Recent research on human macrophage activation has reemphasized the critical role of the lymphokine-secreting T cell in converting quiescent macrophages to efficient microbicidal phagocytes. Interferon-gamma, a key lymphokine secreted by antigen-triggered T4+ helper cells, is capable of inducing the macrophage to act against a diverse group of microbial targets, in particular, intracellular pathogens. In animal models, treatment with recombinant interferon-gamma is beneficial in systemic intracellular infections, and inhibition of endogenous interferon-gamma activity impairs host resistance. Trials in patients with cancer, leprosy, and the acquired immunodeficiency syndrome (AIDS) have shown that interferon-gamma can activate the mononuclear phagocyte in humans. This research and the identification of patients whose T cells fail to produce interferon-gamma properly has set the stage for evaluating the role of macrophage-activating immunotherapy using interferon-gamma in various human infectious diseases.

A substantial proportion of vaccine-preventable diseases occur among adults. Each year, there are more than 20,000 influenza-associated deaths during epidemics, approximately 40,000 deaths related to pneumococcal disease, and one to five cases of diphtheria. More than 300,000 hepatitis B infections occur annually, mostly in patients 15 to 29 years old. From 1982 to 1986, 96% of patients with tetanus were age 20 and older. Among young adults, 5% to 20% are susceptible to rubella and measles, and outbreaks occur where these persons congregate. Most adults are not immunized, despite recommendations for vaccines against these diseases. Vigorous efforts are needed to implement strategies to reduce disease incidence, morbidity, and death among adults.

Life-threatening opportunistic cytomegalovirus infection is a complication of the acquired immunodeficiency syndrome (AIDS) that occurs in 7.4% or more of patients with AIDS. Cytomegalovirus retinitis, colitis, esophagitis, and gastritis are the commonest manifestations of severe cytomegalovirus end-organ disease. Extensive trials with intravenous ganciclovir, a nucleoside analogue with myelosuppressive toxicity, have shown that ganciclovir halts the progression of cytomegalovirus retinitis and gastrointestinal disease. Since relapse is common when therapy is discontinued, most patients with AIDS need life-long maintenance therapy. The clinical response to ganciclovir therapy is usually accompanied by diminished shedding of the virus. Based on limited data, foscarnet, a pyrophosphate analogue, also appears to have some efficacy in treating cytomegalovirus infection. Unlike ganciclovir, foscarnet does not cause myelosuppression. An important direction for future clinical research is the development of more effective and less toxic therapy, as well as orally bioavailable drugs for maintenance therapy.

Pulmonary hypertension may develop whenever chronic obstruction of pulmonary arterial blood flow occurs. Although repeated pulmonary embolism is thought to be the usual underlying cause, there is little clinical evidence to support this theory. Studies of the pulmonary vascular endothelium have shown that perturbations of the normal endothelium can create a procoagulant environment, which could lead to the development of thrombosis in situ at the level of the large or smaller pulmonary vessels. Some patients develop proximal pulmonary thromboemboli, which may be the result of retrograde propagation of thrombus after an initial pulmonary embolus. Others present with unexplained pulmonary hypertension secondary to thrombotic occlusion of the pulmonary microvasculature. A perfusion lung scan will show abnormalities that should lead to correct clinical diagnosis and confirmatory evaluation. Thromboendarterectomy in selected cases provides dramatic clinical improvement in patients with proximal thromboemboli. Vasodilators may be effective in some patients with obstruction at the arteriolar level. Both groups should be treated with chronic warfarin anticoagulant therapy to protect against progression of thromboembolism.

Evaluation of demonstrated clinical efficacy of magnetic resonance (MR) imaging in the central nervous system.

Hepatocellular carcinoma is the most frequent cancer worldwide, responsible for approximately 1,000,000 deaths annually, most of them in the Far East and in sub-Saharan Africa. It usually presents at an advanced stage and has a poor prognosis. There is evidence of an etiologic role for hepatitis B virus infection in the etiology of hepatocellular carcinoma. Carriers of the virus are 94 times more at risk for hepatocellular carcinoma than noncarriers. In many cases hepatitis B virus DNA is integrated within the cellular genome of the tumor. Programs have been established to detect hepatocellular carcinoma at an early stage; persons at high risk are regularly screened by measurement of serum alpha-fetoprotein levels and ultrasound examination of the liver. Surgical resection offers the only hope of cure at present, as chemotherapy, radiotherapy, and immunotherapy have not shown promise. Ideally, surgery should be done on small asymptomatic tumors.

Norfloxacin is an oral fluoroquinolone antimicrobial agent recently released for the treatment of uncomplicated and complicated urinary tract infections. The drug antagonizes DNA gyrase, an enzyme essential for bacterial DNA replication. Norfloxacin is more potent and broader in spectrum than the earlier developed analogue, nalidixic acid, and is active in vitro against virtually all bacterial pathogens causing urinary tract and gastrointestinal infections, aerobic gram-negative bacilli causing sepsis in neutropenic patients, and Neisseria gonorrhoeae. The drug is administered orally twice daily and achieves high concentrations in urine, stool, renal tissue, and bile. Norfloxacin was at least as effective as currently used agents in treating urinary tract infections, and, in limited studies, bacterial gastroenteritis, gonorrhea, bacterial prostatitis, and prevention of gram-negative bacillary infection in neutropenic patients. Adverse drug effects were mild and included disturbances of the gastrointestinal tract and the central nervous system. Norfloxacin shows promise as an antibacterial agent for genitourinary and gastrointestinal infections.

During the last 10 years, there have been major advances in the understanding of varicella-zoster virus and the diseases it causes. The molecular biology of the virus is being unraveled with the aid of new molecular technologies. Varicella, usually a benign manifestation of primary infection, and zoster, a result of reactivation of latent virus, can cause considerable morbidity in patients with immune impairment. Antiviral drugs, especially acyclovir, ameliorate severe infections but still have little role in the treatment of most normal patients with varicella or zoster. Varicella can be prevented when necessary by patient isolation and passive prophylaxis with varicella-zoster immune globulin. An experimental live vaccine also prevents varicella, but problems regarding its virulence for immunosuppressed patients and the durability of the protective response are still being addressed.

Focal hepatosplenic candidiasis has been recognized with increasing frequency in recent years. We reviewed the cases of eight patients seen between 1982 and 1985, and information on 60 patients whose cases have been reported in the world literature. The characteristics of focal hepatosplenic candidiasis include persistent fever in a neutropenic patient whose leukocyte count is returning to normal, often coupled with abdominal pain; an elevated alkaline phosphatase level; and less commonly, rebound leukocytosis. The characteristic "bull's eye" lesions seen with hepatic ultrasound examination or computed tomography generally are not detectable until neutrophil recovery has occurred. Diagnosis can be established only by biopsy evidence of yeasts or pseudohyphae in the granulomatous lesions. Cultures are frequently negative, however, especially in patients who have been pretreated with antifungal agents. We review the evolving nature of hepatosplenic candidiasis, focusing on diagnosis and treatment.

In an attempt to overcome limitations inherent in conventional computer-aided diagnosis, investigators have created programs that simulate expert human reasoning. Hopes that such a strategy would lead to clinically useful programs have not been fulfilled, but many of the problems impeding creation of effective artificial intelligence programs have been solved. Strategies have been developed to limit the number of hypotheses that a program must consider and to incorporate pathophysiologic reasoning. The latter innovation permits a program to analyze cases in which one disorder influences the presentation of another. Prototypes embodying such reasoning can explain their conclusions in medical terms that can be reviewed by the user. Despite these advances, further major research and developmental efforts will be necessary before expert performance by the computer becomes a reality.

Campylobacter pylori has recently been isolated from gastric mucosal biopsy specimens. Campylobacter pylori has many attributes in common with other campylobacters but it may represent a new genus. It produces abundant quantities of urease, and this property has been used to develop a rapid diagnostic test. The organism is found predominantly beneath the gastric mucus layer that lines the surface epithelium of the stomach. Infection with C. pylori causes an acute histologic gastritis which may become chronic. The bacterium is the etiologic agent in type-B gastritis. Prevalence of the organism in asymptomatic persons appears to be age related. Campylobacter pylori is found commonly in patients with peptic ulcer disease, always in association with chronic gastritis. Eradication of the organism is associated with healing of the gastritis and a lower relapse rate in duodenal ulcer disease. A role for the organism in other upper gastrointestinal diseases is unproven.

The proposed role of maintenance of calcium homeostasis in the prevention and nonpharmacologic treatment of hypertension has prompted controversial interpretations of the data on which the proposal is based. To provide a more current perspective, we summarize the epidemiologic data, results of clinical studies of calcium metabolism in humans with hypertension, effects of controlled interventions of calcium supplementation in humans, and findings from laboratory studies intended to elucidate possible mechanisms. Data from the epidemiologic and clinical trials support a protective role for calcium in regulating arterial pressure. A potentially important relationship between the "calcium hypothesis" and "salt-sensitivity" may provide further insights into the mechanisms involved. Results of experiments in vascular physiology indicate that dietary calcium's effect in lowering blood pressure is mediated in part through direct action on the vasculature.

In the 5 years since its release for clinical use, acyclovir (9-[2-hydroxyethoxymethyl]guanine) has proved to be a safe and effective agent for therapy of herpes simplex and varicella-zoster infections. The drug's availability in topical, oral, and intravenous preparations has allowed its use in a range of clinical situations. Acyclovir must be phosphorylated by viral thymidine kinase in infected cells, where it then acts to inhibit viral DNA replication specifically. Epstein-Barr virus and human cytomegalovirus infections do not seem to respond to acyclovir therapy, although in-vitro effects on these viruses may be seen. Acyclovir is well absorbed and distributed, with cerebrospinal fluid levels 50% that of plasma. Clearance is almost entirely by the renal route, with a half-life of 20 hours in the anuric patient. Acyclovir has an excellent safety profile, its major adverse effect being transient serum creatinine elevations during high-dose intravenous use. Major uses include treatment of primary and recurrent genital herpes and herpes encephalitis and prophyllaxis and therapy of mucocutaneous herpes and varicella-zoster infections in immunocompromised patients. Resistance to acyclovir in herpes simplex virus is rarely encountered and does not seem to be due to long-term chronic suppressive therapy.

Traditional approaches to prophylaxis of atherosclerosis have focused on one aspect of the pathogenesis of this multifactorial disease, such as platelet function or blood lipids, and therefore have had limited success. Epidemiologic studies show a striking inverse correlation of consumption of fish rich in the two omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, and mortality from cardiovascular disease. In studies of volunteers and patients, reductions in platelet responsiveness, lowering of blood lipids, and improvements of blood flow, as well as improvements in other values implicated in the pathogenesis of atherosclerosis, were induced with eicosapentaenoic and docosahexaenoic acids. These findings indicate that these omega-3 fatty acids have a larger prophylactic potential than traditional approaches. This potential must be scrutinized in meticulously designed and conducted trials with clinical endpoints.