Annual Review of Medicine - Volume 53, 2002

The diagnosis of deep vein thrombosis (DVT) and pulmonary embolism (PE) has been improved and simplified over the past decade thanks to advances in noninvasive and readily accessible technology. With high degrees of sensitivity and specificity, venous ultrasonography is favored as the initial investigation for DVT. To diagnose PE, most clinicians rely on diagnostic algorithms that combine clinical assessment, noninvasive lung studies, and, if necessary, venous ultrasonography of the legs and D-dimer testing. Substantial progress has also occurred in the treatment of acute venous thromboembolism with the introduction of low-molecular-weight heparins. This class of antithrombotic agents has changed initial therapy from an inpatient, intravenous regimen that required laborious monitoring to an outpatient practice using weight-adjusted doses of once-daily subcutaneous injections. In addition, several new anticoagulants with theoretical advantages over existing agents have entered phase III studies. Aspects of thrombosis treatment that remain controversial include vena caval interruption and the indications for thrombolysis and surgical thromboembolectomy.

Cyclooxygenase (COX), also known as prostaglandin endoperoxide synthase, is the key enzyme required for the conversion of arachidonic acid to prostaglandins. Two COX isoforms have been identified, COX-1 and COX-2. In many situations, the COX-1 enzyme is produced constitutively (e.g., in gastric mucosa), whereas COX-2 is highly inducible (e.g., at sites of inflammation and cancer). Traditional nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both enzymes, and a new class of COX-2 selective inhibitors (COXIBs) preferentially inhibit the COX-2 enzyme. This review summarizes our current understanding of the role of COX-1 and COX-2 in normal physiology and disease.

Traditionally, clinicians have viewed heart failure either as a problem of excessive salt and water retention caused by abnormalities of renal blood flow, or as a hemodynamic problem associated with a reduced cardiac output and excessive peripheral vasoconstriction. Recently, clinicians have begun to adopt a neurohormonal model in which heart failure progresses because of the toxic effects of endogenous biological systems that become activated in heart failure. We review the rationale for existing heart failure therapies and discuss the reasoning behind the development of some emerging therapies.

In thrombotic thrombocytopenic purpura (TTP), a multimeric form of von Willebrand factor (vWf) that is larger than ordinarily found in the plasma causes systemic platelet aggregation under the high-shear conditions of the microcirculation. A divalent cation–activated, vWf-cleaving metalloprotease that metabolizes large vWf multimers to smaller forms in normal plasma is severely reduced or absent in most patients with TTP. The vWf-cleaving metalloprotease either is not produced or is defective in children with chronic relapsing TTP. When the enzyme is provided by the infusion of normal plasma, these patients remain free of TTP symptoms for about three weeks. An IgG autoantibody to the vWf-cleaving metalloprotease is found transiently in many adult patients with acute idiopathic, recurrent, and ticlopidine/clopidogrel-associated TTP. These patients require plasma exchange, i.e., concurrent replacement of the inhibited vWf-cleaving metalloprotease by plasma infusion and plasmapheresis. The vWf-cleaving metalloprotease is present in fresh-frozen plasma, in cryoprecipitate-depleted plasma (cryosupernatant), and in plasma that has been treated with solvent and detergent. The pathophysiology of platelet aggregation in bone marrow transplantation/chemotherapy–associated thrombotic microangiopathy, and in the hemolytic-uremic syndrome, is not established. In neither condition is there a severe decrease in plasma vWf–cleaving metalloprotease activity.

Whole-body positron emission tomography (PET) imaging with ¹⁸F deoxyglucose (FDG) is a molecular imaging modality that detects metabolic alterations in tumor cells that are common to neoplastic cells. FDG-PET has recently been approved by the Health Care Finance Administration for Medicare reimbursement for diagnosing, staging, and restaging lung cancer, colorectal cancer, lymphoma, melanoma, head and neck cancer, and esophageal cancer. This review discusses the scientific evidence that led to the emergence of PET imaging as an accepted clinical tool in patients with solitary pulmonary nodules, lung cancer, colorectal cancer, melanoma, lymphoma, breast cancer, and other cancers. When possible, we compare the performance of PET to that of anatomical imaging. We discuss future clinical applications of this imaging modality.

Attention deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder presenting for treatment in youth. ADHD is often chronic with prominent symptoms and impairment spanning into adulthood. ADHD is often associated with co-occurring anxiety, mood, and disruptive disorders, as well as substance abuse. The diagnosis of ADHD by careful review of symptoms and impairment is both reliable and valid. Recent genetic, imaging, neurochemistry, and neuropsychological data support the biological underpinning of the disorder. All aspects of an individual's life must be considered in the diagnosis and treatment of ADHD. Pharmacotherapy, including stimulants, antidepressants, and antihypertensives, plays a fundamental role in the management of ADHD across the lifespan.

The increasing shortage of human cadaveric organs for purposes of transplantation has become the critical limiting factor in the number of transplants performed each year. Some of this deficit is being met by the use of organs or partial organs from living donors, but this source is insufficient. Xenotransplantation—the transplantation of organs between species, namely from the pig to human—could provide a solution if immunologic and other associated problems could be solved. When a pig organ is transplanted into a primate, hyperacute rejection, induced by anti-pig antibody and mediated by complement and the coagulation system, develops rapidly. This immediate problem can now be overcome, but the return or persistence of anti-pig antibody leads to a delayed form of humoral rejection, acute humoral xenograft rejection, which leads to destruction of the organ within days or weeks. We review the various approaches being investigated to overcome this barrier. Whether they will also prevent subsequent acute cellular rejection remains unknown. Brief mention is made of the potential physiologic incompatibilities between pig and human organs, as well as the microbiologic safety aspects of xenotransplantation. Finally, the question of patient and societal acceptance of xenotransplantation is discussed.

By destroying CD4+ T cells, human immunodeficiency virus-1 (HIV-1) infection results in immunodeficiency and the inability of the immune system to contain the virus in most individuals. Although treatment of HIV-1 infection with potent antiretroviral medications has resulted in enormous clinical benefit, there is a growing recognition of the limitations of this therapy. As a result, novel approaches to treating HIV-1 infection are being considered. One such strategy is immunotherapy, which seeks to boost immune responses against HIV-1 and control the virus. This approach is based on studies of other viruses in which a coordinated immune response contains the chronic infection. Recent studies show that CD4+ helper responses, CD8+ T cell activity, and antibodies may contribute to control of the virus without antiretroviral therapy in some HIV-positive individuals. Based on this understanding of the immunologic correlates of control of HIV-1, exciting new immunotherapeutic strategies for HIV-1 infection are being designed and tested.

Over the past decade, the number of treatments available for bipolar disorder has undergone an extraordinary expansion. In that period, valproate and olanzapine have received regulatory approval in the United States for the acute treatment of mania, and carbamazepine has been indicated for this condition in many other countries. In addition to those agents, a number of other anticonvulsants (in particular lamotrigine, gabapentin, and topiramate) are in trials, as are the atypical antipsychotics clozapine and risperidone, and other novel compounds. This article critically reviews the evidence from controlled trials of these proposed “mood stabilizers,” highlighting the strengths and limitations of the data for each compound. A major challenge to the field is the capacity to prove the prophylactic properties of agents for which effectiveness in acute mania and/or bipolar depression has been demonstrated. Finally, as the mechanisms of agents such as lithium are now becoming apparent, and the possibility of understanding the molecular defects underpinning the condition is no longer highly fanciful, the prospect of targeted therapies is considered feasible by both academia and the pharmaceutical industry.

Heart transplantation has evolved over the past 30 years into a mainstay of therapy for heart failure patients. As the surgical technique and basic immunology were defined, heart transplantation became a real therapeutic option. Over the next few decades, thoracic transplant teams at Stanford University and other institutions refined this mode of therapy. This review addresses the history, current surgical technique, recipient and donor selection, postoperative care, immunosuppression, short- and long-term complications, and clinical outcomes associated with this procedure.

Development of a preventive vaccine for HIV is the best hope of controlling the AIDS pandemic. Evidence from natural history studies and experiments in animal models indicates that immunity against HIV is possible, suggesting that vaccine development is feasible. These studies have shown that sufficient levels of neutralizing antibody against HIV can prevent infection, although the effect is type-specific. In contrast, HIV-specific cytotoxic T lymphocyte (CTL) activity has broad cross-reactivity, and although CTL activity alone cannot prevent HIV infection, it can control the level of viremia at a low level. Evaluation of candidate vaccines in human trials has focused on approaches that can safely elicit HIV-specific antibody and T cell responses. Current strategies have been unable to induce antibody with broad neutralizing activity against primary HIV isolates. However, recombinant poxvirus and DNA vaccines have elicited CTL responses that are broadly cross-reactive against primary HIV isolates from diverse clades. Future advances will require the discovery of new immunogens that can induce neutralizing antibody, as well as efficacy trial evaluation of regimens optimized for CTL induction.

Epithelial cancers are a major worldwide health problem. Since the mid-1970s, advances in multidisciplinary cancer therapeutics have only slightly improved the mortality rate from epithelial malignancies. Chemoprevention is the use of specific natural or synthetic chemical agents to reverse, suppress, or prevent progression to invasive cancer. Chemopreventive medicine is based on translating basic biologic research into clinical chemical interventions, thus attempting to impede carcinogenesis. Its principles build on the concepts of field cancerization (diffuse epithelial injury that results from carcinogen exposure) and multistep carcinogenesis (a stepwise accumulation of cellular and genetic alterations that progress to cancer). Chemoprevention targets the carcinogenic process at earlier and potentially more reversible stages, focusing on the inhibition of one or many steps in the progression towards cancer. Strategies of chemoprevention include primary prevention in groups at high risk, reversal of premalignant lesions, and prevention of second primary tumors.

This review focuses on several topics related to the epidemiology of diabetes and cardiovascular disease (CVD). These include the CVD risk factors common in the metabolic syndrome, behavioral risk factors and diabetes, gender differences in the association between diabetes and CVD risk, and how the clinical definition of diabetes influences the association of diabetes and CVD. Nontraditional risk factors potentially linking diabetes and CVD are also discussed, including chronic inflammation, advanced glycation endpoints, autonomic neuropathy, sleep-disordered breathing, and genetic susceptibility to diabetes-associated CVD risk.

The peripheral T cell pool is damaged by HIV-1 infection and can be regenerated by production of new T lymphocytes either from the thymus or from proliferation of post-thymic T cells. A critical question for AIDS patients is whether treatment with antiretroviral drugs can restore the capability to produce new T lymphocytes. The development of a new assay of thymus function in adults (the measurement of T cell receptor excision circles, TRECs), and studies of thymus biopsies in untreated and treated HIV-1-infected patients, have suggested that in select patients the thymus can regenerate on antiretroviral therapy. New strategies to overcome the thymic atrophy of aging are needed to improve thymic function in the majority of AIDS patients.

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system (CNS). Diagnosis rests upon identifying typical clinical symptoms and interpreting supportive laboratory and radiological investigations. The etiology is unknown; however, strong evidence suggests that MS is an autoimmune disease directed against CNS myelin or oligodendrocytes. Genetic factors are important in the development of MS. Contributing environmental determinants (possibly including infectious agents) appear important but remain unidentified. Both cell-mediated and humorally mediated immune mechanisms contribute to pathological injury. Axonal damage occurs in addition to demyelination and may be the cause of later permanent disability. Distinct pathological subtypes may differentiate among patients with MS. Treatment is directed at acute attacks (with corticosteroids) and reduction of attack frequency (primarily with type-1 β interferons and glatiramer acetate). Research into the causes and treatments of MS has expanded our knowledge of this disease and promises improved care for MS patients in the future.

Comprehensive gene expression profiling using DNA microarrays is providing a molecular classification of cancer into disease categories that are homogeneous with respect to pathogenesis and clinical behavior. Gene expression profiling revealed that diffuse large B cell lymphoma (DLBCL) consists of at least two molecularly distinct diseases that are derived from distinct stages of B cell differentiation and have strikingly different clinical outcomes. By contrast, chronic lymphocytic leukemia (CLL) was found to be a single disease defined by a characteristic gene expression signature. Nonetheless, gene expression profiling distinguished two clinically divergent CLL subtypes and provided evidence that signaling through the B cell antigen receptor may play a role in the clinically aggressive subtype. Gene expression analysis also illuminated the mechanism of lymphomagenesis caused by BCL-6 translocations and provided evidence that the NF-κB signaling pathway is a new molecular therapeutic target in DLBCL.

I review evidence that leptin is a liporegulatory hormone that controls lipid homeostasis in nonadipose tissues during periods of overnutrition. When adipocytes store excess calories as triacylglycerol (TG), leptin secretion rises so as to prevent accumulation of lipids in nonadipose tissues, which are not adapted for TG storage. Whenever leptin action is lacking, whether through leptin deficiency or leptin resistance, overnutrition causes disease of nonadipose tissues with generalized steatosis, lipotoxicity, and lipoapoptosis. Examples of such disorders of liporegulation include generalized lipodystrophies, mutations of leptin and leptin receptor genes, and diet-induced obesity. Lipotoxicity of pancreatic β-cells, myocardium, and skeletal muscle leads, respectively, to type 2 diabetes, cardiomyopathy, and insulin resistance. In humans this constellation of abnormalities is referred to as the metabolic syndrome, a major health problem in the United States. When lipids overaccumulate in nonadipose tissues during overnutrition, fatty acids enter deleterious pathways such as ceramide production, which, through increased nitric oxide formation, causes apoptosis of lipid-laden cells, such as β-cells and cardiomyocytes. Lipoapoptosis can be prevented by caloric restriction, by thiazolidinedione treatment, and by administration of nitric oxide blockers. There is now substantial evidence that complications of human obesity may reflect lipotoxicity similar to that described in rodents.

Osteoporosis is a condition of increasing importance and prevalence in all parts of the world and particularly in Asia. Recent advances have led to the introduction of effective drugs that decrease bone resorption and stabilize bone mass. However, these drugs have been identified by serendipity rather than rational drug design and are not ideal because of limited bioavailability, mode of administration, or other unwanted effects. There is still a place for even more suitable and effective resorption inhibitors than those currently available. The more compelling need in this field is an acceptable drug that is anabolic for bone, that safely and acceptably increases bone mass and improves the disturbances in bone microarchitecture that characterize established and advanced osteoporosis. Possible approaches to identifying more effective resorption inhibitors and new anabolic agents are discussed.

Support for prostate cancer screening efforts is provided by observational studies reporting decreases in prostate cancer–specific mortality in areas where screening is performed with digital rectal exam (DRE) and measurement of serum prostate-specific antigen (PSA) levels. The combination of PSA and DRE is an excellent cancer-screening tool with sensitivity and positive predictive value superior to that of mammography and breast exam. Use of percent free PSA further improves the specificity of PSA testing, particularly in the range of 4–10 ng/ml, at which most false positive PSA tests occur. Men older than 50 with a >10-year life expectancy should be considered for prostate cancer screening. Those with an abnormal DRE or a PSA above 4 ng/ml should be referred to a urologist for further discussion of the risks and benefits of a prostate biopsy. Furthermore, those with a significant change in either DRE or PSA results, or those at higher risk for prostate cancer with a PSA level above 2.5 ng/ml, should also be referred for evaluation.