with its resident macrophages is the major site for sequestration of IgG-coated blood cells in humans, as in animals. Splenectomy may also lead to a decrease in the production of IgG antierythrocyte antibody because the spleen contains a large B-cell pool. However, as the antibody concentration is increased, splenectomy becomes less effective in preventing the clearance of IgG-coated cells because the liver becomes the dominant organ in erythrocyte clearance. Splenectomy should be considered in patients who are not responsive to steriods or require more than 10 to 20 mg of prednisone per day or substantial dosages of steroid every other day for maintenance. Each patient requires individual evaluation of underlying diseases, surgical risk, extent of anemia, and steroid intolerance. The response rate to splenectomy in IgG-mediated disease is approximately 50 to 70%; however, the vast majority of the responses are partial remissions. Probably the patients who are least responsive to splenectomy are those whose erythrocytes are coated with large amounts of IgG. The partial remissions that occur with splenectomy are often quite helpful in that they result in lessening of the hemolytic rate, with a rise in the hemoglobin concentration, and/or allow a reduction in the amount of glucocorticoid needed to control the hemolytic anemia. Patients who are unresponsive to steroids, require moderate to high maintenance doses, or have glucocorticoid intolerance can be considered for splenectomy. Immunization with pneumococcal vaccine should be performed before splenectomy to decrease the likelihood of post-splenectomy pneumococcal infection. Splenectomy, like glucocorticoid therapy, is usually not effective in patients with cold hemagglutinin disease because IgM-coated erythrocytes are cleared predominately in the liver. An occasional case in which a patient with an apparent IgM-induced hemolytic anemia responded to splenectomy has been reported. This result may be due to decreased production of IgM antibody by the spleen in these few patients or to the presence of an IgG cold agglutinin. Several immunosuppressive agents have been used in the treatment of immune hemolytic anemia. The drugs most commonly used include the thiopurines (6-mercaptopurine, azathioprine, and thioguanine) and alkylating agents (cyclophosphamide and chlorambucil). Immunosuppressive agents act by decreasing the production of antibody, and therefore it generally takes at least 4 weeks before any therapeutic result is observed. These drugs are rarely needed in the treatment of childhood autoimmune hemolytic anemia. Patients are selected for immunosuppressive therapy when a clinically unacceptable degree of hemolytic anemia persists following glucocorticoid therapy and splenectomy. Alternatively, patients may be corticosteroid resistant or intolerant and a poor surgical risk for splenectomy. The dosage of drug should be adjusted to maintain the leukocyte count over 4000, the granulocyte count greater than 2000, and the platelet count over 50,000 to 100,000 per microliter. Alkylating agents (cyclophosphamide or chlorambucil) have been used and appear to have a beneficial effect in up to 50 to 60% of patients. The majority of patients with autoimmune hemolytic anemia do not require transfusion therapy because the anemia has developed gradually and physiologic compensation has occurred. However, occasional patients experience acute and/or severe anemia and require transfusions for support until other treatment reduces the hemolysis. Transfusion therapy is complicated by the fact that the blood bank may be unable to find any "compatible" blood because of the presence of an autoantibody directed at a core component of the Rh locus, which is present on the erythrocytes of essentially all potential donors, regardless of Rh subtype. With this approach, it is unlikely that the donor blood will have a dramatically shortened red cell survival. Furthermore, agglutination of transfused chilled or even room-temperature cells in small peripheral blood vessels can result in severe ischemic changes and vascular compromise. Intravenous gamma-globulin, which has been used extensively in the treatment of immune thrombocytopenic purpura, may be effective in patients with IgG-induced immune hemolytic anemia, probably by interfering with clearance of the IgG-coated cells. Treatment regimens vary from 400 mg/kg/day for 5 days to 2 g/kg given over 2 days, with additional treatment as needed to maintain the effect. Currently, data are incomplete, but gamma-globulin seems less effective in autoimmune hemolytic anemia than in immune thrombocytopenic purpura. Plasmapheresis or exchange transfusion has been used in patients with severe IgG-induced immune hemolytic anemia but has met with limited success, possibly because more than half of the IgG is extravascular and the plasma contains only small amounts of the antibody (most of the antibody being on the red cell surface). Plasmapheresis is useful only as short-term therapy, but it may be life saving in the rare patient with severe, uncontrollable hemolysis. Other measures that have been used effectively in some patients with IgG-induced immune hemolysis are vincristine, vinblastine infusions, and hormonal therapy. Because of the limited side effects (limited masculinizing effects and mild weight gain), danazol is an additional agent for use in some patients with IgG-induced immune hemolytic anemia. The results of these agents in IgM-induced hemolysis suggest that such treatment is ineffective. Folic acid should be given to avoid depletion of folate stores from chronic hemolysis caused by either IgG or IgM antibodies. It occurs in a small percentage of adults and children with acute autoimmune hemolytic anemia. In an 881 even smaller percentage of patients it is also associated with marked neutropenia. Antibodies directed against red cells, leukocytes, and platelets have been demonstrated in some patients with immune pancytopenia. Autoimmune hemolytic anemia in the presence of thrombocytopenia and/or neutropenia is more commonly associated with a chronic or relapsing course. Many patients have associated disorders such as chronic lymphadenopathy or dysgammaglobulinemia. Some patients are hematologically normal between relapses, which may involve depressions in any of the three cell lines. Usually glucocorticoid therapy is effective in controlling the acute episodes and is not needed between relapses. However, some patients have persistent immune cytopenia and require prolonged steroid treatment or more aggressive therapy. Splenectomy may result in improvement, but the risk of infection may be higher in children and adults with pancytopenia than in those with autoimmune hemolytic anemia alone, and relapses are more common. It is now recognized that chronic intravascular hemolysis is the more frequent clinical finding. It is believed to be a disorder of stem cells of a clonal nature and can arise from or evolve into other dysplastic bone marrow diseases, including aplastic anemia, sideroblastic anemia, and myelofibrosis. A major clue to the etiology of this disease is provided by the recent finding that patients have a somatic mutation for a protein (phosphatidylinositol glycan class A) important in the pathway that controls formation of the phosphatidylinositol anchor of several membrane proteins, including complement control proteins. At least 19 proteins are attached to blood cells by a phosphatidylinositol glycan anchor. Three of these proteins protect the cells from complement attack by regulating complement activation on the cell surface. Among the phosphatidylinositol glycan class of proteins are those termed class A, which lack the ability to transfer glucosamine to phosphatidylinositol. The protein is presumed to be an N-acetylglucosamine transferase, and over 100 somatic mutations spread over the entire coding region have been identified. The mutations, mostly deletions or insertions, generally cause a stop codon that results in premature termination of the peptide to yield a truncated protein. These truncated proteins may be either non-functional, partially functional, or unstable. The severity of the hemolysis and the degree of hemoglobinuria depend on the number of circulating abnormal red cells and the degree of expression of the membrane abnormality among these cells. Patients commonly have iron deficiency anemia as well because of the large amount of iron lost in the urine during intravascular hemolysis via persistent hemoglobinuria and hemosiderinuria. Other frequent clinical complaints include abdominal, back, and musculoskeletal pain. Such pain may be associated with intravascular hemolysis and hemoglobinuria, or it may be ischemic and secondary to the complication of venous thrombosis of major or minor vessels. Thrombosis of the hepatic veins (Budd-Chiari syndrome) and the portal, splenic, mesenteric, cerebral, and other veins may occur and is a common cause of death. Platelets and leukocytes also appear to have unusual susceptibility to lysis, and thrombocytopenia, granulocytopenia, or both are common and may be the initial manifestation(s) of the disease. The bone marrow is usually hyperplastic but may be hypocellular, consistent with aplastic anemia. The clinical course is variable and depends on occurrence of the life-threatening complications of progressive bone marrow disease or venous thrombosis.
If not treated antibiotics vs alcohol buy generic minocin 50 mg on-line, the infant suffers liver antibiotics for uti and breastfeeding order minocin 50mg online, central nervous system antibiotic resistance gene in plasmid buy minocin 50 mg without prescription, and renal damage and may succumb to bacterial sepsis antibiotics and breastfeeding purchase 50mg minocin with amex. If excess lactose is ingested antibiotics quinolones minocin 50mg with amex, cataracts infection vaginal discharge purchase 50mg minocin with visa, premature ovarian failure, and growth and mental restriction may not be recognized until adulthood. Phenylalanine is an essential amino acid for growth whose anabolic products include tyrosine, thyroid hormone, adrenergic neurotransmitters, and melanin. Albinism is an example of an inborn error in an anabolic pathway in which the pathophysiologic mechanism is directly related to the lack of an end product (see Mechanism 3, Table 32-2). Tyrosine is converted by the action of a cytosolic tyrosinase first to dopa and then to dopamine. Dopamine can then be converted either to the red-yellow pigment pheomelanin or to the black-brown pigment eumelanin. These reactions occur in the melanosomes produced in the melanocytes and exported to the keratinocytes. Color of skin is an inherited factor that depends on several genes and is a function of the intensity of the pigment in the skin and not the number of melanocytes, which is constant for all humans. Although skin color is a polygenic trait, single genes can have a profound effect on this color, as evidenced by the albino phenotype. Tyrosinase-negative individuals form no pigment, and the gene for tyrosinase has been localized to chromosome 11q14 and many mutations are defined. A wide variation in phenotypic expression of albinism is reported from very severe neurologic deficiency with ocular and sarcomatous skin cancers to mild cosmetic problems. Inborn errors of the urea cycle (see Chapter 211) are represented by defects in the integration of both anabolic and catabolic pathways and the distribution of catalytic proteins between mitochondria and cytosol. The role of the urea cycle is to convert ammonia, a byproduct of protein breakdown, to urea and to synthesize arginine and ornithine. Reactions to complete this anabolic cycle require three mitochondrial enzymes, three cytosolic enzymes, and two mitochondrial transporter proteins. Individuals with defects in any of the enzymes present with varying degrees of hyperammonemia caused by protein ingestion or a catabolic state. With the exception of the gene for ornithine transcarbamylase found on the short arm of chromosome X, the other four proteins are encoded on autosomes and defects are inherited as autosomal recessive traits. Many principles involved in the pathophysiology of inborn errors of metabolism are exemplified by disorders of the urea cycle. A group of inborn errors of metabolism is caused by mutations in nuclear genes that encode mitochondrial proteins. Collectively, they are considered disorders of organic acid metabolism (Table 32-7). For example, branched-chain alpha-ketoacid dehydrogenase is a multienzyme complex located on the matrix side of the mitochondrial inner membrane in all tissues. When any of these proteins is impaired, the autosomal recessive disorder maple syrup urine disease may result (see Chapter 212). Males do not transmit mitochondrial mutations to their offspring, thus the term maternal inheritance (see Table 32-7). Another group of inborn errors of metabolism is collectively categorized as lysosomal disorders (see Chapter 208) to indicate the subcellular localization of these impaired proteins. Most of these enzymes are involved in breakdown of endocytosed membrane components and when defective result in accumulation of their nondegraded substrates in the lysosomes and macrophages of affected organs. I-cell disease is an inborn error of post-translational processing of proteins directed to the lysosome. Clarification of this pathophysiology led to an understanding of the mechanisms by which lysosomal enzymes are polarized to remain in lysosomes. Patients with I-cell disease have inherited defects in the recognition markers required to direct enzymes to the endocytic receptor of plasma membrane and to its capture in the acidic milieu of the lysosome. The misdirected lysosomal enzymes are secreted and are present in excess in plasma but are missing from cells. These extracellular enzymes were found to lack mannose 6-phosphate residues, and this observation led to an understanding of the post-translational mechanisms by which enzymes are both directed to the lysosome and recaptured into endosomes by adding phosphorylated mannose to their protein structure. Inborn errors affecting single enzymes in the degradative pathway for mucopolysaccharides and gangliosides helped define the steps required for the breakdown of these complex macromolecules. Another group of inborn errors of metabolism defined by altered organelle function are peroxisomal diseases (Table 32-8). Primary pathways synthesize plasmalogens (unique fatty acids containing vinyl ethers), cholesterol, and bile acids. Other biosynthetic reactions include gluconeogenesis from amino acids and the formation of oxalic acid by the action of alanine-glyoxylate aminotransferase (see Chapter 205). Catabolic reactions include breakdown of hydrogen peroxide by peroxisomal catalase, a traditional protein of the peroxisome; polyamine oxidation; purine breakdown; ethanol oxidation; phytanic acid hydroxylation; and pipecolic acid degradation. A major function of the peroxisome is beta-oxidation of very long chain fatty acids, those longer than 24 carbons. An understanding of the importance of a number of reactions that occur in the peroxisome has come from identifying patients with either defects in individual biochemical pathways or lack of peroxisomes. The targeting signal for peroxisomal proteins may lie in their carboxyl terminal end, and mutations in the alanine-glyoxylate aminotransferase have resulted in mistargeting of this enzyme to mitochondria with consequent familial hyperoxaluria (see Chapter 205). Disorders affecting the peroxisome are of two types: type 1, the absence of the peroxisome itself caused by defects in its assembly processes; and type 2, the absence of specific enzymes from the peroxisomal milieu caused by mutations in phosphotransfer or specific enzyme structure. Patients expressing these inherited disorders carry a high risk for developing cancers. A large number of inborn errors involve proteins that circulate in blood (see class 3 of Table 32-1). Stable circulating proteins in blood perform a variety of functions, including immunologic, hemostatic, regulatory, hormonal, and interorgan transport of trace metals, lipids, and other nutrients. Some inherited disorders affecting circulating proteins are tabulated in Table 32-9. Proteins involved in oxygen transport, coagulation, and immunity are detailed in other chapters, but the pathophysiologic mechanisms and genetic approaches of screening, diagnosis, and intervention to prevent an expected outcome make them appropriate to consider here as inborn errors of metabolism. These disorders exemplify class 4 of inborn errors of metabolism (see Table 32-1). The enzymes involved in post-translational processing of these proteins may also cause these syndromes. Inborn errors of matrix proteins are exemplified by disorders of collagen metabolism. More than 20 different genes dispersed on 9 chromosomes are currently known to code for more than 11 different types of collagen. In Sodeman W, Sodeman T (eds): Pathologic Physiology Mechanisms of Disease, 7th ed. A traditional compilation of pathophysiologic mechanisms producing inherited diseases. Curiel Gene therapy is a relatively new method of therapeutic intervention targeted at the level of cellular gene expression. In this approach, altering a pathophysiologic state is achieved by delivering nucleic acids into a cell. These nucleic acids may be genes, portions of genes, oligonucleotides, or ribonucleic acid. In conventional therapeutics, as in pharmacotherapy, altering a cell or tissue phenotype is accomplished by altering cell physiology or metabolism at the level of protein expression. For gene therapy, this is accomplished by changing the pattern of expression of the genes whose products may thus achieve the desired effect on the cellular phenotype. From a conceptual standpoint, gene therapy strategies may offer the potential to achieve a much higher level of specificity of action by virtue of the highly specific control and regulatory mechanisms of gene expression that may be targeted in this technique. Additionally, interceding at an earlier stage in disease pathogenesis may offer greater potential to achieve fundamental changes in phenotypic parameters of disease with a more favorable outcome. Lastly, using the body to produce therapeutic proteins, potentially in only certain tissues, has practical advantages of its own. Gene therapy was initially conceptualized as a method to treat acquired genetic diseases. In this regard, more than 5000 monogenetic disorders exist in which the entirety of the disease state may be attributed to a single lesion at a specific genetic locus. Replacing or augmenting a defective gene by delivering its wild-type counterpart thus offers a potential means to rectify definitively the pathogenic basis of the disease state. Inherited genetic diseases, however, are not the only logical targets for gene therapy. The underlying basis for a variety of acquired disorders may be shown to be accumulated lesions in specific genetic loci, as in malignancies associated with mutations in dominant and recessive oncogenes. In these instances also, if the pathogenic basis is established to be lesions in cellular genes, a logical strategy is replacing or adding the mutated genes with the wild-type counterpart to perform the deficient function. The first and foremost criterion for any gene therapy is that the aberrant gene being targeted must be well characterized. In addition, it must be shown that the defined genetic abnormalities are the basis of the observed pathogenesis of the disease state. If the logic of genetic intervention thus exists, clearly defined endpoints of the therapy intervention must exist and an alternate, effective therapy for the targeted disease must not exist. This reflects the fact that, at this juncture, gene therapy is still a radical, experimental therapy that may be justified only in this context. As a first step, it must be possible to deliver the therapeutic gene to the target cells of interest. After delivery, the introduced gene must be expressed at an appropriate level for the desired effect and for sufficient time for this effect to be achieved. Additionally, the delivery and expression of the therapeutic gene must be safe for the target cell and, by extension, for the individual being treated. From a conceptual standpoint, it must be recognized that these goals are all interrelated and, furthermore, that all of them must be addressed to rationally implement any gene therapy strategy. Clinical experience with gene therapy during the past decade shows that serious toxicity is not a problem. Most importantly, it is now evident that a variety of gene transfer maneuvers can alter favorably the cellular phenotype in vitro, although a fundamental limitation exists owing to an insufficient gene delivery and expression into target cells in vivo. In practice, gene therapy implementation in human clinical trials has used two distinct strategies to meet the aforementioned criteria. In selected instances, target cells may be removed from the body, genetically modified extracorporeally, and then reintroduced into the patient. This ex vivo strategy has been applied in those contexts in which the technical capacity exists to readily harvest and manipulate the relevant target cell. As an alternative strategy, the in vivo approach involves directly delivering the therapeutic gene to the relevant target cells in situ in an intact individual. Whereas both approaches have been used in human clinical trials, the preponderance of strategies to date have employed the ex vivo approach. Although this method may offer certain advantages in selected contexts, it must be recognized that using this route presents the technical difficulty associated with accomplishing direct in vivo delivery. The advantages of the ex vivo approach are that it allows gene transfer to the target cells in a defined, in vitro setting, in which delivery efficiencies may be optimized. This approach also allows the modified cells to be characterized from the standpoint of safety before they are reintroduced to the patient. Despite these advantages, this method may be limited to very select settings in which target cells can be propagated ex vivo; at present, this is viable for a very limited set of tissue types. The in vivo approach in theory overcomes this limitation of target tissue accessibility. Delivery in vivo, however, is fraught with considerably greater complexities than the ex vivo approach. Thus, the gene transfer vector in the direct-delivery approach must achieve delivery in the context of significant host barriers, including humoral, reticuloendothelial, and immunologic factors. Earlier protocols were principally of the ex vivo type and relied on recombinant retroviruses as gene transfer vehicles. The technology to derive recombinant retroviruses that can efficiently transfer genes has been sufficiently developed that these vectors have been used for a majority of human protocols (Table 33-1) They can accomplish effective gene transfer to a variety of target cells despite being rendered replication incompetent by genomic deletions. In addition, because these viruses are integrative, they can produce permanent genetic modifications of target cells with the consequence of long-term heterologous gene expression. Whereas the vectors are suited for ex vivo modification of target cells, a variety of limitations have restricted their use in strategies to accomplish direct, in vivo gene transfer. The retrovirus requires proliferative target cells to mediate effective gene transfer. One exception are lentiviruses, the class of retrovirus that includes human immunodeficiency virus, which can integrate also in non-dividing cells. An additional obstacle for retroviruses is the high susceptibility of the virus particle to humoral factors that ablate its gene-transfer capacity. Thus, the basic biology of recombinant retroviruses has been an additional factor restricting initially implemented gene therapy protocols to strategies using ex vivo methodologies. To circumvent the limitations associated with recombinant retroviruses, alternative vector systems have been developed (see Table 33-1). These systems include both non-viral and viral approaches to accomplish gene transfer. In both of these approaches, the goal is to develop a system that can deliver genes in vivo after systemic administration. This development is a step toward deriving a "targetable-injectable" vector-a vector that can deliver therapeutic genes selectively to target cells after direct, in vivo administration. The development of such a vector system would have two very important consequences for potential gene therapy strategies: (1) it Figure 33-1 Methods to modify the adenoviral cellular tropism. Viral tropism is determined by the fiber and its recognition region in the terminus, or "knob" (dotted circle). Binding of the virus to target cells can be modified via either immunologic or genetic methods. Immunologic targeting involves the attachment of molecular conjugates incorporating antibodies against the fiber knob and ligands specific for cognate receptors in target cells. Genetic targeting involves the genetic modification of the fiber gene to generate fiber chimeras with novel ligand specificity.
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The best results reported to date with chemotherapy have generally used repeated cycles of high-dose cytarabine antimicrobial natural order 50mg minocin. Among patients in whom complete remission is achieved infection vaginal generic minocin 50mg, 20 to 40% remain alive in continuous complete remission for more than 5 years antimicrobial drugs quizlet discount 50 mg minocin visa, thus suggesting probable cure antibiotics pancreatitis buy cheap minocin 50 mg line. Patients whose disease is characterized by certain chromosomal abnormalities vyrus 986 m2 50 mg minocin visa, particularly t(8;21) antibiotic resistance united states order 50 mg minocin with amex, t(15;17), and inv(16), do somewhat better, whereas those with 5q-, -7, 11q23, inv(3) or t(6;9) do worse. Patients who have a pre-leukemic phase before their condition evolves into acute leukemia and those whose leukemia is secondary to prior exposure to alkylating agents or radiation respond poorly to chemotherapy. Unfortunately, these remissions tend to be short lived, and few patients in whom relapse occurs after first-line chemotherapy are cured by salvage chemotherapy. If carried out when patients have end-stage disease, approximately 15% of patients can be saved. If the procedure is applied earlier, the outcome with marrow transplantation improves: approximately 30% of patients who undergo transplantation at first relapse or second remission are cured, and 50 to 60% of patients are cured if transplantation is performed in the first remission. The trend in all of these studies has been in favor of transplantation, although not all studies have shown a statistically significant difference. The major limitations to allogeneic transplantation are graft-versus-host disease, interstitial pneumonia, and disease recurrence. Because the incidence of graft-versus-host disease increases with age, most centers limit transplantation to patients of 55 years old or younger. Autologous transplantation offers an alternative for patients without matched siblings to serve as donors. During the granulocytopenic period following induction and consolidation chemotherapy, most patients become febrile, and in approximately 50% of cases a bacterial infection can be documented. The most commonly isolated organisms vary somewhat from medical center to medical center, but generally, gram-positive organisms such as Staphylococcus epidermidis and gram-negative enteric organisms such as Pseudomonas aeruginosa, Escherichia coli, and Klebsiella/Aerobacter are the most commonly isolated bacteria. Even if no cause for fever is found, bacterial infection should be assumed, and in general, all patients with fever and neutropenia should begin receiving broad-spectrum antibiotics. Commonly used antibiotic combinations include a cephalosporin and a semisynthetic penicillin or a semisynthetic penicillin and an aminoglycoside. Once begun, antibiotic use should be continued until patients recover their granulocyte count, even if they become afebrile first. If documented bacterial infection persists despite appropriate antibiotics, the physician should consider removing indwelling catheters and giving granulocyte transfusions. It may be possible to reduce the incidence of bacterial infection through the use of selective gastrointestinal decontamination with, for example, ciprofloxacin or a combination of trimethoprim-sulfamethoxazole plus colistin. The use of protective environments can also reduce the incidence of infection, but this approach is costly and has not been shown to influence overall survival. Frequently, patients taking broad-spectrum antibiotics become afebrile for a time, only to have a second fever develop. Such patients should be carefully reassessed with a high index of suspicion for fungal infection. Granulocytopenic patients who remain febrile for more than a week while taking broad-spectrum antibiotics should be treated empirically with amphotericin for presumed fungal infection. The prophylactic use of fluconazole can reduce the incidence of invasive candidal infections but does not change overall survival. In addition to being granulocytopenic, patients undergoing induction chemotherapy for leukemia have deficient cellular and humoral immunity, at least temporarily, and thus are subject to infections common in other immunodeficiency states, including Pneumocystis carinii infection and a variety of viral infections. Herpes simplex can often complicate existing mucositis and can be treated successfully with acyclovir. Acyclovir is also useful for the treatment of disseminated varicella-zoster virus infection. Myeloid growth factors (granulocyte or granulocyte-macrophage colony-stimulating factor), if given shortly after the completion of chemotherapy, shorten the period of severe myelosuppression by, on average, approximately 4 days. In most studies this accelerated recovery has resulted in fewer days with fever and less use of antibiotics, but it has not improved the complete response rate or altered survival. The platelet count that signals a need for platelet transfusion has been the subject of recent debate. Traditionally, platelet transfusions from random donors were used to maintain platelet counts above 20,000/muL, but more recently it has been demonstrated that lowering this threshold to 10,000/muL is safe in patients with no active bleeding. Occasionally, cells (presumably T cells) within the blood product can engraft in an immunosuppressed leukemic patient and cause a graft-versus-host reaction. Transfusion-induced graft-versus-host disease is manifested as a rash, low-grade fever, elevated values in liver function tests, and falling blood counts. This syndrome can be prevented by irradiating all blood products with at least 1500 cGy before transfusion. An outstanding review of the various categories of genetic abnormalities associated with leukemia, including the types of genes involved, the molecular alterations seen, and the presumed functional changes that result. Lymph nodes are found throughout the body along the course of lymphatics, strategically 959 located to allow filtering of lymphatic fluid and interdiction of microorganisms and abnormal proteins. Lymphatic fluid enters the node in afferent lymphatic vessels that empty into the subcapsular sinus. The fluid then transverses the node to exit in a single efferent lymphatic vessel. In doing so, the lymph and its contents are exposed to immunologically active cells throughout the node. Lymph nodes are populated predominantly by macrophages, dendritic cells, B lymphocytes, and T lymphocytes. B lymphocytes are located primarily in the follicles and perifollicular areas, whereas T lymphocytes are found primarily in the interfollicular or paracortical areas of the lymph node. These cells function together to provide antigen processing, antigen presentation, antigen recognition, and proliferation of effector B and T lymphocytes as part of the normal immune response to microorganisms or foreign proteins. Because the normal immune response leads to proliferation and expansion of one or more of the cellular components of lymph nodes, it also often leads to significant lymph node enlargement. In young children, who are continuously undergoing exposure to new antigens, palpable lymphadenopathy is the rule. In adults, lymph nodes larger than 1 to 2 cm in diameter are generally considered abnormal. However, lymph nodes 1 to 2 cm in diameter in the groin are sufficiently frequent to often be considered "normal. For example, cervical lymphadenopathy would be typical in a patient with pharyngitis. Generalized immune proliferation and lymphadenopathy can occur with a systemic disorder of the immune system, disseminated infection, or disseminated neoplasia. Malignancies of the immune system might be manifested as localized or disseminated lymphadenopathy. The differential diagnosis of lymphadenopathy (Table 178-1) is vast, with the underlying causes responsible for either proliferation of immunologically active cells or infiltration of the lymph node by foreign cells or substances. In practice, the cause of enlarged lymph nodes is often not certain even in retrospect; in these cases, unrecognized infectious processes are generally blamed. Infections by bacteria, mycobacteria, fungi, chlamydiae, parasites, and viruses are the major causes of lymph node enlargement. Lymph nodes in the drainage area of essentially all pyogenic infections can enlarge. In certain infections such as bubonic plague caused by Yersinia pestis, dramatic regional lymph node enlargement with fluctuant lymph nodes. In some parts of the world, cervical lymphadenopathy is a sufficiently frequent manifestation of tuberculosis to lead to the institution of antituberculosis therapy rather than biopsy. A variety of non-malignant disorders of the immune system can lead to localized or disseminated lymphadenopathy (see Chapter 282). Autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus often have accompanying lymphadenopathy, which can pose a diagnostic challenge because of the increased incidence of lymphoma in patients with these disorders. In the lymphadenopathy that occurs as a reaction to drugs such as phenytoin, lymph node biopsy findings can sometimes be confused with those of lymphoma. Several of these malignancies are usually manifested as lymphadenopathy, and it can be seen in all. Malignancies of all organ systems can metastasize to the lymph nodes and cause lymphadenopathy, which is usually seen in the drainage area of the primary tumor. Amyloidosis can cause lymphadenopathy in patients with multiple myeloma, hereditary amyloidosis, or amyloidosis associated with chronic inflammatory states. In patients actually seen in practices in the United States with lymphadenopathy, diagnoses will not be determined in a high proportion of patients (Table 178-2). Alternatively, if a patient has an immunologic disorder that is known to cause lymphadenopathy, such as rheumatoid arthritis, this disorder is usually an acceptable explanation; however, progressive lymphadenopathy in such patients should trigger a biopsy because these patients are at a increased risk for lymphoma. Localized, progressive lymphadenopathy, particularly when associated with fever, sweats, or weight loss, requires biopsy to exclude lymphoma. Evaluation of a patient with lymphadenopathy includes a careful history, a thorough physical examination, laboratory tests, and sometimes imaging studies to determine the extent and character of the lymphadenopathy (Table 178-3). The age of the patient and any associated systemic symptoms might be important hints in the evaluation. Cervical lymphadenopathy in a child would be much less worrisome than equally prominent lymphadenopathy in a 60-year-old. The occurrence of fever, sweats, or weight loss raises the possibility of a malignancy of the immune system. Location: cervical, supraclavicular, epitrochlear, axillary, intrathoracic (hilar versus mediastinal), intra-abdominal (retroperitoneal versus mesenteric versus other), iliac, inguinal, femoral Localized versus disseminated Tenderness/inflammation Size Consistency might become apparent by identification of a site of infection, a particular medication, a travel history, or a previous malignancy. Physical examination allows the identification of localized versus widespread lymphadenopathy. The particular sites of involvement can be important hints to the diagnosis inasmuch as infections and carcinomas are likely to cause lymphadenopathy in the lymphatic drainage of the site of the disorder. In general, lymph nodes that are tender are more likely to be due to an infectious process, whereas painless adenopathy raises the concern of malignancy. Lymph node consistency can also aid in the diagnosis: typically, lymph nodes containing metastatic carcinoma are rock hard, lymph nodes containing lymphoma are firm and rubbery, and lymph nodes enlarged in response to an infectious process are soft. The larger the lymph node, the more likely a serious underlying cause exists, and lymph nodes greater than 3 to 4 cm in diameter in an adult are very concerning. Physical examination to assess lymph node size is only marginally accurate and reproducible; although it is by far the most widely used method, more precise methods are available with various imaging techniques. Although the technique is no longer widely available today, lymphangiography provides an extremely accurate assessment of the lower abdominal lymph nodes and, because of retained contrast material, allows repeat examinations and assessment of the response to therapy. Lymph node aspiration or biopsy is often necessary for an accurate diagnosis of the cause of the lymphadenopathy. Is the patient very concerned about malignancy and unable to be reassured that malignancy is unlikely? If none of the preceding are true, perform a complete blood count and if it is unrevealing, monitor for a pre-determined period (usually 2 to 6 weeks). Although lymphomas can sometimes be diagnosed with this approach, it is inappropriate as an initial diagnostic maneuver for lymphoma. Cutting needle biopsies will occasionally provide sufficient material for an unequivocal diagnosis and subtyping of the lymphoma. However, in general, excisional biopsy, which is most likely to provide the pathologist with adequate material to perform histologic, immunologic, and genetic studies, is the most appropriate approach. Patients with lymphadenopathy (Table 178-5) come to medical attention in several ways. Lymphadenopathy might also come to medical attention as an unexpected finding on routine physical examination or as part of the evaluation of another complaint. Finally, patients might be found to have unexpected lymphadenopathy on imaging studies of the chest or abdomen. In general, very large or very firm lymph nodes in the presence of systemic symptoms such as unexplained fever, sweats, or weight loss should lead to a lymph node biopsy. Patients who have lymph nodes in the drainage area of a previously treated malignancy. Carcinoma can often be diagnosed in this manner, although it is a poor approach for the diagnosis of lymphoid malignancies. For cervical lymph nodes, excisional biopsy should be delayed in a patient who has head and neck cancer as a diagnostic consideration. For the most common situation, in which a lymph node is soft, not larger than 2 to 3 cm and the patient has no obvious systemic illness, observation for a brief period is usually the best approach. Performance of a complete blood count and examination of a peripheral smear can be helpful in recognizing a systemic illness. If the lymph node does not regress over the course of a few weeks or if it grows in size, a biopsy should be performed. For example, a biopsy might be done more quickly in a patient who is very anxious about malignancy or who needs a definitive diagnosis expeditiously. The spleen is the largest lymphatic organ in the body and is sometimes approached clinically as though it were a very large lymph node. However, although it also participates in the primary immune response to invading microorganisms and foreign proteins, the spleen has many other functions. It functions as a filter for the blood and is responsible for removing from the circulation senescent red cells, as well as blood cells and other cells coated with immunoglobulins. Blood enters the spleen, filters through the splenic cords, and is exposed to the immunologically active cells in the spleen. The splenic red pulp occupies more than half the volume of the spleen and is the site where senescent red cells are identified and 961 destroyed and red cell inclusions are removed by a process known as pitting. In the absence of splenic function, inclusions known as Howell-Jolly bodies are seen in circulating red blood cells. The presence of Howell-Jolly bodies in the peripheral blood indicates that the patient has had a splenectomy or has a process that has rendered the spleen non-functional. The white pulp of the spleen contains macrophages, B lymphocytes, and T lymphocytes, participates in the recognition of microorganisms and foreign proteins, and is involved in the primary immune response. Absence of this splenic function makes individuals particularly sensitive to certain infections, including sepsis with encapsulated organisms such as Streptococcus pneumoniae. As with lymphadenopathy, the conditions associated with splenomegaly are extremely numerous (Table 178-6).
Annular calcification antibiotics z pack and alcohol order 50 mg minocin, endocarditis antibiotic resistance timeline 50 mg minocin fast delivery, collagen vascular disease antibiotics for acne australia purchase minocin 50mg without prescription, and rheumatic heart disease are less common causes bacterial conjugation generic minocin 50 mg on-line. Recently antibiotics for streptococcus viridans uti generic 50 mg minocin with mastercard, use of the weight loss agents dexfenfluramine virus 48 horas minocin 50mg with amex, fenfluramine, and possibly phentermine has been implicated in causing valve damage. Common causes of severe acute mitral regurgitation include ruptured chordae tendineae, ischemic papillary muscle dysfunction or rupture, and infective endocarditis. Chronic severe mitral regurgitation is more likely to be due to myxomatous degeneration of the valve, rheumatic heart disease, or annular calcification. The pathophysiology of mitral regurgitation can be divided into three phases, as shown in Figure 63-3. In acute mitral regurgitation of any cause, the sudden option for ejection of blood into the left atrium "wastes" a portion of the left ventricular stroke volume as backward rather than forward flow. The combined regurgitant and forward flows cause a volume overload of the left ventricle, stretching existing sarcomeres toward their maximum length. Thus, use of the Frank-Starling mechanism is maximized, and end-diastolic volume increases concomitantly. In this phase of mitral regurgitation, eccentric cardiac hypertrophy has developed and end-diastolic volume has increased substantially. Increased end-diastolic volume combined with normal contractile function permits ejection of a larger total stroke volume and therefore a larger forward stroke volume than in the acute phase. Because the radius term in the Laplace equation has increased with increasing left ventricular volume, afterload and end-systolic volume return to normal. In this stage, contractile dysfunction causes a large increase in end-systolic volume with a fall in both total and forward stroke volume. However, the relatively favorable loading conditions in this phase still permit a normal ejection fraction despite contractile dysfunction. Although increased end-diastolic volume and decreased end-systolic volume both act in concert to increase total stroke volume, forward stroke volume is subnormal because a large portion of the total stroke volume is regurgitated into the left atrium. This regurgitant volume increases left atrial pressure, so the patient experiences heart failure with low cardiac output and pulmonary congestion despite normal left ventricular contractile function. In many cases, severe acute mitral regurgitation necessitates emergent surgical correction. However, patients who can be managed through the acute phase may then enter the phase of compensation. In this phase, eccentric left ventricular hypertrophy and increased end-diastolic volume, combined with normal contractile function, allow for ejection of a sufficiently large total stroke volume to allow forward stroke volume to return toward normal. Left atrial enlargement allows for accommodation of the regurgitant volume at a lower filling pressure. In this phase, the patient may be relatively asymptomatic even during rather strenuous exercise. While severe mitral regurgitation may be tolerated for many years, the lesion eventually causes left ventricular dysfunction. The now damaged ventricle has impaired ejection performance and end-systolic volume increases. In turn, greater left ventricular residual volume at end-systole increases end-diastolic volume and end-diastolic pressure, and the symptoms of pulmonary congestion may 333 reappear. Additional left ventricular dilatation may worsen the amount of regurgitation by causing further enlargement of the mitral annulus and malalignment of the papillary muscles. Although there is substantial contractile dysfunction, the increased preload and the presence of the regurgitant pathway, which tends to normalize afterload despite ventricular enlargement, augment ejection fraction and may maintain it in a relatively normal range. The causes of left ventricular contractile dysfunction in mitral regurgitation may relate to loss of contractile proteins and abnormalities in calcium handling. In at least some cases, contractile dysfunction is reversible by timely mitral valve replacement. An attempt to discover potential causes should be made by questioning for a prior history of a heart murmur or abnormal cardiac examination, rheumatic heart disease, endocarditis, myocardial infarction, or the use of anorexigenic drugs. Volume overload of the left ventricle displaces the apical impulse downward and to the left. In severe mitral regurgitation, S2 is followed by S3, which does not necessarily indicate heart failure but reflects rapid filling of the left ventricle by the large volume of blood stored in the left atrium during systole. The typical murmur of mitral regurgitation is a holosystolic apical murmur that often radiates toward the axilla. There is a rough correlation between the intensity of the murmur and the severity of the disease, but this correlation is too weak to use in clinical decision making because the murmur may be soft when cardiac output is low. In acute mitral regurgitation, the presence of a large V wave may produce rapid equilibration of left atrial and left ventricular pressure, reducing the driving gradient and shortening the murmur. Pulmonary hypertension may develop and produce right-sided signs including a right ventricular lift, increased P2, and, if right ventricular dysfunction has developed, signs of right-sided heart failure. The electrocardiogram usually shows left ventricular hypertrophy and left atrial abnormality. The chest radiograph usually demonstrates cardiomegaly; the absence of cardiomegaly indicates either that the mitral regurgitation is mild or that it has not been chronic enough to allow cardiac dilatation to occur. Echocardiography demonstrates the extent of left atrial and left ventricular enlargement. Ultrasonic imaging of the mitral valve is excellent and therefore offers clues to the mitral valve abnormalities responsible for the regurgitation. Color flow Doppler interrogation of the valve helps assess the severity of regurgitation, but since this technique images flow velocity rather than actual flow, it is subject to errors in interpretation. The Doppler technique is excellent for excluding the presence of mitral regurgitation and for distinguishing between mild and severe degrees; however, color flow Doppler examination may not be sufficient for more exact quantification of mitral regurgitation or to determine if the severity of the lesion is sufficient to cause eventual left ventricular dysfunction. When the severity of mitral regurgitation is in doubt or if mitral valve surgery is contemplated, cardiac catheterization is helpful in resolving the severity of the lesion; it should include coronary arteriography in patients older than age 40 or with symptoms suggesting coronary disease (see Chapter 46). In severe acute mitral regurgitation, the patient is usually symptomatic with heart failure or even shock. The goal of medical therapy is to increase forward cardiac output while concomitantly reducing regurgitant volume (see Chapter 48). Arterial vasodilators reduce systemic resistance to flow and thereby preferentially increase aortic outflow and simultaneously decrease the amount of mitral regurgitation and left atrial hypertension. If hypotension already exists, vasodilators such as nitroprusside will lower blood pressure further and cannot be used. In such cases, intra-aortic balloon counterpulsation is preferred if the aortic valve is competent. Counterpulsation increases forward cardiac output by lowering ventricular afterload while augmenting systemic diastolic pressure. Vasodilator therapy is clearly effective in the treatment of acute mitral regurgitation and in chronic aortic regurgitation (see later). However, perhaps because afterload is usually not increased in chronic asymptomatic mitral regurgitation, vasodilators have had little effect in reducing left ventricular volume or in improving normal exercise tolerance in mitral regurgitation. In patients with symptomatic mitral regurgitation, angiotensin-converting enzyme inhibitors have been demonstrated to reduce left ventricular volumes and to improve symptoms. However, mitral valve surgery rather than medical therapy usually is preferred in most symptomatic patients with mitral regurgitation. The timing of mitral valve surgery must weigh the risks of the operation and of a prosthesis, if one is inserted, versus the risk of irreversible left ventricular dysfunction if surgery is delayed unwisely. For most other types of valve disease, surgical correction usually requires the placement of a prosthetic valve, but in mitral regurgitation the native valve can often be repaired. Because conservation of the native valve obviates the risks of a prosthesis, the option of mitral valve repair should influence the patient and physician toward earlier operation. In the standard mitral valve replacement, the mitral valve leaflets and its apparatus are removed and a prosthetic valve is inserted. Although this operation almost guarantees mitral valve competence, destruction of the mitral valve apparatus is problematic. It is clear that the mitral valve apparatus has a much wider physiologic function than simply to prevent mitral regurgitation. The apparatus is responsible for coordinating left ventricular contraction and for helping to maintain the efficient prolate ellipsoid shape of the left ventricle. Destruction of the apparatus leads to a sudden fall in left ventricular function and an often permanent decline in postoperative ejection fraction. Thus, this operation is used only in circumstances in which the native valve cannot be repaired, such as in severe rheumatic deformity or in ischemic mitral regurgitation. In this procedure, a prosthetic valve is inserted but the continuity between the native leaflets and the papillary muscles is maintained. This procedure has the advantage of ensuring mitral valve competence while preserving the left ventricular functional aspects of the mitral apparatus. Even if only the posterior leaflets and chordae are preserved, the patient benefits both from improved postoperative ventricular function and better survival. In many cases, it is possible to preserve both anterior and posterior chordal attachments, although anterior continuity can be associated with left ventricular outflow tract obstruction. Although the patient benefits from both restored mitral valve competence and maintenance of left ventricular function, insertion of a prosthesis still carries all prosthesis-associated risks. Repair restores valve competence, maintains the functional aspects of the apparatus, and avoids insertion of a prosthesis. Repair is most applicable in cases of posterior chordal rupture; anterior involvement and rheumatic involvement make repair more difficult. In all cases, the feasibility of repair depends on the pathoanatomy that is causing the mitral regurgitation and on the skill and experience of the operating surgeon. Most patients with the symptoms of dyspnea, orthopnea, or fatigue should undergo surgery irrespective of which operation is performed because they already have lifestyle limitations from their disease. Furthermore, the mere presence of symptoms may worsen prognosis despite relatively well-preserved left ventricular function. The onset of left ventricular dysfunction in mitral regurgitation may occur without causing symptoms. Early surgery is warranted to prevent muscle dysfunction from becoming severe or irreversible. Whether valve repair or replacement is eventually performed, survival is prolonged to or toward normal if surgery is performed before ejection fraction declines to less than 0. Thus, patients with severe mitral regurgitation should be followed 334 yearly with a history, a physical examination, and an echocardiographic evaluation of left ventricular function. Once the patient reports symptoms or echocardiography demonstrates the onset of left ventricular dysfunction, surgery should be undertaken. Patients older than 75 years of age may have poor surgical results, especially if coronary disease is present or if mitral valve replacement rather than repair must be performed. Thus, while elderly patients with symptoms refractory to medical therapy may benefit from surgery, there is little compelling reason to commit elderly asymptomatic patients to a mitral valve operation. In some cases, prolapse is simply a consequence of normal left ventricular physiology without significant medical impact, while in other cases there is severe valvular deformity associated with an increased risk of stroke, arrhythmia, endocarditis, and progression to severe mitral regurgitation. Examples of the former situation are those that produce a small left ventricle. At the other end of the spectrum, severe redundancy and deformity of the valve, which occurs in myxomatous valve degeneration, clearly increases the risk of the complications noted earlier. However, in some cases, mitral valve prolapse is associated with a symptom complex including palpitation, syncope, and chest pain. The exact cause-and-effect relationship between the presence of mitral valve prolapse and these symptoms has been difficult to draw. In some cases, chest pain is associated with a positive thallium scintigram indicating the presence of true ischemia despite normal epicardial coronary arteries, perhaps because excessive tension on the papillary muscles increases oxygen consumption and causes ischemia. Palpitation, syncope, and presyncope, when present, are linked to autonomic dysfunction, which seems to be more prevalent in mitral valve prolapse. On physical examination, the mitral valve prolapse syndrome produces characteristic findings of a mid-systolic click and a late systolic murmur. The click occurs when the chordae tendineae are stretched taut by the prolapsing mitral valve in mid-systole. As this occurs, the mitral leaflets move past their coaptation point, permit mitral regurgitation, and cause the late systolic murmur. Maneuvers that make the left ventricle smaller, such as the Valsalva maneuver, cause the click to come earlier and the murmur to be more holosystolic and often louder. In some cases of echocardiographically proven mitral valve prolapse, neither the click nor the murmur is present; in other cases, only one of these findings is present. Echocardiography is useful to prove that prolapse is present, to image the amount of regurgitation and its physiologic effects, and to discern the pathoanatomy of the mitral valve. Although an echocardiogram is not necessary to diagnose prolapse in patients with the classic physical findings, the echocardiogram adds significant prognostic information because it can detect those patients who have specifically abnormal valve morphology and in whom most of the complications of the disease occur. About a decade ago it became clear that the mitral annulus did not exist in a single plane but had a saddle-back shape. Thus, prolapse demonstrated in the four-chamber echocardiographic view should be confirmed in the parasternal long-axis view. Echocardiographic diagnoses made before the understanding that the mitral valve plane was multidimensional (circa 1987) may have been made in error. Most patients with mitral valve prolapse have a benign clinical course; even for complication-prone patients with redundant and misshapen mitral leaflets, complications are relatively rare. Approximately 10% of patients with thickened leaflets suffer either infective endocarditis, stroke, progression to severe mitral regurgitation, or sudden death. The progression to severe mitral regurgitation varies with gender and age, and men are approximately twice as likely to progress as women. By the age of 50 years, only approximately 1 in 200 men requires surgery to correct mitral regurgitation. Because most patients with mitral valve prolapse are asymptomatic, therapy is unnecessary. Patients with mitral valve prolapse and its characteristic murmur should observe standard endocarditis prophylaxis (see Chapter 326). On the other hand, patients with otherwise normal valve leaflets shown to prolapse during echocardiography with no heart murmur do not require endocarditis precautions.
