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- Volume 49, 1998
Annual Review of Medicine - Volume 49, 1998
Volume 49, 1998
- Review Articles
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Chronic Fatigue Syndrome: An Update
Vol. 49 (1998), pp. 1–13More LessAmong the many patients who seek medical care for the complaint of fatigue, a small number suffer from chronic fatigue syndrome (CFS). CFS is a poorly understood condition characterized by debilitating fatigue and associated symptoms lasting at least six months. Studies indicate that the illness is not simply a manifestation of an underlying psychiatric disorder, but rather is an illness characterized by activation of the immune system, various abnormalities of several hypothalamic-pituitary axes, and reactivation of certain infectious agents.
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The Extracellular Calcium-Sensing Receptor: Its Role in Health and Disease
Vol. 49 (1998), pp. 15–29More LessThe recent cloning of an extracellular calcium (Ca2+o)-sensing receptor (CaR) from parathyroid, kidney and other cell types has clarified the mechanisms through which Ca2+o exerts its direct actions on various cells and tissues. In the parathyroid, the CaR mediates the inhibitory effects of Ca2+o on parathyroid hormone (PTH) secretion and likely on expression of the PTH gene and parathyroid cellular proliferation. In the kidney, the receptor mediates direct inhibition of the reabsorption of divalent cations in the cortical thick ascending limb, and it likely underlies the inhibitory actions of hypercalcemia on the urinary-concentrating mechanism in the medullary thick ascending limb and inner medullary collecting duct. The identification of inherited diseases of Ca2+o-sensing that arise from mutations in the CaR gene has proven, by genetic means, the central role of the CaR in mineral ion homeostasis and the importance of the receptor in regulating the parathyroid and kidney. An allosteric CaR agonist (“calcimimetic”) is currently being tested for the treatment of primary hyperparathyroidism, and CaR-based therapeutics will likely be applicable to other disorders in which CaRs are under- or overactive. Thus the discovery of the CaR and its associated diseases has documented that Ca2+o plays an essential role as an extracellular first messenger, in addition to serving its better recognized role as an intracellular second messenger.
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Homocysteine and Cardiovascular Disease
Vol. 49 (1998), pp. 31–62More LessAn elevated level of total homocysteine (tHcy) in blood, denoted hyperhomocysteinemia, is emerging as a prevalent and strong risk factor for atherosclerotic vascular disease in the coronary, cerebral, and peripheral vessels, and for arterial and venous thromboembolism. The basis for these conclusions is data from about 80 clinical and epidemiological studies including more than 10,000 patients. Elevated tHcy confers a graded risk with no threshold, is independent of but may enhance the effect of the conventional risk factors, and seems to be a particularly strong predictor of cardiovascular mortality. Hyperhomocysteinemia is attributed to commonly occurring genetic and acquired factors including deficiencies of folate and vitamin B12. Supplementation with B-vitamins, in particular with folic acid, is an efficient, safe, and inexpensive means to reduce an elevated tHcy level. Studies are now in progress to establish whether such therapy will reduce cardiovascular risk.
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The Open-Artery Hypothesis
A. Solomon, and B. GershVol. 49 (1998), pp. 63–76More LessEarly reperfusion of an infarct-related coronary artery results in myocardial salvage, with subsequent improvement in left ventricular function and survival. However, late reperfusion, which occurs at a time when myocardial salvage is no longer possible, still exerts a favorable impact on left ventricular function and survival. This concept is known as the open-artery hypothesis. Possible mechanisms for this benefit include improved infarct healing, limitation of ventricular remodeling, decreased ventricular arrhythmias, and reperfusion of hibernating myocardium. Although an open infarct-related coronary artery is crucial, it has not been proven that opening an occluded coronary artery using angioplasty is beneficial. A large randomized clinical trial is clearly needed.
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Pathophysiology of Atrial Flutter
Vol. 49 (1998), pp. 77–83More LessAtrial flutter is a macroreentrant tachyarrhythmia most often contained within the right atrium. Typical atrial flutter is defined on an electrocardiogram by the classic “sawtooth” pattern of flutter waves with negative polarity in leads II, III, and aVF. In contrast to atrial fibrillation, which is sustained by multiple reentrant wavelets defined by anatomic and/or functional barriers, typical atrial flutter is sustained by a single reentrant circuit defined by anatomical barriers. The isthmus of atrial tissue bordered by the inferior vena cava and the tricuspid annulus forms a critical zone of slow conduction in the reentry circuit of atrial flutter. The goal of radiofrequency catheter ablation is to create a line of conduction block across this isthmus. This line of block interrupts the flutter circuit and often provides long-term freedom from recurrence.
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New Approaches to Supporting the Failing Liver
Vol. 49 (1998), pp. 85–94More LessWith the continued, growing disparity between the numbers of organ donations and patients waiting for liver transplantation, various efforts have been made to optimize the allocation of organs, as well as to devise means to support the failing liver. Over the years, the development of bioartificial liver-assist devices has aimed at replacing the three main functions of hepatocytes, which are synthetic, metabolic, and excretory. The application of porcine hepatocytes in humans to carry out biotransformation, as well as other metabolic functions and refinement of the membrane separator, have yielded some promising results in supporting patients with acute liver failure. Further advances will need to be made before these bioartificial devices can be considered for routine application in clinical settings.
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Assessing Risks, Costs, and Benefits of Laparoscopic Hernia Repair
Vol. 49 (1998), pp. 95–109More LessLaparoscopic inguinal herniorrhaphy (LIHR) was introduced with the following potential advantages: less postoperative discomfort and pain, reduced recovery time that allows earlier return to full activity, easier repair of a recurrent hernia, the ability to treat bilateral hernias concurrently, the performance of a simultaneous diagnostic laparoscopy, ligation of the hernia sac at the highest possible site, improved cosmesis, and decreased incidence of recurrence. Potential disadvantages include complications, such as bowel, bladder, and vascular injuries; potential adhesive complications at sites where the peritoneum has been breached or prosthetic material has been placed; the apparent need, at least at the present, for a general anesthetic; and the increased cost because of expensive equipment needs. Most surgeons agree that LIHR has a role in the management of patients with a recurrent hernia after a conventional inguinal herniorrhaphy (CIHR), bilateral inguinal hernia, or a need for laparoscopy for another procedure, such as laparoscopic cholecystectomy. The routine use of LIHR for the unilateral, uncomplicated hernia is a more contentious issue.
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Detection of Minimal Residual Disease: Relevance for Diagnosis and Treatment of Human Malignancies
Vol. 49 (1998), pp. 111–122More LessMinimal residual disease (MRD) is the tumor burden that is present after a course of treatment that has resulted in clinical remission. For hematopoietic malignancies, techniques for detection of this minimal tumor burden are being used to monitor MRD. These involve methods that are capable of identifying very low numbers of neoplastic cells in an otherwise normal marrow or lymph node. Patients with demonstrable residual neoplastic cells tend to do worse than patients without detectable cells; however, results depend on the timing of the assay and whether the detectable neoplastic cells appear to be increasing in number with subsequent assays. For bone marrow transplantation, assays incorporating chimerism analyses, cytogenetics, and morphology are used to regulate therapy.
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Chronic Pain
Vol. 49 (1998), pp. 123–133More LessChronic pain is an emotional experience and is defined as pain lasting greater than six months. It is important to understand the neurophysiology of pain in order to treat it. Nociceptors in the periphery travel to the substantia gelatinosa of the spinal cord while secondary and tertiary afferents transmit information from the dorsal horn to the brain. Modification of pain information may take place in these ascending pathways or in descending pathways. Treatment of chronic pain is most successful when it is approached in a multidisciplinary fashion with the focus not only on treatment of underlying etiology, but also on the secondary impacts of pain on the patient's life. The management of chronic pain requires special expertise. Most of the experts in chronic pain assessment and management organize themselves into pain treatment centers. These centers vary widely in their approach to the problem. The most sophisticated is a multidisciplinary center that is university-based and includes teaching and research. Treatment of chronic pain includes a variety of medications, psychological support, and rehabilitation. Multidisciplinary pain management is also an integral part of the palliative care and hospice concept used to treat cancer pain.
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Advances in the Medical Treatment of Epilepsy
Vol. 49 (1998), pp. 135–162More LessTreatment options for epilepsy, especially using antiepileptic drugs, have increased substantially in the past five years. Since 1993, four novel antiepileptic drugs have been approved and marketed in the United States: felbamate, gabapentin, lamotrigine, and topiramate. Two others, tiagabine and vigabatrin, are likely to be approved in the near future. For many patients, these agents offer the realistic promise of improved seizure control, often with fewer adverse effects and less significant drug interactions compared with older agents. In addition, fosphenytoin, a water-soluble phenytoin prodrug with a number of advantages over intravenous phenytoin, has been released. There are new administration options for carbamazepine, diazepam, and valproic acid. For drug-resistant or -intolerant patients, there has been renewed interest in alternative therapies, especially the ketogenic diet. Taken together, these represent significant therapeutic advances that are benefiting patients with epilepsy. At the same time, improved understanding of the basic mechanisms of epileptogenesis, and of the cellular and molecular actions of available antiepileptic drugs, creates a framework for designing unique therapeutic strategies that are targeted at key sites of vulnerability involved in the development and maintenance of the epileptic state.
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How to Screen for Colon Cancer1
Vol. 49 (1998), pp. 163–172More LessThe biology of colorectal cancer provides a unique opportunity for early detection and prevention. There is now evidence that screening of asymptomatic average-risk individuals over 50 years of age can reduce mortality resulting from colorectal cancer. New recommendations from the US Preventive Services Task Force endorse screening with fecal occult blood tests or sigmoidoscopy. The best method for population screening remains uncertain. The cost of screening is an important issue in the development of public policy. This review discusses the various screening options, examines the “downstream” effects of screening, and reviews the anticipated costs and effectiveness. Ultimately, the effectiveness of any screening program depends on patient compliance. Further research is needed to determine the best methods of enhancing patient adherence to a screening program.
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The Role of Glutamatergic Neurotransmission in the Pathophysiology of Alcoholism
Vol. 49 (1998), pp. 173–184More LessRecent evidence suggests that ethanol abuse produces its diverse effects on the brain to a substantial degree by disrupting the function of the major excitatory neurotransmitter, glutamate. Ethanol, at concentrations associated with behavioral effects in humans, inhibits the N-methyl-d-aspartate (NMDA) receptor, which mediates the post-synaptic excitatory effects of glutamate. Tolerance to ethanol results in up-regulation of the NMDA receptor so that abrupt withdrawal produces a hyperexcitable state that leads to seizures, delerium tremens, and excitotoxic neuronal death. Ethanol's inhibition of the NMDA receptor in the fetal brain likely contributes to the CNS manifestations of fetal alcohol syndrome. Therapeutic strategies aimed at correcting glutamatergic dysregulation in alcoholism need to be explored.
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Evaluation of the Patient with Recurrent Bacterial Infections1
Vol. 49 (1998), pp. 185–199More LessRecurrent bacterial infection is a complaint encountered regularly in the course of both adult and pediatric care. Defects of neutrophils and monocytes are most commonly associated with recurrent infection, but abnormalities of immunoglobulins and complement must be considered. Defensins, small antibacterial peptides, have been implicated recently in some of the infectious diathesis of cystic fibrosis. A thorough history and physical examination focused on severity, sequelae, and microbiology of infections can usually determine whether a patient needs further evaluation. The diseases and syndromes most frequently associated with recurrent infection are presented, along with discriminating clinical, pathologic, and microbiologic features.
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Human Ehrlichioses: Newly Recognized Infections Transmitted by Ticks
Vol. 49 (1998), pp. 201–213More LessHuman ehrlichioses are tick-borne infections caused by bacteria in the genus Ehrlichia. Human monocytic ehrlichiosis is caused by Ehrlichia chaffeensis and human granulocytic ehrlichiosis is caused by an agent similar to Ehrlichia equi. E. chaffeensis infects mononuclear phagocytes and is transmitted by Lone Star ticks (Amblyomma americanum) found in the south central and eastern United States. The agent of human granulocytic ehrlichiosis infects mostly neutrophils, is transmitted by Ixodes species ticks, and occurs mostly in the upper midwest and northeast United States. Despite the undifferentiated presentation of both ehrlichioses with fever, headache, myalgias, leukopenia, thrombocytopenia, and elevated liver enzyme activities, the diagnostic methods are distinct. Occasional severe complications include meningoencephalitis, adult respiratory distress syndrome, shock, and opportunistic infections. Immunocompromised patients are at high risk for death. An adverse outcome is associated with delayed diagnosis and therapy; thus, empirical treatment is advocated. Treatment with doxycycline usually results in prompt defervescence and cure.
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Surgical Implications of Obesity
Vol. 49 (1998), pp. 215–234More LessObesity is perhaps the most significant public health problem facing the United States today. Obese patients are at increased risk for numerous medical problems, which can adversely affect surgical outcome. However, these risks have not uniformly translated into increased or prohibitive operative morbidity and mortality in this population. With appropriate perioperative precautions and monitoring, the incidence of serious cardiovascular and pulmonary complications can be minimized. Obese patients can be treated as safely and effectively as their normal weight counterparts under most circumstances and should not be denied surgical treatment for any disorder when surgery constitutes the most appropriate therapy. When indicated, surgical treatment should be considered for patients with clinically severe obesity, since currently it appears to offer the best long-term results for weight control and amelioration of comorbidity.
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Exercise, Glucose Transport, and Insulin Sensitivity
Vol. 49 (1998), pp. 235–261More LessPhysical exercise can be an important adjunct in the treatment of both non–insulin-dependent diabetes mellitus and insulin-dependent diabetes mellitus. Over the past several years, considerable progress has been made in understanding the molecular basis for these clinically important effects of physical exercise. Similarly to insulin, a single bout of exercise increases the rate of glucose uptake into the contracting skeletal muscles, a process that is regulated by the translocation of GLUT4 glucose transporters to the plasma membrane and transverse tubules. Exercise and insulin utilize different signaling pathways, both of which lead to the activation of glucose transport, which perhaps explains why humans with insulin resistance can increase muscle glucose transport in response to an acute bout of exercise. Exercise training in humans results in numerous beneficial adaptations in skeletal muscles, including an increase in GLUT4 expression. The increase in muscle GLUT4 in trained individuals contributes to an increase in the responsiveness of muscle glucose uptake to insulin, although not all studies show that exercise training in patients with diabetes improves overall glucose control. However, there is now extensive epidemiological evidence demonstrating that long-term regular physical exercise can significantly reduce the risk of developing non–insulin-dependent diabetes mellitus.
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The Molecular Ggenetics of the Long QT Syndrome: Genes Causing Fainting and Sudden Death
Vol. 49 (1998), pp. 263–274More LessThe congenital long QT syndrome is an autosomal-dominant genetic disorder of cardiac electrical repolarization. It is caused by mutations of at least six genes, of which four, all encoding for cardiac ion channels, have been identified: KVLQT1, HERG, and Min K encode for cardiac potassium ion channels, and SCN5A encodes for the cardiac sodium ion channel. In each case the altered ion channel function produces prolongation of the action potential and propensity to torsade de pointes ventricular tachycardia. A fifth gene locus is known to be on chromosome 4, but the gene has not been isolated. At least one other gene must exist, and there may be several more. Long QT syndrome is a frequent but often overlooked cause of unexpected syncope and sudden death in children and young adults. Characteristic findings are prolongation of the QT interval and T wave abnormalities on the electrocardiogram. However, the QT interval at presentation is normal about 10% of the time and just borderline prolonged another 30%, so diagnosis may be difficult. Symptoms are syncope and sudden death, typically occurring during exercise or emotional upset. The manifestations vary, depending on the genotype present. The phenotype also probably varies, depending on the specific mutation involved. Phenotypic heterogeneity is also caused by variable penetrance and expressivity.
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Infection Genomics: Nramp1 as a Major Determinant of Natural Resistance to Intracellular Infections
Vol. 49 (1998), pp. 275–287More LessThe scope of the tuberculosis (TB) epidemic in the world today is enormous, with about 30 million active cases. Current research into preventing the spread of TB is focused on development of new drugs to inactivate Mycobacterium tuberculosis, the causative agent of TB, as well as on identifying the critical steps of host defense to infection with Mycobacteria, which might also yield therapeutic targets. Our infection genomics approach toward the latter strategy has been to isolate and characterize a mouse gene, Bcg (Nramp1), which controls natural susceptibility to infection with Mycobacteria, as well as Salmonella and Leishmania. Through comparative genomics, we have identified the homologous human NRAMP1 gene, alleles of which are now being used for tests of linkage with TB and leprosy.
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Gastric Lymphoma of Mucosa-Associated Lymphoid Tissue and Helicobacter pylori
Vol. 49 (1998), pp. 289–299More LessAlthough the majority of primary gastric lymphomas are of high-grade non-Hodgkin's type, a significant number are low-grade B cell lymphomas. The recognition that the majority of the latter have characteristic clinicopathological features that are different from those of their nodal counterparts has led to the suggestion that these lymphomas arise specifically from within organized extranodal lymphoid tissue; this tissue resembles that seen constitutively in the intestine (mostly located in the terminal ileum as Peyer's patches) and is termed mucosa-associated lymphoid tissue (MALT). The paradox of this proposal is that there is no MALT in the gastric mucosa in normal individuals from which a primary lymphoma can arise. However, it has been shown that organized lymphoid tissue with all the features of MALT can be acquired in the gastric mucosa, and this is seen most frequently, but not exclusively, in association with infection by Helicobacter pylori H. pylori). Subsequent studies have confirmed a close association between H. pylori infection and gastric MALT lymphoma with the infection preceding the development of the lymphoma. In vitro studies have demonstrated that there is an immunologically based drive to tumor cell proliferation in low-grade gastric MALT lymphomas associated with the presence of H. pylori. Clinical studies have shown that, at least in early lesions, eradication of the organism can result in tumor regression in 60 to 92% of cases.
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Xenotransplantation: Problems and Prospects
Vol. 49 (1998), pp. 301–310More LessResearch in xenotransplantation has increased enormously in the last eight years. As the shortage of allogeneic organs has intensified, the possibility of using organs from pigs has become more attractive. Current data suggest that hyperacute rejection can be overcome in a clinically acceptable manner. However, additional likely rejection factors, probably related to endothelial cell activation, are being identified that likely lead to delayed xenograft rejection, a phenomenon that can occur in the absence of T lymphocytes. Reviewed here are various genetic engineering approaches that might help overcome these rejection factors, resulting eventually in a multi-transgene donor pig. Other concerns and current controversies in the field are also discussed.
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Diagnosis and Management of Congenital Adrenal Hyperplasia
Vol. 49 (1998), pp. 311–328More LessCongenital adrenal hyperplasia is a family of inborn errors of steroidogenesis, each characterized by a specific enzyme deficiency that impairs cortisol production by the adrenal cortex, and can lead to sexual ambiguity in both genetic males and females. The enzymes most often affected are 21-hydroxylase, 11β-hydroxylase, and 3β-hydroxysteroid dehydrogenase, and less often, 17α-hydroxylase/17, 20-lyase and cholesterol desmolase. Decreased production of cortisol results in increased pituitary secretion of adrenocorticotropic hormone. The elevated adrenocorticotropic hormone stimulates both the accumulation of precursor steroids in the impeded pathways and excessive steroid synthesis in other adrenal biosynthetic pathways unaffected by the enzyme deficiency. Correct identification of the enzyme affected is achieved by the observation of clinical syndromes reflecting distinct hormonal patterns, and it is measured quantitatively as low levels of cortisol and other adrenal steroids, as well as increased levels of steroids proximal to the blocked step. Many of the corresponding genes for the described enzymes have been isolated and characterized, and specific mutations causing many cases of congenital adrenal hyperplasia have been identified. These advances have important implications for early prenatal diagnosis and prenatal treatment.
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Adoptive Immunotherapy Following Allogeneic Bone Marrow Transplantation
Vol. 49 (1998), pp. 329–340More LessSome of the recent advances in our knowledge of immune recognition have provided new tools to circumvent or reverse some of the major disadvantages of allogeneic bone marrow transplantation (BMT). The pretransplant conditioning regimen produces a major defect in the immune system that greatly favors the occurrence of life-threatening infections, caused particularly by Epstein-Barr virus and cytomegalovirus. However, adoptive transfer of virus-specific cytotoxic T lymphocytes can reconstitute specific immunity and/or cure viral disease in immunocompromised post-BMT patients. The other major drawback of allogeneic BMT is graft-versus-host disease (GVHD). Although potentially detrimental, it is closely associated with an antileukemia reaction (graft-versus- leukemia, GVL). The most direct evidence of the GVL effect has been provided by the efficacy of donor leukocyte infusions (DLI). DLI can induce long-lasting remissions, especially in patients with chronic myeloid leukemia who relapse post-BMT. Although allogeneic cell therapy should still be considered a “naive” form of immunotherapy, work in progress on the identification of leukemia-specific antigens will improve the outcome and enlarge its applications.
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Functional Neuroimaging Studies of Depression: The Anatomy of Melancholia
Vol. 49 (1998), pp. 341–361More LessFunctional brain imaging techniques, which permit noninvasive measures of neurophysiology and neuroreceptor binding, are powerful and sensitive tools for research aimed at elucidating the pathophysiology of major depression. The application of these technologies in depression research has produced several studies of resting cerebral blood flow (BF) and glucose metabolism in subjects imaged during various phases of illness and treatment. This review examines these data and the principles relevant to their interpretation and discusses the insights they provide into the anatomical correlates of depression. Within the anatomical networks implicated in emotional processing by other types of evidence, these BF and metabolic data demonstrate that major depression is associated with reversible, mood state–dependent, neurophysiological abnormalities in some structures and irreversible, trait-like abnormalities in other structures. In some of the regions in which trait-like abnormalities appear, abnormal metabolic activity appears at least partly related to the anatomical abnormalities identified in magnetic resonance imaging (MRI) studies of depression.
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Endovascular Treatment of Abdominal Aortic Aneurysms
Vol. 49 (1998), pp. 363–373More LessAbdominal aortic aneurysms (AAA) may now be treated by endovascular placement of an arterial graft. These grafts are inserted through the femoral artery and then secured to the aorta above and below the aneurysm. The procedure reduces the risk of many perioperative complications and reduces hospital costs and length of stay. Several FDA-approved clinical trials are currently in progress with a variety of different devices. None is available for general use at this time. Overall, more than 800 grafts have now been placed, with a primary success rate of greater than 80%. Several complications have been reported, but the incidence of complications has generally decreased as proficiency has improved. The most troublesome problem has been leak of blood around the graft with continued risk of aneurysm rupture; therefore, follow-up CT scans and clinical examinations are mandatory to allow for appropriate treatment. Future modifications of current devices and techniques for delivery can be expected to reduce the incidence of currently identified problems. Endovascular grafting for AAA offers important potential advantages over conventional repair and may become increasingly important in the management of patients who have an abdominal aortic aneurysm.
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Clostridium difficile Infection
Vol. 49 (1998), pp. 375–390More LessClostridium difficile infection is associated with broad-spectrum antibiotic therapy and is the most common cause of infectious diarrhea in hospital patients. Pathogenic strains of C. difficile produce two protein exotoxins, toxin A and toxin B, which cause colonic mucosal injury and inflammation. Infection may be asymptomatic, cause mild diarrhea, or result in severe pseudomembranous colitis. Diagnosis depends on the demonstration of C. difficile toxins in the stool. The first step in management is to discontinue the antibiotic that caused diarrhea. If diarrhea and colitis are severe or persistent, oral metronidazole is the treatment of choice. Oral vancomycin is also effective, but it is more expensive than metronidazole and its widespread use may encourage the proliferation of vancomycin-resistant nosocomial bacteria. Diarrhea and colitis usually improve within three days after a patient starts taking metronidazole or vancomycin, but 20% suffer a relapse of diarrhea when these agents are discontinued.
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Diagnosis and Treatment of Pre–Insulin Dependent Diabetes
Vol. 49 (1998), pp. 391–405More LessThe development of genetic and serological markers of autoimmune Type I diabetes has allowed us to begin to identify subjects at risk for the development of Type I diabetes. Assessment of these variables can assign risk to subjects and permit the implementation of immune intervention trials in an attempt to alter the course of pre-diabetes. This review discusses relevant aspects of the genetics and diagnosis of pre-diabetes, and both current and future clinical trials that are attempting to prevent the full expression of clinical diabetes in these individuals.
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Angiogenesis and Tumor Metastasis
Vol. 49 (1998), pp. 407–424More LessAngiogenesis, the recruitment of new blood vessels, is an essential component of the metastatic pathway. These vessels provide the principal route by which tumor cells exit the primary tumor site and enter the circulation. For many tumors, the vascular density can provide a prognostic indicator of metastatic potential, with the highly vascular primary tumors having a higher incidence of metastasis than poorly vascular tumors. Tumor angiogenesis is regulated by the production of angiogenic stimulators including members of the fibroblast growth factor and vascular endothelial growth factor families. In addition, tumors may activate angiogenic inhibitors such as angiostatin and endostatin that can modulate angiogenesis both at the primary site and at downstream sites of metastasis. The potential use of these and other natural and synthetic angiogenic inhibitors as anticancer drugs is currently under intense investigation. Such agents may have reduced toxicity and be less likely to generate drug resistance than conventional cytotoxic drugs. Clinical trials are now underway to develop optimum treatment strategies for antiangiogenic agents.
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Hereditary Breast Cancer
Vol. 49 (1998), pp. 425–436More LessGenetic predisposition is responsible for 5–10% of all breast cancer, and a much larger percent of early-onset disease. Within the past few years, a number of genes associated with a high risk of breast cancer have been identified, including BRCA1, BRCA2, p53, and the Cowden disease gene PTEN/MMAC1. These genes appear to function as tumor suppressors, and although their mutation frequency in the general population is low, certain populations have a carrier frequency of up to 1% for particular BRCA1 and BRCA2 mutations. The isolation of these genes is likely to provide important insight into the pathogenesis of human cancer. The clinical application of these molecular discoveries raises controversial issues regarding presymptomatic testing for patients suspected of harboring cancer predisposing mutations.
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Proliferation and the Monoclonal Origins of Atherosclerotic Lesions
Vol. 49 (1998), pp. 437–460More LessBenditt's observation of the monoclonal origin of the atherosclerotic lesion has been controversial because it appeared to conflict with conventional wisdom. A new method based on a polymerase chain reaction amplification of the DNA of an X-inactivated gene from microdissected tissue confirms that Benditt was correct. However, this monoclonal expansion can also be found in nonatherosclerotic intima and media. These new data suggest that plaque clonality may represent expansion of preexisting patches of cells arising during development of the media. This developmental view does not conflict with other recent evidence that plaque expansion is associated with mutation or viral events. However, if plaques arise from patches, then early developmental mechanisms may be critical to the later evolution of the lesions.
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New Considerations in the Treatment of Sickle Cell Disease
Vol. 49 (1998), pp. 461–474More LessThe familial pattern of recurring pain and early death seen so often among those affected by sickle cell disease has been long recognized within African cultures, though its first clear description in Western medical literature did not appear until 1910 (1). Although most common in persons of African ancestry, the mutation giving rise to the sickle gene arose independently in several locations where malaria was prevalent (2), traveled with migrating populations, and is now widely distributed among regions and ethnic groups. Recognizing the qualitative abnormality of sickle hemoglobin as a prototype, Pauling & Castle established the notion of a molecular disease (3). Ironically, while the biochemistry and molecular biology of sickle cell disease has been intensively investigated, research into patient care has been limited in scope until recently. Prospective study of large patient groups diagnosed at birth is now providing insight into the disease's natural history and facilitating investigational treatments. Newborn diagnosis, combined with study of new drugs, cytokines, surgical procedures, and a more proactive utilization of transfusion is leading to greatly improved care and survival. Life expectancy is increasing (4) but adults are experiencing more complications of chronic organ dysfunction. A few patients have been cured by stem-cell transplantation, but difficult problems will continue to limit its application.
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Dyspepsia: Current Understanding and Management
Vol. 49 (1998), pp. 475–493More LessDyspepsia, defined as “pain or discomfort centered in the upper abdomen” is reported by one in four adults in Western societies. The most important causes are non-ulcer (functional) dyspepsia, peptic ulcer, gastroesophageal reflux, and, rarely, gastric cancer. Persons with heartburn alone are not considered to have dyspepsia. The division of dyspepsia into symptom-based subgroups (ulcer-like, dysmotility-like, reflux-like, and unnspecified dyspepsia) has proven to be of doubtful value for the clinician, as it has a low predictive value for identifying the causes of dyspepsia. Upper endoscopy remains the “gold standard” test; ultrasound and blood tests have a low yield. The role of Helicobacter pylori in peptic ulcer disease is well known, but the clinical role of the infection in non-ulcer dyspepsia remains very controversial. In uninvestigated dyspeptic patients who are H. pylori infected based on a non-invasive test, empiric anti–H. pylori therapy is a reasonable and probably cost-effective option. In documented non-ulcer dyspepsia, prokinetics are superior to placebo while antisecretory therapy is of less certain efficacy.
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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 57 (2006)
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Volume 55 (2004)
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Volume 54 (2003)
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Volume 53 (2002)
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Volume 52 (2001)
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Volume 51 (2000)
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Volume 50 (1999)
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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 0 (1932)