Annual Review of Medicine - Volume 50, 1999

Postural hypotension may result from various neurogenic and non-neurogenic causes. It may be a key feature of certain disorders, such as the primary chronic autonomic failure syndromes; it can complicate a variety of diseases, such as diabetes mellitus; and its prevalence increases with advancing age. When symptomatic, it may result in loss of consciousness and thus cause injury. Postural hypotension can be suspected from the patient's history and is readily documented in the clinic by measuring lying and standing blood pressure. The diagnosis ideally should be confirmed in the laboratory with additional tests to determine the cause and evaluate the functional deficit, so as to aid treatment. Treatment of the causative disorder is often curative when there are non-neurogenic causes. A combination of nonpharmacological and pharmacological measures is needed in the management of neurogenic postural hypotension.

Red cell substitutes are solutions that can potentially be used in emergencies or during surgery when rapid expansion of the blood volume with an oxygen carrier is needed. The three main types of products in development are based on cell-free hemoglobin, perfluorocarbon emulsions, or liposome-encapsulated hemoglobin. None is currently approved for clinical use, but several are in advanced clinical trials. Outside the red blood cell, hemoglobin is subject to degradation and heme loss. It readily diffuses in the plasma space and effectively scavenges nitric oxide. These properties must be understood and controlled if hemoglobin-based products are to fulfill their promise. The development of red cell substitutes affords us a deeper insight into how oxygen is delivered to tissues in the microcirculation and how blood-flow distribution is regulated within and between organs. As red cell substitutes become available to clinicians and scientists, clinical applications are expected to expand.

Escherichia coli O157:H7 is an increasingly common cause of a variety of illnesses, including bloody diarrhea and the hemolytic uremic syndrome. This emerging infectious agent was first identified in 1982 and has been isolated with increasing frequency since then. This chapter reviews the epidemiology, clinical spectrum, diagnosis, treatment, and prevention of infections with E. coli O157:H7.

Until recently, the only cure for relapse after allogeneic bone marrow transplantation (BMT) has been a second BMT. Recently, infusions of leukocytes collected from the original transplant donor have been used to induce a direct graft-versus-leukemia (GVL) reaction in patients with relapsed disease. Adoptive immunotherapy with donor leukocyte infusions (DLI) results in complete remission for 60–80% of patients with relapsed chronic-phase CML; therapy is also effective for relapse of diseases other than CML, although response rates are lower. Adoptive immunotherapy induces remissions for the majority of patients with post-transplantation Epstein-Barr virus-related lymphomas and other viral-associated illnesses. The extraordinary success of DLI demonstrates that it is now possible to harness the GVL potential of the human immune system for clinical benefit. The necessary effector cells and target antigens required for GVL reactivity are poorly defined but are the subject of intensive investigation. Future trials will investigate strategies that retain and enhance the GVL effects while limiting toxicity from this therapy, and they may define methods of successful allogeneic adoptive immunotherapy outside the setting of allogeneic BMT.

Sleep disorders are very prevalent in the general population and are associated with significant medical, psychological, and social disturbances. Insomnia is the most common. When chronic, it usually reflects psychological/behavioral disturbances. Most insomniacs can be evaluated in an office setting, and a multidimensional approach is recommended, including sleep hygiene measures, psychotherapy, and medication. The parasomnias, including sleepwalking, night terrors, and nightmares, have benign implications in childhood but often reflect psychopathology or significant stress in adolescents and adults and organicity in the elderly. Excessive daytime sleepiness is typically the most frequent complaint and often reflects organic dysfunction. Narcolepsy and idiopathic hypersomnia are chronic brain disorders with an onset at a young age, whereas sleep apnea is more common in middle age and is associated with obesity and cardiovascular problems. Therapeutic naps, medications, and supportive therapy are recommended for narcolepsy and hypersomnia; continuous positive airway pressure, weight loss, surgery, and oral devices are the common treatments for sleep apnea.

Progression through the cell cycle is governed by cyclin-dependent kinases (cdks), whose activity is inhibited by the cdk inhibitors. Cyclins, cdks, and cdk inhibitors are frequently deregulated in cancers. This chapter reviews the prognostic significance of alterations in cdk inhibitors. Loss of p27 protein provides independent prognostic information in breast, prostate, colon, and gastric carcinomas, and immunohistochemical (IHC) staining for p27 may eventually become part of routine histopathologic processing of cancers. Loss of IHC staining for p21 may be prognostic in certain cancers but conflicting results are reported in breast cancer. Reports on homozygous deletion of p16 and p15 genes suggest the value of larger, prospective studies with standardized treatment protocols to definitively establish the prognostic utility of p15/p16 deletions in acute leukemias. Larger trials and the development of a consensus on methods for deletion analysis, IHC staining, and tumor scoring will be needed to move these molecular assays from bench to bedside.

Chemokines constitute a large family of chemotactic cytokines that act at G protein-coupled receptors to regulate diverse biological processes, including leukocyte trafficking, angiogenesis, hematopoiesis, and organogenesis. They are believed to be both beneficial in host defense against infectious agents and harmful in diseases marked by pathologic inflammation; however, actual clinical roles in these areas have not yet been established. Recently, unexpected ways have been discovered in which medically important pathogens, including HIV-1, exploit or subvert the chemokine system. These and other recent results suggest that targeting specific chemokines and chemokine receptors may have therapeutic utility in both inflammation and infectious disease.

Advances in the diagnosis and early management of congenital heart disease in recent decades have led to increasing numbers of individuals being sufficiently well to participate in social as well as truly competitive sports. Physicians are increasingly asked whether such participation is safe, advisable, and efficacious, yet few guidelines exist to help them make these decisions. There are three apparent subgroups of patients: (a) those with mild or repaired problems, who function normally or nearly so and may fully participate; (b) those with severe functional deficit or known high risk, for whom strenuous exertion must be strictly proscribed; and (c) those who fall in between, with some limitations and some risk—these patients present a great challenge to the wisdom and clinical skill of the physician.

This chapter focuses on recent developments in our understanding of the etiology, epidemiology, and treatment of recurrent mood disorders. It addresses the changing relationship between endogenous and exogenous factors over time in the etiology of mood episodes. In the area of epidemiology, the chapter presents new information on the prevalence of various subtypes and male/female differences in lifetime risk. Complications of the mood disorders, such as suicide, and important comorbidities, including alcoholism and substance abuse, are discussed. In the area of treatment, the life-long nature of many of the mood disorders is described, as is the consequent role of the primary care physician in their management. The evidence for the efficacy of the depression-specific psychotherapies, cognitive therapy and interpersonal therapy, is reviewed. Current issues in the pharmacotherapy of mood disorders are discussed, including the relative efficacy of the older antidepressants versus the newer selective serotonin reuptake inhibitors (SSRIs) and the treatment of various subtypes of mood disorders, including dysthymia, chronic depression, and atypical depression. Finally, the chapter describes recent advances in the treatment of bipolar disorder.

This chapter reviews the biology of gastroesophageal reflux disease, relating pathophysiology to medical and surgical therapy. Various definitions of the disease are presented and workable criteria are developed to identify patients with the disease. The central importance of the lower esophageal high-pressure zone as a barrier to reflux is emphasized, along with an analysis of its biomechanical alteration in disease. The composition of the refluxed gastric juice is characterized in regard to its potential for mucosal injury. Evidence is provided that cardiac-type mucosa is an acquired sequel to acid-induced squamous mucosal injury in the terminal esophagus. A hypothesis regarding the process of intestinalization of cardiac-type mucosa to form Barrett's esophagus is presented. An integrated concept of the pathophysiology of gastroesophageal reflux disease is constructed. Practical concepts regarding the treatment of gastroesophageal reflux disease are developed, based on a review of studies on the natural history of the disease and the long-term outcome of therapy.

Human tumors express a number of protein antigens that can be recognized by T cells, thus providing potential targets for cancer immunotherapy. Dendritic cells (DCs) are rare leukocytes that are uniquely potent in their ability to present antigens to T cells, and this property has prompted their recent application to therapeutic cancer vaccines. Isolated DCs loaded with tumor antigen ex vivo and administered as a cellular vaccine have been found to induce protective and therapeutic anti-tumor immunity in experimental animals. In pilot clinical trials of DC vaccination for patients with non-Hodgkin's lymphoma and melanoma, induction of anti-tumor immune responses and tumor regressions have been observed. Additional trials of DC vaccination for a variety of human cancers are under way, and methods for targeting tumor antigens to DCs in vivo are also being explored. Exploitation of the antigen-presenting properties of DCs thus offers promise for the development of effective cancer immunotherapies.

Hantaviruses chronically infect rodents without apparent disease, but when they are spread by aerosolized excreta to humans, two major clinical syndromes result: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Both diseases appear to be immunopathologic, and inflammatory mediators are important in causing the clinical manifestations. In HPS, T cells act on heavily infected pulmonary endothelium, and it is suspected that gamma interferon and tumor necrosis factor are major agents of a reversible increase in vascular permeability that leads to severe, noncardiogenic pulmonary edema. HFRS has prominent systemic manifestations. The retroperitoneum is a major site of vascular leak and the kidneys suffer tubular necrosis. Both syndromes are accompanied by myocardial depression and hypotension or shock. HFRS is primarily a Eurasian disease, whereas HPS appears to be confined to the Americas; these geographic distinctions correlate with the phylogenies of the rodent hosts and the viruses that coevolved with them.