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Annual Review of Medicine - Volume 45, 1994
Volume 45, 1994
- Review Articles
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The Role of Oncogenes in Hematologic Malignancies
Vol. 45 (1994), pp. 1–11More LessOncogenes are activated forms of cellular genes involved in normal cell growth and development. Some oncogenes play a role in human malignancies. In hematologic malignancies, researchers have identified many transcription factors as oncogenes based on one of the following criteria: their association with transforming retroviruses in animals, their translocation into either the immunoglobulin or T-cell receptor loci, or the production of fusion proteins resulting from chromosomal translocations. The molecular characterization of oncogenes in hematologic malignancies has led to the discovery of new methods for diagnosis and detection of minimal residual disease. In the future, researchers probably will develop novel treatment strategies to interfere with the function of these oncogenes.
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Neuromuscular Control of the Oropharynx and Esophagus in Health and Disease1
Vol. 45 (1994), pp. 13–22More LessThe oropharynx and esophagus convey swallowed materials from the mouth to the stomach and protect the airways from aspiration. These functions are subserved by complex neuromuscular interactions that coordinate the timing of the peristaltic contractions of the swallowing organs. The oropharynx and upper esophagus are composed of striated muscle, whereas the distal esophagus is composed of smooth muscle. The central nervous system completely controls peristalsis in the striated muscle organs. In the distal esophagus, neuromuscular mechanisms intrinsic to the esophagus control peristalsis. Diseases of the striated muscle, of the smooth muscle, or of the nervous system can lead to a derangement of peristalsis and disrupt the propulsion of swallowed materials to the stomach.
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Natural History of Autosomal Dominant Polycystic Kidney Disease
Vol. 45 (1994), pp. 23–29More LessAt least two different genes, which have been mapped to chromosomes 4 and 16, cause autosomal dominant polycystic kidney disease, a disorder with renal and extrarenal manifestations. Although gene-linkage testing is possible, the disease is diagnosed mainly through ultrasonography. Renal disease is characterized clinically by hypertension, acute and chronic pain, and variable progression to end-stage renal disease. Extrarenal manifestations include liver cysts, which may lead to complications; ruptured intracranial aneurysms; cardiac valvular disease; colonic diverticula; and inguinal hernias. Disease management is directed at minimizing and treating the complications of this illness.
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The Earliest Diagnosis of Acute Myocardial Infarction
Vol. 45 (1994), pp. 31–44More LessAcute myocardial infarction results from the cessation of myocardial blood flow caused by thrombotic occlusion of a coronary artery. Rapid restoration of blood flow to the ischemic myocardium minimizes cardiac damage and improves early and long-term morbidity and mortality. Chest pain is the first symptom of myocardial infarction, but in some patients with silent ischemia, the disease can be diagnosed only in retrospect. In symptomatic patients, myocardial infarction should be accurately and promptly diagnosed so that reperfusion therapy can begin immediately. Electrocardiography is the simplest diagnostic modality. Although regional ST-segment elevation is specific, it is not sensitive. In contrast, new computerized algorithms for electrocardiographic analysis and serial monitoring increase sensitivity without decreasing specificity. In the emergency room, echocardiography is used to diagnose patients with no prior history of coronary artery disease whose electrocardiograms proved nondiagnostic.
Time-consuming perfusion nuclear studies are inferior to echocardiography but may nevertheless enable physicians to diagnose myocardial infarction in the emergency room. Although the presence of excess creatine kinase is a sign of myocardial necrosis, its increase is delayed for a few hours after coronary occlusion. Doctors can diagnose myocardial infarction as early as two hours after coronary occlusion with the help of simpler automatic assays of MB-creatine kinase mass that use monoclonal antibodies. Other investigational markers of myocardial necrosis include myoglobin and troponin. Elevation of a circulating protein marker also signifies established necrosis, but physicians hope to achieve reperfusion through therapy before irreversible damage occurs.
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Molecular Genetics of Human Thyroid Neoplasms
Vol. 45 (1994), pp. 45–52More LessCancers are thought to develop as a result of sequential mutations of genes important in the control of cellular growth. Recently investigators identified a number of genetic defects that affect oncogenes and tumor-suppressor genes and that provide insight into the biology of benign and malignant thyroid neoplasms. Future implications for thyroid tumor diagnosis and prognosis are considered in this chapter.
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Therapy of Carotid Arteriosclerosis
Vol. 45 (1994), pp. 53–69More LessCarotid arteriosclerotic disease is the most readily treatable type of lesion leading to stroke. Its management involves lowering those risk factors over which the patient has control. Patients should regulate hypertension, quit smoking, seek medical attention for treatable cardiac abnormalities, and take steps to reduce increased blood lipids. For symptomatic carotid disease, regardless of whether surgery is offered, platelet inhibitors are obligatory. The recommended dose is 650 mg aspirin per day (or up to 1300 mg, if tolerated). For patients whose symptoms continue despite aspirin therapy or who are aspirin intolerant, ticlopidine is the only recommended platelet inhibitor.
Cerebral arterial bypass surgery is not an effective treatment for carotid arteriosclerosis. Carotid endarterectomy helps patients with ≥ 70% stenosis as determined by strict arteriographic measurements. We do not yet have sufficient data to determine whether endarterectomy would benefit patients with lower levels of carotid stenosis or asymptomatic patients with any degree of stenosis.
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Monoclonal Proteins and Renal Disease
Vol. 45 (1994), pp. 71–77More LessRenal insufficiency, which is present initially in almost half of patients with multiple myeloma, usually results from myeloma kidney or hypercalcemia. Neither the class of light chain nor the isoelectric point plays an important role in kidney failure. Acute renal failure must be treated with appropriate fluids and with electrolytes and hemodialysis if necessary. Plasma exchange may be helpful, but has not been proven as such. The presence of a nephrotic syndrome and a monoclonal κ or λ light chain in the urine almost always indicates primary amyloidosis (AL) or light-chain deposition disease. Amyloid fibrils must be distinguished from the fibrils of immunotactoid glomerulopathy.
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Intestinal Transplantation
Vol. 45 (1994), pp. 79–91More LessIntestinal transplantation is often the only alternative form of treatment for patients dependent on total parenteral nutrition for survival. Although a limited number of intestinal transplantations have been performed, results with FK 506 immunosuppression are comparable to those for other organ transplants. The impact of successful intestinal transplantation on gastroenterology will likely be similar to the impact of kidney and liver transplantation on nephrology and hepatology.
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BIOLOGICAL AND CLINICAL ASPECTS OF HEMATOPOIETIC STEM CELLS1
Vol. 45 (1994), pp. 93–104More Less▪ AbstractRecent advances in cell isolation techniques have greatly enhanced our understanding of the phenotype and function of hematopoietic stem cells in mice and humans. Many clinical studies have established the efficacy of using peripheral blood stem cells to supplement or replace bone marrow transplantation as a therapeutic modality for several types of malignancies. This new approach to malignant disease management, perhaps in combination with posttransplantation cytokine therapy, promises to completely alter the clinical course of bone marrow transplantation.
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Collagenous Colitis and Lymphocytic Colitis
Vol. 45 (1994), pp. 105–118More LessCollagenous and lymphocytic colitis are newly recognized causes of choric watery diarrhea that typically affect middle-aged patients. Although endoscopic studies are normal, inflammatory changes and (in the case of collagenous colitis) collagen deposition occur histologically in the colonic mucosa. The pathogenesis of these disorders remains a mystery, but the possible causes are intriguing. Patients may experience spontaneous remissions and relapses, but treatment with sulfasalazine or prednisone is usually effective for patients with distressing symptoms.
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TREATMENT OF VENTRICULAR ARRHYTHMIAS AFTER RECOVERY FROM MYOCARDIAL INFARCTION
Vol. 45 (1994), pp. 119–138More Less▪ AbstractDemonstrated associations between postmyocardial infarction ventricular arrhythmias and a higher subsequent risk of both sudden and all-cause mortality have prompted a search for effective and safe treatment modalities. Recently completed clinical trials have provided a rationale for treatment recommendations in some specific settings. Beta-blocking therapy is recommended for postinfarction patients with frequent or complex ventricular premature beats. In contrast, calcium antagonist therapy is not helpful in these cases, and Class I antiarrhythmic therapy is actually harmful. Early indications of benefit from Class III antiarrhythmic therapies, particularly amiodarone, are under evaluation in large trials. Patients with sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) occuring late after myocardial infarction require therapy. Viable therapeutic methods include individualized antiarrhythmic therapy selected by the noninvasive approach, individualized antiarrhythmic therapy selected by the invasive approach, empiric amiodarone therapy, transcatheter or surgical ablative therapy (for VT), and use of an implantable cardioverter defibrillator. Clinical trial data have yet to determine which of these approaches is most effective under which circumstances. Postinfarction patients with nonsustained VT are the focus of several ongoing treatment trials. Early data suggest that risks requiring specific therapy are reached only by those patients who also have significant left ventricular dysfunction. The presence of inducible sustained ventricular tachycardia at an electrophysiologic study may further risk stratify such patients. High-risk patients with nonsustained ventricular tacycardia, left ventricular dysfunction, and inducible sustained ventricular tachycardia should participate in ongoing clinical trials. In the absence of this opportunity, intensive treatment should be considered.
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TRANSPLANTATION OF THE HEART AND LUNGS IN CHILDREN
Vol. 45 (1994), pp. 139–148More Less▪ AbstractHeart transplantation in children with complex congenital heart disease or cardiomyopathies has become an effective form of therapy for patients with no other surgical options. Because pediatric pulmonary transplantation is a relatively new procedure, long-term follow-up data are not yet available. However, the intermediate-term results of pediatric lung transplantation appear similar to those for heart and lung transplantation. Children represent a particularly difficult patient group for transplant of thoracic organs, and recipients must be selected carefully. Additionally, physicians must pay close attention to multiple medical conditions relating to the underlying disease process in order to achieve optimal results.
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MOLECULAR BASIS OF HEREDITARY DISORDERS OF CONNECTIVE TISSUE
Vol. 45 (1994), pp. 149–163More Less▪ AbstractThe molecular basis for several hereditary disorders of connective tissues has been elucidated in recent years. In this chapter, we discuss recent advances in the molecular characterization of a number of these disorders and examine their clinical applications.
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HIRUDIN: Clinical Potential of a Thrombin Inhibitor
Vol. 45 (1994), pp. 165–177More Less▪ AbstractHirudin is the most potent and specific known inhibitor of thrombin, the enzyme that plays a key regulatory function in hemostasis and blood coagulation. The importance of thrombosis in cardiovascular disease has recently highlighted the limitations of existing antithrombotic drugs and the potential value of direct thrombin inhibition as an effective approach to antithrombotic therapy. Hirudin and a small peptidomimetic analog—hirulog—are being developed as alternatives to heparin for the treatment of unstable angina, for prevention of abrupt closure and restenosis following coronary angioplasty, for prevention of deep vein thrombosis after major orthopedic surgery, and as an adjunct to fibrinolytic therapy. Direct thrombin inhibitors have several potential advantages over heparin: They can inhibit thrombin bound to clots or extracellular matrices, which are relatively resistant to heparin; they do not require antithrombin III as a cofactor, which may lead to a more predictable dose response; and they are not inhibited by activated platelets, which release platelet factor 4 and other molecules that neutralize heparin. The results of early clinical studies suggest that hirudin and hirulog may be more efficacious and more predictable and may have fewer bleeding complications than heparin for several clinical indications.
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Cellular and Molecular Abnormalities in the Vascular Endothelium of Diabetes Mellitus
Vol. 45 (1994), pp. 179–188More Less▪ AbstractDiabetic vascular complications affect both micro- and macrovasculature, primarily in the retina, renal glomeruli, and multiple sites in the macrovessels. This review presents a summary of the abnormal function found in vivo and in cultured vascular cells exposed to elevated levels of glucose. We also discuss the various biochemical hypotheses that have been proposed to explain the adverse effects of hyperglycemia on vascular cells.
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HYPERCALCEMIA OF MALIGNANCY: The Central Role of Parathyroid Hormone-Related Protein
Vol. 45 (1994), pp. 189–200More Less▪ AbstractHypercalcemia is the most common metabolic complication of cancer. Malignancy-associated hypercalcemia (MAHC) can be divided into two syndromes, humoral hypercalcemia of malignancy (HHM) and local osteolytic hypercalcemia (LOH), based on whether a circulating hormone or local paracrine factors mediate accelerated bone resorption. Over the past decade, studies have shown that parathyroid hormone-related protein is the cause of the HHM syndrome, and recent data suggest that this protein may also play a paracrine role in some patients with local osteolytic hypercalcemia. Study of the regulation of parathyroid hormone-related protein gene expression is beginning to shed some light on the molecular mechanisms responsible for this common clinical problem.
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NONRENAL COMPLICATIONS OF THE NEPHROTIC SYNDROME
Vol. 45 (1994), pp. 201–210More Less▪ AbstractThe nephrotic syndrome is a consequence of urinary loss of intermediate-sized plasma proteins and the resulting homeostatic responses to those losses. Plasma protein composition is changed greatly. Pathphysiologic changes are a consequence of the nature of the proteins lost and of the proteins that are increased in plasma to replace them. Plasma oncotic pressure (π) falls because of the replacement of relatively small plasma proteins by larger ones. Decreased π increases transudation of fluid into the interstitum and favors edema. This is exacerbated by causing renal insensitivity to atrial natriuretic factor (ANF), primary renal sodium retention, and plasma volume expansion. Many proteins lost in the urine, such as erythopoietin and IgG, are not defended by increased synthesis. Their loss may result in reduced immunity, anemia, and endocrinopathies. Albumin synthesis can be increased by dietary protein augmentation; however, urinary protein losses also increase, offsetting any palliative effect of increased albumin synthesis on albumin stores. The synthesis of many other proteins secreted by the liver is also increased, causing an elevation in plasma levels of several large proteins, including lipoproteins and elements of the coagulation cascade. This results in hyperlipidemia and, in conjunction with the urinary loss of smaller proteins that impede coagulation, a hypercoagulable state. Lipoprotein catabolism is also reduced as a consequence of proteinuria contributing to increased lipid levels.
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THALASSEMIA: Pathophysiology of Red Cell Changes
Vol. 45 (1994), pp. 211–218More Less▪ AbstractThe thalassemias are extremely heterogeneous in terms of their clinical severity, and their underlying pathophysiology relates directly to the extent of accumulation of excess unmatched globin chains: α in βthalassemia and βin the αthalassemias. However, the accumulation of each separate globin chain affects red cell membrane material properties and the state of red cell hydration very differently. These observations presumably account for the varying extent of ineffective erythropoiesis and peripheral blood hemolysis in the major variants of thalassemia.
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ETIOPATHOGENESIS AND TREATMENT OF PSYCHOSIS
Vol. 45 (1994), pp. 219–234More Less▪ AbstractPsychotic illnesses (schizophrenia and schizoaffective and affective psychosis) have a lifetime prevalence of 2–3% and probably occur at a similar rate in all human societies. No etiologically significant environmental precipitants have been identified, and this suggests that these diseases are primarily genetic. Brain studies reveal that in schizophrenic patients, development of cerebral asymmetry is arrested, which may be associated with a small reduction in cortical mass. Episodes of illness can be ameliorated by dopamine (in particular D2) antagonists, drugs that are antipsychotic rather than merely antischizophrenic. The discovery of at least five dopamine receptor subtypes and their genes paves the way for new approaches to treatment. However, whether psychotic patients undergo a primary disturbance of dopaminergic transmission remains unclear.
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DIET AND NEPHROLITHIASIS
Vol. 45 (1994), pp. 235–243More Less▪ AbstractPharmacologic therapy of recurrent nephrolithiasis continues to be the mainstay of the strategy to prevent recurrence. This approach persists even in the face of increasing evidence of a marked benefit of mere entry into a nonpharmacologic diet and fluid modification protocol at a clinic specializing in the evaluation and therapy of recurrent nephrolithiasis (the “Stone Clinic effect”). This review examines the role of diet in the pathogenesis of various forms of nephrolithiasis and the effectiveness of dietary therapy in preventing new stone formation. Recent and older evidence support a primary role for modification of diet, particularly diet protein and sodium intake, in the prevention of recurrent nephrolithiasis.
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METABOLIC INTERACTIONS OF DIABETES AND PREGNANCY
Vol. 45 (1994), pp. 245–260More Less▪ AbstractMany of the embryonic and fetal abnormalities that occur in pregnancies complicated by maternal diabetes are the result of development in a metabolically abnormal environment. Diabetic embryopathy (birth defects and spontaneous abortions) results from maternal metabolic abnormalities during the first 6–7 weeks of gestation. The embryopathy appears to be multifactorial in origin, and the resulting defects remain important causes of morbidity and mortality in diabetic pregnancies. Diabetic fetopathy (predominantly macrosomia and neonatal hypoglycemia) results from fetal overnutrition and hyper-insulinemia during the second and third trimesters. Fetopathy may cause significant morbidity not only in the perinatal period, but also in later life as overweight infants grow up to be overweight children and young adults. Careful regulation of maternal metabolism from the preconceptional period onward can reduce greatly or even eliminate the excess risks that have been incurred by infants of diabetic mothers in the past. Successful management of maternal diabetes requires knowledge of the alterations in intermediary metabolism that normally occur during pregnancy, as discussed in this chapter.
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PATHOGENESIS AND HOST RESPONSE IN Pneumocystis carinii PNEUMONIA
Vol. 45 (1994), pp. 261–272More Less▪ AbstractPneumocystis carinii (PC) pneumonia is recognized as the leading cause of opportunistic pulmonary infections in immunocompromised hosts during the past decade. Although much remains unknown about pathogenesis and host response in PC, in recent years, studies of PC have provided us with an increasing base of knowledge about this organism and its relationship to the host. These studies have led to a better understanding of mechanisms of PC attachment and injury to host cells. New information about the interaction of PC with pulmonary surfactant provides insight about the pathophysiology of PC pneumonia. The interplay of the organism, host inflammatory cells, release of cytokines, generation of toxic metabolites, and involvement of both cellular and humoral immunity is complex, but understanding the pathogenesis of PC pneumonia is necessary in order to develop new therapies for this disorder.
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THE PRESENT USE OF ELECTROCONVULSIVE THERAPY1
Vol. 45 (1994), pp. 273–281More Less▪ AbstractPhysicians attempting to treat certain severe mental disorders have recently shown renewed interest in electroconvulsive therapy (ECT). A number of technical innovations have made ECT safer, as well as more effective. These innovations include oxygenation, muscular relaxation, unilateral nondominant electrode placement, use of brief-pulse stimuli, titrated stimulus dosing, electroencephalographic (EEG) monitoring, determination of seizure adequacy, and pharmacologic enhancement of treatment response.
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Malaria, the Red Cell, and the Endothelium
Vol. 45 (1994), pp. 283–295More Less▪ AbstractErythrocytes infected with mature stages of Plasmodium falciparum malaria adhere to vascular endothelial cells in postcapillary venules of several organs. In some patients, infected cells also form rosettes with uninfected erythrocytes. The special pathology of acute cerebral malaria appears to result from excessive adherence of infected cells in cerebral vessels coupled with occlusion of cerebral blood flow in microvessels by infected cell rosettes. Several endothelial cell proteins have been identified as potential receptors for infected erythrocyte adherence to vascular endothelium, including thrombospondin, CD36, intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (ELAM-1). The receptor on infected erythrocytes that mediates adhesion to endothelial cells has been identified as a very large malarial protein on infected cells called PfEMP1. PfEMP1 has been shown to bind to CD36 and thrombospondin in vitro. Antibody-mediated blockade or reversal of infected erythrocyte adherence to vascular endothelium is postulated not only to decrease the pathology of blood-stage malaria, but also to lead to infected cell destruction and clearance, especially in the spleen. PfEMP1 is therefore a prime candidate malarial protein for inclusion in a multicomponent asexual malaria vaccine.
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- Review Articles
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MOLECULAR EVENTS IN THE PATHOGENESIS OF HEPADNAVIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA
Vol. 45 (1994), pp. 297–323More Less▪ AbstractChronic hepadnavirus infection is associated with hepatocellular carcinoma (HCC) in natural hosts such as humans, woodchucks, and Beechey ground squirrels. Several possible oncogenic mechanisms have been identified, including a potential role of the hepadnavirus x (hbx) gene, which transactivates transcription regulated by certain cis-acting sequences, e.g. regulatory sequences of the hepatitis B virus (HBV) and heterologous regulatory sequences of other viruses and cellular genes. The oncogenic potential of hbx is suggested by the observation of HCCs in hbx transgenic mice, the oncogenic transformation of cells expressing hbx in culture, and the transactivation of oncogenes c-myc and c-jun by hbx. Cis-activation of cellular oncogenes N-myc and c-myc by viral promoter insertion has been a common finding in woodchuck hepatitis virus (WHV)-associated HCCs of woodchucks. No such cis-activation of any cellular gene has been shown in virus-associated HCCs of ground squirrels or humans. Amplification and overexpression of the c-myc gene has been a common finding in HCCs of ground squirrels, and is rare in woodchuck or human HCCs. Point mutations in the p53 gene and allelic deletion of p53 have been common findings in human HCCs, but have not been found in HCCs in woodchucks and have been found rarely in ground squirrels. How each of these genetic changes in the different hosts contributes to HCC remains to be determined, but apparently different changes in different HCCs of hepadnavirus-infected hosts suggest that several separate genetic events may contribute to the development of HCC. These events may differ in each host, and some may not result from a direct virus-specific mechanism. Chronic hepadnavirus infection is often associated with chronic necroinflammatory liver disease and cirrhosis, a pathologic process common to several other risk factors for HCC. This suggests that this pathologic process (necroinflammatory disease) may be hepatocarcinogenic regardless of the inciting agent. Thus hepadnavirus infection may play an important role in the development of HCC by causing chronic hepatitis and HCC with the same mechanisms by which other risk factors for HCC cause chronic necroinflammatory liver disease and HCC.
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FACTORS AFFECTING OUTCOME AFTER RECOVERY FROM MYOCARDIAL INFARCTION
Vol. 45 (1994), pp. 325–339More Less▪ AbstractPatients surviving acute myocardial infarction are susceptible to heart failure, recurrence of angina, reinfarction, arrhythmias, and sudden cardiac death. Most deaths occur in the first six months after infarction. Advancing age is the most important nonmodifiable prognostic factor for long-term prognosis, whereas left ventricular function assessed clinically or measured as either ejection fraction or end-systolic volume is the most important modifiable factor. Other significant long-term prognostic factors include: postinfarction angina at rest, inducible ischemia during exercise testing with or without radioisotope imaging, severity and extent of coronary artery disease, patency of the infarct-related artery, late ventricular arrhythmias, decreased heart rate variability, cigarette smoking, hypercholesterolemia, and diabetes mellitus. Identification of these adverse prognostic factors permits risk stratification and enables physicians to determine the most appropriate and cost-effective treatment.
Most patients should have a stress test for inducible ischemia and a noninvasive (echo or radionuclide) assessment of left ventricular function. For high-risk patients such as those with prior infarction, heart failure, early postinfarction angina, or frequent late ventricular arrhythmias, coronary angiography and ventriculography prior to discharge are recommended. Assessment of late potentials and heart rate variability will help identify a subgroup of patients at risk for ventricular arrhythmias and cardiac death. However, a more accurate prediction of reinfarction is not possible at present, and no reliable test for atherosclerotic plaque instability has been developed.
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PROGNOSIS IN CONGESTIVE HEART FAILURE
Vol. 45 (1994), pp. 341–350More Less▪ AbstractPrognostic variables such as the ejection fraction and peak oxygen consumption can be used to place patients with heart failure in risk strata. Some vasodilators have been shown to improve survival at all stages of heart failure with the probability of benefit increasing as the prognosis worsens. Quantitative estimates of survival among groups defined by prognostic variables and treatments should be used to make more informed benefit-to-risk assessments.
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PROSTATE CARCINOMA
Vol. 45 (1994), pp. 351–359More Less▪ AbstractOver the last several years, the development of prostate-specific antigen (PSA) testing and technical refinements of anatomic radical prostatectomy have revolutionized the care of patients with prostate cancer. Serum PSA testing often allows early diagnosis of organ-confined prostate cancer. Anatomical radical prostatectomy has a high probability of completely eradicating these tumors, with minimal long-term morbidity. Use of PSA testing after therapy confirms the long-term ability of surgery to eradicate early-stage prostate cancer.
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ENDOTHELIAL-LEUKOCYTE ADHESION MOLECULES IN HUMAN DISEASE
Vol. 45 (1994), pp. 361–378More Less▪ AbstractAn effective host response to infection or tissue damage requires focal accumulation of leukocytes. Leukocyte adhesion to the vessel wall, a key step in this process, depends on the ordered expression of specific endothelial cell surface molecules. The endothelial molecules that support adhesion include selectins that recognize leukocyte cell surface glycoconjugates as well as members of the immunoglobulin superfamily that interact with leukocyte integrins. Although inflammation can occur with minimal damage to the vessel wall and surrounding tissues, control mechanisms sometimes appear to fail, and the inflammatory response itself becomes a significant clinical problem. In this review, we discuss endothelial-leukocyte adhesion molecules with particular emphasis on their expression and function in human disease. Pathophysiological processes presented include atherosclerosis, ischemia-reperfusion injury, acute lung injury, rheumatoid arthritis, and graft rejection. A more detailed description of the discovery and characterization of the key molecules appears in the antecedent article entitled “Endothelial-Leukocyte Adhesion Molecules” (1).
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MECHANISM OF EPILEPSY1
Vol. 45 (1994), pp. 379–389More Less▪ AbstractEpilepsy is a collection of diverse disorders that together affect approximately 1% of the general population. Current therapies are largely symptomatic and are aimed at controlling seizures in affected individuals. This review focuses on emerging insights into mechanisms underlying the most common form of epilepsy—complex partial epilepsy—and also addresses progress in molecular genetic approaches. Such developments will hopefully lead to more effective therapies.
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GONADOTROPIN-RELEASING HORMONE AND ITS ANALOGS
Vol. 45 (1994), pp. 391–405More Less▪ AbstractGnRH and its analogues have led to exciting new avenues of therapy in virtually every subspecialty of internal medicine as well as in gynecology, pediatrics, and urology. Since their discovery in 1971, it has been demonstrated that GnRH and its analogues enable medical professionals to influence the hypothalamic-pituitary-gonadal axis in two distinct classes of therapeutic applications. The first provides natural sequence GnRH in a pulsatile fashion via portable infusion pumps to mimic the normal physiology of hypothalamic GnRH secretion and restores reproductive potential to infertile men and women with disorders of endogenous GnRH secretion. The second mode uses long-acting GnRH agonists administered in a depot delivery to produce a paradoxical desensitization of pituitary gonadotropin secretion which, in turn, results in a complete ablation of the reproductive axis. This biochemical castration induced by GnRH agonist administration is a safe, effective, complete, and reversible method of removing the overlay of gonadal steroids from a variety of diseases which they are known to exacerbate. These diseases include endometriosis and uterine fibroids in women, prostate cancer in men, and precocious puberty in both sexes.
This review examines the physiologic and pharmacologic principles underlying the advances produced by these agents, the mechanism of action of GnRH and its analogues at the cellular level, and the individual therapeutic applications to which these analogues have been applied. Because virtually every subspecialty of medicine will be touched by the GnRH analogues, this review provides an overview and background of their use.
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USE AND ABUSE OF HUMAN GROWTH HORMONE
Vol. 45 (1994), pp. 407–420More Less▪ AbstractRecombinant human growth hormone (hGH) has been available for nearly a decade. Side effects are rare. Its efficacy in promoting growth acceleration has been widely confirmed in children with GH deficiency (GHD), Turner syndrome, idiopathic short stature, chronic renal failure, and a variety of other conditions. The dramatic increase in height velocity in the first year of therapy partially attenuates in subsequent years in all patient groups, and convincing final height data are only available in GHD and Turner syndrome.
Pediatric endocrinologists continue to be troubled by definitions of GHD. Although profound GHD is relatively obvious, other patients with severe growth failure but borderline or normal endocrine testing also respond to hGH therapy. Thus many endocrinologists use auxologic criteria [e.g. low growth velocity, height <-3 standard deviation (SD), poor predicted adult height] as the de facto basis for therapy, leading to a blurred distinction between treatment of disease and enhancement of normal characteristics and, finally, raising questions about the ultimate benefit of hGH therapy. Brief clinical trials of hGH therapy in adults both with and without GHD have reported increased muscle mass, decreased fat, and improvement in quality of life. Internists may soon be faced with treatment decisions analogous to those confronting pediatricians, i.e. whether to use hGH to repair aspects of the normal aging process.
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MODULATION OF THE IONIC MILIEU OF THE AIRWAY IN HEALTH AND DISEASE
Vol. 45 (1994), pp. 421–434More Less▪ AbstractAirway surface liquid (ASL) is an integral part of lung defense mechanisms. Ion transport by airway epithelia regulates the volume and composition of this fluid. A better understanding of the mechanisms of ion transport will enable the development of new therapies for airway diseases associated with defects in these mechanisms. A useful model of a disease with abnormal airway epithelial ion transport is cystic fibrosis (CF), a distinct genetic syndrome of altered lung defense mechanisms characterized by chronic bacterial infection and a steady decline in lung function. Traditional therapies for CF include antibacterial drugs and augmentation of clearance of secretions, but investigators are now studying pharmacological approaches to target the more basic defect of the disease, i.e. abnormal sodium and chloride ion transport. Early treatment in childhood, prior to lung damage, might prevent or at least retard the decline in pulmonary function that remains the hallmark of CF. Ion transport dysfunction may also contribute to other airway diseases such as asthma and chronic bronchitis. Pharmacological intervention at this level may prove beneficial in these common lung diseases as well.
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CELLULAR AND MOLECULAR BIOLOGY OF ALZHEIMER'S DISEASE AND ANIMAL MODELS
Vol. 45 (1994), pp. 435–446More Less▪ AbstractAlzheimer's disease (AD), the most common dementing disorder of late life, is a major cause of disability and death in the elderly. Neurobiological, genetic, and molecular studies have defined the vulnerable neural systems, abnormalities in cytoskeletal proteins in neurons, the biology of the β-amyloid precursor protein (APP) and β-amyloid (Aβ, βA4), and several APP mutations linked to the disease. More recently, investigators have begun to develop animal models essential for delineating pathogenetic mechanisms and for developing and testing new therapies for treating AD in humans. This review focuses primarily on recent progress in investigation of animal models of AD (including aged nonhuman primates and transgenic mice), which have begun to clarify some of the questions raised by investigation of the disease in humans.
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ANTIDEPRESSANTS IN LONG-TERM TREATMENT
Vol. 45 (1994), pp. 447–457More Less▪ AbstractOne of the most important recent developments in the management of depression is the recognition of the need for long-term treatment. Treatment of an episode of depression must continue after apparent response in order to consolidate response and prevent relapse. A continuation treatment period of at least four months after response of the acute episode is required in all patients with depression. Most depression is recurrent, and prophylactic treatment with antidepressants reduces the risk of new episodes. This treatment needs to be continued over very long periods, because the risk of new episodes does not appear to diminish with time.
In selecting an antidepressant for long-term treatment efficacy, safety and tolerability in the long term should be taken into account since not all antidepressants have been adequately tested, and some do not appear to be effective. The most thoroughly tested antidepressants are the tricyclic imipramine and the new selective serotonin reuptake inhibitors.
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STRATEGIES FOR ATTENUATING PROTEIN-CATABOLIC RESPONSES IN THE CRITICALLY ILL
Vol. 45 (1994), pp. 459–480More Less▪ AbstractSpecialized enteral and parenteral nutrition are now a standard components of care in critically ill patients. This adjunctive therapy corrects and prevents nutrient deficiencies, attenuates the loss of body protein, and improves clinical outcomes in malnourished patients. Several novel strategies designed to improve the metabolic and clinical effects of specialized nutrition are under vigorous clinical investigation.
These new approaches include increased emphasis on enteral feeding to maintain intestinal absorptive, immune, and barrier function; administration of conditionally essential amino acids (glutamine, arginine); use of specialized lipid products and antiox idants; and administration of growth factors such as human growth hormone. Randomized, controlled clinical trials will define the clinical and metabolic efficacy and cost-effectiveness of these therapies in specialized nutrition support.
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INFLAMMATORY HEART DISEASE: Pathogenesis, Clinical Manifestations, and Treatment of Myocarditis
Vol. 45 (1994), pp. 481–490More Less▪ AbstractMyocarditis is an uncommon cause of cardiac disease that can result in arrhythmia, congestive heart failure, and death. Myocardial injury in myocarditis is due in part to activated cellular and humoral immune components directed toward normal cardiac tissue. Although numerous therapies for myocarditis, including corticosteroids and immunosuppressive agents, have been applied in animal experiments and in human studies, none have demonstrated survival benefit over untreated controls. In many patients, myocarditis may spontaneously resolve. Information about myocarditis pathogenesis, manifestations, and treatment has been useful in disease management. Further research into the inflammatory nature of myocarditis may provide the basis for more favorable outcomes of intervention in this disease.
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TUMOR NECROSIS FACTOR: A Pleiotropic Cytokine and Therapuetic Target
Vol. 45 (1994), pp. 491–503More Less▪ AbstractAdvances in the molecular biology of human diseases indicate that the most striking manifestations of illness may be caused not by exogenous pathogenic or tumor porducts, but rather by toxic peptides produced by the host itself. Tumor necrosis factor (TNF), a polypeptide cytokine produced during infection, injury, or invasion, has proved spivotal in triggering the lethal effects of septic shock syndrome, cachexia, and other systemic manifestations of disease. Because removing TNF from the diseased host may prevent development of the illness, this factor has recently been the focus of intensive research. This review discusses the biology of this cytokine, with particular emphasis on its potential therapeutic role in septic shock and cachexia.
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MALE SEX DETERMINATION: Current Concepts of Male Sexual Differentiation
Vol. 45 (1994), pp. 505–524More Less▪ AbstractIn order for an infant to develop as a phenotypically complete male or female, a cascade of complex molecular and morphological events must occur at the appropriate time and in the correct sequence during ontogeny. The male embryo's genetic sex is determined by its chromosomal constituents, the most important of which is the sex-determining gene, or testis-determining factor (TDF), on the Y chromosome. Male gonadal sex, or testis formation, is subsequently thought to be determined by this gene and by other secondary pathways. The male gonad, in turn, normally produces hormones such as testosterone and Mullerian inhibiting substance (MIS) that regulate differentiation of the internal and external genitalia, thus determining phenotypic sex. When an abnormality develops in any of the above three processes, an intersex infant with ambiguous genitalia results from the incongruent genetic, gonadal, and phenotypic sex. Clinically, such 46XY males with intersex abnormalities present challenges for gender assignment, timely surgical intervention, and appropriate hormonal therapy.
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THE COURSE AND TREATMENT OF LUPUS NEPHRITIS
Vol. 45 (1994), pp. 525–537More Less▪ AbstractRenal involvement by systemic lupus is variable; some patients have minimal clinical and histologic involvement, whereas others have fulminant renal failure and severe proliferative renal lesions on biopsy. The World Health Organization (WHO) classification has greatly aided in the study of lupus nephritis. This classification defines six major patterns of renal involvement, each with characteristic clinical correlates and a typical course and prognosis. Transformations from one pattern of lupus nephritis to another may occur, and there may also be prominent involvement of the tubulointerstitial compartment and vasculature. Treatment of the renal lesions may be directed at the individual class of lupus nephritis. Thus patients with mesangial involvement (WHO Class II) do not require therapy directed at their kidney lesions. Many patients with biopsies showing focal proliferative disease (WHO Class III) and all patients whose biopsies show diffuse proliferative lesions (WHO Class IV) require vigorous treatment, which has included high-dose daily and alternate-day corticosteroids, azathioprine, i.v. pulse methylprednisolone, plasmapheresis, total lymphoid irradiation, cyclosporine, and oral and i.v. cyclophosphamide. Controlled trials have yielded reasonable evidence for the safety and efficacy of some treatments, whereas others have been used only in uncontrolled studies. When used judiciously, such vigorous therapy can improve the renal survival of patients with severe lupus nephritis.
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Previous Volumes
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Volume 75 (2024)
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Volume 74 (2023)
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Volume 73 (2022)
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Volume 72 (2021)
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Volume 71 (2020)
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Volume 70 (2019)
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Volume 69 (2018)
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Volume 68 (2017)
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Volume 67 (2016)
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Volume 66 (2015)
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Volume 65 (2014)
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Volume 64 (2013)
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Volume 63 (2012)
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Volume 62 (2011)
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Volume 61 (2010)
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Volume 60 (2009)
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Volume 59 (2008)
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Volume 49 (1998)
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Volume 48 (1997)
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Volume 47 (1996)
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Volume 46 (1995)
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Volume 45 (1994)
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Volume 44 (1993)
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Volume 43 (1992)
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Volume 42 (1991)
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Volume 41 (1990)
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Volume 40 (1989)
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Volume 39 (1988)
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Volume 38 (1987)
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Volume 37 (1986)
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Volume 36 (1985)
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Volume 35 (1984)
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Volume 34 (1983)
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Volume 33 (1982)
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Volume 32 (1981)
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Volume 31 (1980)
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Volume 30 (1979)
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Volume 29 (1978)
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Volume 28 (1977)
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Volume 27 (1976)
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Volume 26 (1975)
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Volume 25 (1974)
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Volume 24 (1973)
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Volume 23 (1972)
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Volume 22 (1971)
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Volume 21 (1970)
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Volume 20 (1969)
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Volume 19 (1968)
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Volume 18 (1967)
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Volume 17 (1966)
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Volume 16 (1965)
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Volume 15 (1964)
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Volume 14 (1963)
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Volume 13 (1962)
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Volume 12 (1961)
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Volume 11 (1960)
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Volume 10 (1959)
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Volume 9 (1958)
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Volume 8 (1957)
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Volume 7 (1956)
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Volume 6 (1955)
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Volume 5 (1954)
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Volume 4 (1953)
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Volume 3 (1952)
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Volume 2 (1951)
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Volume 1 (1950)
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Volume 0 (1932)