To define the mechanisms underlying left ventricular diastolic dysfunction in patients with congestive heart failure and normal systolic function and to identify the patients at risk for this syndrome.

Zidovudine, a nucleoside analog, was the first agent proved to be effective in the management of human immunodeficiency virus type 1 (HIV-1) infection. After demonstration of zidovudine's in-vitro activity against HIV-1 in 1985, the drug was rapidly evaluated in phase I and phase II clinical trials and was found to be effective in decreasing both mortality and the incidence of opportunistic infections in patients with the acquired immunodeficiency syndrome (AIDS) and advanced AIDS-related complex; the drug was also found to have a substantial but tolerable toxicity profile. Since the licensure of zidovudine in 1987, an intensive clinical research effort has established the drug's efficacy in the prevention of disease progression in asymptomatic and mildly symptomatic HIV-infected persons and has established the success of lower-dose therapy in patients at all stages of disease. The current recommendation is to use zidovudine at a dose of 500 to 600 mg/d in both symptomatic and asymptomatic persons with CD4 counts of less than 500/mm3. The major toxicities of anemia and neutropenia are less frequent at the lower doses presently used and can be managed by dose reduction or by use of hematopoietic growth factors. The inexorable disease progression seen despite zidovudine therapy and the isolation of clinical strains of HIV-1 resistant to zidovudine in vitro highlight the limitations of prolonged monotherapy with this agent. Although alternative dideoxynucleoside agents (for example, didanosine [dideoxyinosine and zalcitabine dideoxycytidine]) are available for the management of HIV-infected persons, zidovudine remains the cornerstone of antiretroviral therapy. Current research efforts are directed at elucidating the clinical relevance of zidovudine resistance and studying regimens in which zidovudine is used in combination with other agents. This latter approach holds great promise for improving efficacy, limiting toxicity, and perhaps preventing the emergence of viral resistance. For the forseeable future, zidovudine will continue to play a role in the development and in our understanding of antiretroviral therapy.

Pulmonary complications, both infectious and noninfectious, are an important cause of morbidity in patients with various types of immunosuppression. The appropriate response to these clinical problems requires an understanding of pulmonary host defense and of the various types of systemic immunosuppression. Infectious and noninfectious pulmonary complications may vary according to the type of immunosuppression as well as to the degree and duration of immunosuppression. Appropriate clinical management also requires an understanding of the clinical problems commonly seen in specific groups of immunosuppressed patients and an understanding of the sensitivity, specificity, and potential complications associated with the available diagnostic approaches to those patients. Because respiratory disease in these patient groups may progress rapidly to respiratory failure, an expeditious evaluation based on the knowledge of likely causes of respiratory disease and prompt specific or empiric therapy are indicated. Specific sets of algorithms for the evaluation of both focal and diffuse pulmonary disease may facilitate such an evaluation. In addition, an aggressive approach to the prevention of pulmonary disease including immunization, prophylaxis, and immunomodulation (for example, colony stimulating factors) may be warranted in specific subgroups at risk.

The concept of autocrine secretion, its subsequent modifications, its application for understanding pathogenesis of disease, and its potential for developing new approaches to prevention and treatment are reviewed. Peptide growth factors (cytokines) act as local autocrine and paracrine mediators of tissue homeostasis. Many diseases, including cancer, atherosclerosis, rheumatoid arthritis, and other fibrotic diseases characterized by chronic inflammation, are associated with aberrant expression and cellular coordination of the homeostatic action of these regulatory molecules. Modern biotechnology and pharmacology offer unique opportunities for the therapeutic prevention and treatment of these molecular and cellular lesions, using either cytokines or other agents that modify their synthesis and activity.

To characterize the epidemiology, clinical manifestations, and immunologic risk factors for infections with Streptococcus pneumoniae among persons infected with human immunodeficiency virus (HIV); and to delineate a practical approach for diagnosis, treatment, and prevention of these infections.

To review available information on cough and angioneurotic edema associated with angiotensin-converting enzyme (ACE) inhibitors.

To review the status of surgical and medical therapy for diabetic retinopathy from the perspective of the non-ophthalmologist.

To review methods of preventing or minimizing the adverse effects associated with the transfusion of passenger leukocytes present in cellular blood components and to define groups of patients who are at risk for adverse effects.

To review data on the type, mechanism, and prevalence of the proarrhythmic effect of drugs used to treat atrial fibrillation or flutter.

Immediately after the liberation of Kuwait by a coalition of allied forces in March 1991, representatives of Physicians for Human Rights traveled to Kuwait and conducted an inquiry into human rights violations allegedly perpetrated by Iraqi forces. The inquiry focused on the abuses that were said to have occurred in health care institutions. Human rights abuses by the Iraqis in Kuwaiti hospitals were documented, but certain allegations proved to be unfounded. However, Kuwaiti abuses of those accused of collaborating with the Iraqi invaders, in particular Palestinian citizens of Kuwait, were also observed. The trip and inquiry generated questions about the scope and applicability of medical ethical principles to physicians in different cultures and in situations unlike those in which medicine is normally practiced. In light of the Kuwait experience, Physicians for Human Rights has drawn tentative conclusions about the universal nature of medical ethics.

To assess the effectiveness of beta-blockers and endoscopic sclerotherapy in the prevention of first bleeding and reduction of mortality in patients with cirrhosis and esophagogastric varices.

Because atrial fibrillation is associated with substantial morbidity, restoration of sinus rhythm is desirable. Long-term maintenance of sinus rhythm often requires chronic antiarrhythmic therapy. Class I antiarrhythmic drugs such as quinidine or propafenone maintain sinus rhythm in approximately 50% of patients at 1 year and have risks for proarrhythmia and noncardiac toxicity. Studies of low-dose amiodarone for atrial fibrillation have reported sinus rhythm maintenance in 53% to 79% of patients during a mean follow-up of 27 months. Amiodarone has a lower incidence of proarrhythmia and heart failure exacerbation compared with class I drugs. Most noncardiac side effects are dose related, and low-dose amiodarone (less than 300 mg/d) is well tolerated. The time has come for a large-scale prospective evaluation of low-dose amiodarone treatment early in the course of atrial fibrillation.

The irritable bowel syndrome is a common chronic disorder having a broad clinical spectrum of severity. Although only a small proportion of those afflicted seek medical help for their symptoms, a subset have severe and intractable symptoms. A positive diagnosis should be established from the history and physical examination; endoscopic and radiologic investigations should be minimized. We suggest that the physician also assess the severity of the illness based on its symptomatic and functional features and the patient's behavioral response. Classifying the disorder in this manner permits a graduated treatment approach that emphasizes education, reassurance, and dietary adjustment for mild symptoms. Moderate symptom severity requires, in addition, identification and modification of factors exacerbating symptoms, psychotherapeutic and behavioral techniques and, if a certain symptom type predominates, pharmacologic agents directed toward the presumed gastrointestinal motor dysfunction. For severe symptoms, physician-based behavior modification and psychopharmacologic agents are helpful. When the disorder is intractable, referral may be needed, for example, to a pain treatment center. In all cases, the skillful physician must ensure continued psychosocial support to enhance coping and continued focus on the palliative aspects of care rather than on cure.

To develop a practical strategy that facilitates the management of patients with the irritable bowel syndrome (IBS).

One quarter to one third of Americans are overweight; as many as 40% of women and 24% of men are trying to lose weight at any given time; many have tried a variety of methods, such as diets, exercise, behavior modification, and drugs. In controlled settings, participants who remain in weight loss programs usually lose approximately 10% of their weight. However, one third to two thirds of the weight is regained within 1 year, and almost all is regained within 5 years. For many overweight persons, achieving and maintaining a healthy weight is a lifelong challenge. Successful weight loss improves several cardiovascular risk factors and diabetic control; effects on mortality are not clear. Several epidemiologic studies have found that weight loss is associated with increased mortality but the reasons for weight loss were not known. Survey data also confirm that many Americans who are not overweight, particularly young women, are trying to lose weight, which may have adverse physical and psychological consequences. Because of the importance of these issues, research on weight and on weight loss and control should assume a high priority on the nation's health agenda.

Recent observations strongly suggest a significant role for genetic factors in innate resistance to infection by Mycobacterium tuberculosis. This relation was discovered in a study of tuberculosis in Arkansas nursing homes and was supported by data from three outbreaks of tuberculosis in two prisons. A person's resistance level was found to correlate with the region of his or her ancestry. Ancestors of person's in the more resistant group tended to derive from densely populated areas and cities rife with tuberculosis, whereas the ancestors of person's in the more susceptible group tended to derive from areas once free of tuberculosis. In accordance with current genetic theory, those persons who are less resistant to tuberculosis would be expected to be more resistant to infections endemic to the region once inhabited by their ancestors. Isolation of the gene previously shown to confer specific innate (nonimmune) resistance to tuberculosis should result in the creation of a more rational approach to increasing the capacity of human macrophages to kill tubercle bacilli without producing a positive tuberculin skin test.

Noninvasive stress testing is generally recommended to detect patients who are at increased risk for cardiac death and myocardial infarction. Such tests depend on the presence of a physiologically significant coronary stenosis to detect disease. The low prevalence of events in patients who are able to exercise, however, results in a poor positive predictive value. Also, recent data suggest that a significant number of morbid events result from rapid progression of disease in segments of the coronary artery that initially had only minimal obstruction. Further, from a therapeutic standpoint, only catheterization has been shown in randomized trials to predict which patients are candidates for bypass surgery. Thus, noninvasive testing as an intermediate step to select those patients who require invasive study remains an attractive but unproven hypothesis.

Rising health care expenditures have led to numerous cost-control proposals. An examination of the ethical questions surrounding the role that physicians play in the control of health care costs suggests that unilateral rationing decisions by individual physicians at the bedside are morally unacceptable. Such decisions are arbitrary, ineffective in redistributing health care resources, and formally unjust. Restrictive gatekeeping (the creation of financial incentives for physicians to limit care given to individual patients) also seems unacceptable because of its morally significant effects. First, it disguises the role of those actually responsible for cost-control decisions; second, it routinely creates a "moral stress test" by forcing physicians to act in ways that are contrary to their own interests in order to serve the needs of patients; third, it undermines the trust between doctor and patient; and fourth, it rations by class of persons rather than class of technology. In contrast, a morally sound system would attempt to control costs by honestly informing patients and assigning responsibility justly, would encourage physicians to act in the interests of patients, would foster trust, and would recognize the great importance of equal treatment for all patients. Such a system would depend on input from an informed public and would apply equally to all members of society.

The insulin-like growth factor (IGF) family of peptides, binding proteins, and receptors are ubiquitous and important for normal human growth and development. Modern techniques including specific radioimmunoassays, radioreceptor assays and recombinant DNA technology have improved our understanding of the role of IGFs in growth and development. In addition to enhancing our understanding of normal physiology, these techniques assess changes in these hormones, binding proteins, and receptors in pathologic conditions including growth retardation, acromegaly, malnutrition, diabetes, and malignancy. Further, these studies have led to improvement in the assessment of responses to certain therapies used in the treatment of these diseases and may lead to improvements in these therapies.