Annual Review of Medicine - Volume 54, 2003

Vascular development involves vasculogenesis, in which endothelial cells form a primary tubular network, as well as angiogenesis, in which vessel size and structure are modified based upon flow and branching occurs to insure that all cells receive adequate O2 delivery. In adults, angiogenesis occurs in response to tissue hypoxia/ischemia and plays an important role in determining the progression of ischemic heart disease and cancer. A critical molecular pathway induced by hypoxia/ischemia is the activation of hypoxia-inducible factor 1, a transcriptional activator of genes encoding vascular endothelial growth factor and other important mediators of angiogenesis. Novel therapeutic approaches that involve stimulating angiogenesis in ischemic tissue and inhibiting angiogenesis in neoplastic tissue are currently being evaluated in clinical trials.

Stem cell transplantation is being used to treat a number of hematologic malignancies as well as hematologic and immune deficiency states. The ages of patients being offered this therapy and the donor marrow sources have been expanded. One persistent problem has been graft-versus-host disease (GVHD). This article reviews the basic biology of GVHD, clinical manifestations of acute and chronic GVHD, prophylaxis and treatment of acute GVHD, and treatment of chronic GVHD.

Palliative medicine includes clinical palliative care, education, and research that focus on the quality of life of patients with advanced disease and their families. The domain of palliative medicine is the relief of suffering: physical, psychological, social, and spiritual. Palliative medicine and care for patients at the end of life and their families include the following key components: compassionate communication; exploration of patient and family values and goals of care; expert attention to relief of suffering; management of pain, depression, delirium, and other symptoms; awareness of the manifestations of grief; and sensitivity to the concerns of bereaved survivors.

Lung cancer results from multiple changes in the genome of susceptible pulmonary cells caused by exposure to carcinogens found in tobacco smoke, the environment, or the workplace. Recent studies suggest that histologically apparent lung cancer is due to the sequential accumulation of specific genetic and morphologic changes to the normal epithelial cells of the lung. Positive signallers, such as those mediated by the oncogene RAS, and negative signallers, such as those mediated by the tumor suppressor retinoblastoma protein (RB), contribute to unchecked cell growth and proliferation. Other key molecular derangements can also be considered hallmarks of cancer, including evasion of apoptosis and senescence, angiogenesis, tissue invasion, and metastases. Epigenetic inactivation of genes via DNA methylation provides another novel way of evading normal cellular control mechanisms. The new knowledge of the human genome coupled with global methods of detecting genetic abnormalities and profiling gene expression in tumor cells may enable us to understand the signaling pathways of lung cancer cells. These are molecular targets for new cancer therapeutics such as receptor tyrosine kinase inhibitors. This information could advance risk assessment, early detection, prognosis, and therapy for lung cancer.

Sickle hemoglobin (HbS), as a result of its polymer-related and oxidant effects, damages the sickle erythrocyte, provokes inflammation, and causes endothelial injury. All these elements cause the phenotype of sickle cell disease. Novel treatments inhibit HbS polymerization by inducing fetal hemoglobin expression, prevent or repair erythrocyte dehydration by slowing cellular potassium and water loss, and replace HbS-producing erythroid progenitors by stem cell transplantation. Future treatment prospects include gene therapy, interruption of the interaction of sickle cells with the endothelium, inhibition of oxidative damage, and protection of an injured endothelium.

Chronic obstructive pulmonary disease (COPD) is a leading cause of death and disability but has only recently been explored from a cellular and molecular perspective. In COPD, chronic inflammation leads to fixed narrowing of small airways and alveolar wall destruction (emphysema). This is characterized by increased numbers of alveolar macrophages, neutrophils, and cytotoxic T lymphocytes, and the release of multiple inflammatory mediators (lipids, chemokines, cytokines, growth factors). There is also a high level of oxidative stress, which may amplify this inflammation. There is increased elastolysis and probable involvement of matrix metalloproteinases. The inflammation and proteolysis in COPD is an amplification of the normal inflammatory response to cigarette smoke. Unlike asthma, this inflammation appears to be resistant to corticosteroids, prompting a search for novel anti-inflammatory therapies that may prevent the relentless progression of the disease.

Calorie restriction (CR) is the most effective and reproducible intervention for increasing lifespan in a variety of animal species, including mammals. CR is also the most potent, broadly acting cancer-prevention regimen in experimental carcinogenesis models. Translation of the knowledge gained from CR research to human chronic disease prevention and the promotion of healthy aging is critical, especially because obesity, which is an important risk factor for several chronic diseases, including many cancers, is alarmingly increasing in the Western world. This review synthesizes the key biological mechanisms underlying many of the beneficial effects of CR, with a particular focus on the insulin-like growth factor–1 pathway. We also describe some of the opportunities now available for investigations, including gene expression profiling studies, the development of pharmacological mimetics of CR, and the integration of CR regimens with targeted, mechanism-based interventions. These approaches will facilitate the translation of CR research into strategies for effective human chronic disease prevention.

Erectile dysfunction (ED) is a highly prevalent and often undertreated condition. It may be a symptom of underlying, chronic illness and can have a negative impact on quality of life, psychosocial health, and relationships. The aging of the population, as well as the introduction of new treatment options, such as sildenafil, has led to increased public awareness of this disorder. New oral therapeutic agents are on the horizon. This article provides an overview of the physiology of erection, the pathophysiology of ED, and modern patient evaluation. Management options, including traditional therapeutic approaches as well as the new generation of oral agents, are also presented.

Clinical and biological features of patients with the idiopathic hypereosinophilic syndrome (HES) are heterogeneous. Recent evidence suggests at least two distinct underlying hematological disorders involving myeloid and lymphoid cells, respectively. We therefore suggest that the term idiopathic should be abandoned in the classification of HES. This review defines the “myeloproliferative” and “lymphocytic” variants of the HES and addresses the management of each variant, focusing on diagnosis and treatment of the newly identified lymphocytic variant.

We propose a set of standards to aid the physician in the care of older patients. These standards are based on the practical experiences of our own group and of others with years of clinical practice in geriatric medicine. The standards also reflect the guidelines, position papers, and deliberations of various organizations concerned with the care of older people. This article does not discuss specific illnesses or the common geriatric syndromes. The proposed standards cover comprehensive care and assessment, especially of vulnerable elders and prevention of disease and disability. We also propose standards for facilitation of care across the health service continuum, care of the nursing home resident, and palliative and hospice care.

Recent advances have made rheumatoid arthritis (RA) amenable to treatment. Clinical studies in patients with early and established RA have broadened understanding of its pathogenesis and have fundamentally changed the therapeutic approach to this disease. Quantum leaps in therapy—including the use of early, aggressive therapy, combination therapy, and the introduction of anti-cytokine agents—have improved patients' quality of life, eased clinical symptoms, retarded the progression of joint destruction, and delayed disability. We review clinical evidence supporting these therapeutic approaches. Diagnostic and therapeutic challenges are highlighted, and a decision tree to guide treatment in patients with early or established RA is provided.

We studied families with multiple members affected with renal cancer to delineate clinically distinct forms of inherited renal cancer, and to identify and characterize the genes responsible for these disorders. Today, cancer geneticists recognize seven clinically distinct, inherited forms of epithelial renal cancer; genes responsible for five inherited predispositions have been found. Positional cloning efforts for one kidney cancer gene are nearing completion. These discoveries will provide diagnostic tests for these diseases, a foundation for studies of the relationship between genotype and phenotype, and a basis for studies of the pathophysiology of the diverse types of epithelial renal cancer.

Sudden death due to ventricular fibrillation (VF) is the leading cause of death in the United States. Early defibrillation is the most important determinant of survival and is the key element in cardiopulmonary resuscitation. Obstacles to rapid defibrillation by trained emergency personnel persist, but the development of the automated external defibrillator (AED) promises to realize the goal of widespread early defibrillation and translate to an improved chance for survival for the cardiac arrest victim. Technological advancements have made the AED safe, easy to use, accurate, and effective in terminating VF. Use of the AED by trained nontraditional first responders (e.g., firefighters, police officers, flight crews) has improved survival rates in a variety of settings and forms the basis for public-access defibrillation.

Space medicine has evolved considerably through past U.S. missions. It has been proven that humans can live and work in space for long durations and that humans are integral to mission success. The space medicine program of the National Aeronautics and Space Administration (NASA) looks toward future long-duration missions. Its goal is to overcome the biomedical challenges associated with maintaining the safety, health, and optimum performance of astronauts and cosmonauts. This program investigates the health effects of adaptation to microgravity: the nature of their pathologies, the effects of microgravity on pathophysiology, and the alterations in pharmacodynamics and treatment. A critical capability in performing research is the monitoring of the health of all astronauts and of the spacecraft environment. These data support the evidence-based approach to space medicine, incorporating past studies of microgravity-related conditions and their terrestrial counterparts. This comprehensive approach will enable safe and effective exploration beyond low Earth orbit.

The availability of chromosomal markers that span the human genome and improved high-throughput technology for genotyping and sequencing have led to major advances against genetic diseases. Genes have been identified for several disorders responsible for arrhythmias and sudden death. These genes all encode ion channels and are referred to as channelopathy genes. Congenital long QT syndrome is caused by mutations in genes encoding sodium or potassium channels. Brugada syndrome, only recently described, is due to mutations in a sodium channel and is an important cause of sudden death, particularly in Southeast Asia. Familial polymorphic ventricular tachycardia is due to a defect in the ryanodine receptor. A locus mapped to 10q32 is responsible for familial atrial fibrillation. Treatments based on knowledge of the molecular defect are being implemented for long QT syndrome and will probably provide paradigms for targeted treatment of acquired arrhythmias.

Chronic lower-extremity occlusive disease is most often manifested by mild symptoms of claudication that can be managed conservatively. When conservative therapy fails, endovascular procedures may be effective, particularly if the disease extent is minimal. Surgery may be considered for selected patients with claudication who fail endovascular therapy or are not candidates for it. Patients with more severe symptoms of lower-extremity occlusive disease typically have more extensive disease that is treated best with surgery or with a combination of surgery and endovascular therapy. Occasionally, endovascular procedures are performed on patients with more extensive disease who are poor candidates for traditional open surgery because of severe comorbidity. Further advances in endovascular technology may improve patency after endovascular procedures in these patients.

Immunodeficiency alters the risk of cancer. Specific types of immune dysfunction are associated with different tumor risks, but most tumors are related to oncogenic viruses. In acquired immunodeficiency due to the human immunodeficiency virus (HIV), HIV itself rarely directly causes cancer; rather, it provides the immunologic background against which other viruses can escape immune control and induce tumors. The most common malignancies are Kaposi's sarcoma and non-Hodgkin's lymphoma. This chapter discusses the pathophysiologic background of these tumors, how they have been affected by the use of anti-HIV medications, and their clinical management.

An outbreak of bovine spongiform encephalopathy (BSE) arose in the United Kingdom as a result of prions entering and being recycled through the ruminant food chain. Humans have since developed a variant form of Creutzfeldt-Jakob disease (vCJD), also mostly in the United Kingdom, that occurs in younger individuals and causes prominent psychiatric and/or behavioral manifestations early in disease. Laboratory studies now provide strong evidence that the causative agent of BSE in cattle and vCJD in humans share a common origin. Because of a lack of information regarding the incubation period of vCJD and the number of people who may have been exposed, the future scope of this disease remains unknown. Control of the current and any future outbreaks in cattle requires strict measures to prevent contamination of the animal food chain with prions of any species. Prevention of human exposure mandates the avoidance of neural tissue in all human foods.

Observational studies provide overwhelming evidence that a low high-density lipoprotein (HDL)–cholesterol level increases the risk of coronary events, both in healthy subjects and in patients with coronary heart disease. Based on in vitro experiments, several mechanistic explanations for the atheroprotective function of HDL have been suggested. However, few of these were verified in vivo in humans or in experiments with transgenic animals. The HDL functions currently most widely held to account for the antiatherogenic effect include participation in reverse cholesterol transport, protection against endothelial dysfunction, and inhibition of oxidative stress. This review summarizes current views on the molecular mechanism underlying these atheroprotective effects of HDL.