The ability to localize the sites of origin of arrhythmias or those sites critical to their maintenance or their life-threatening consequences has provided the potential for ablating these arrhythmias by delivering shocks through catheters at these critical sites. The capability of treating various arrhythmias by the delivery of shocks through catheters placed at specific intracardiac sites is being studied. These techniques are being evaluated for the creation of atrioventricular blocks to control the ventricular response during supraventricular arrhythmias and for the ablation of bypass tracts and foci of ventricular tachycardia. Complications, including cardiac rupture, and variable success rates make it imperative that such studies only be done by well-trained electrophysiologists. As current techniques evolve, catheter ablation may prove to be a reasonable alternative to pharmacologic or surgical management of patients with disabling arrhythmias.

When vomiting is not related to preventing the entry of physically or chemically unsuitable substances into the absorbing gut, it may be regarded as pathologic. The commonest causes of chronic vomiting are structural lesions affecting the mucosa of the upper gastrointestinal tract (often with luminal obstruction) and psychogenic disorders. Diseases affecting extrinsic and intrinsic neural control of gut motility and visceral smooth muscle may also cause unexplained vomiting. A stratified management approach to patients with vomiting is suggested. The first assessment is aimed at exclusion of mucosal lesions of the upper gut and systemic or psychiatric disease that may affect it. Second is a therapeutic trial, usually with a prokinetic agent. The final phase, reserved for recalcitrant undiagnosed patients, is evaluation at special centers with gastric emptying studies, gastrointestinal manometry, other electrophysiologic studies, and, in a few patients, laparotomy with examination of full-thickness biopsy specimens of the small intestine.

Cellular oncogenes comprise a small family of genes, highly conserved throughout vertebrate evolution, that code for proteins with diverse functions including DNA binding, protein kinase, and cellular growth factor activities. Cellular oncogenes are important in certain aspects of the proliferation and differentiation of normal cells. Under some circumstances these genes may also induce malignant transformation of normal cells. Various mechanisms may underlie their involvement in carcinogenesis. Incorporation of all, or part of, cellular oncogenes into RNA tumor viruses, mutations in gene structure, or translocation of cellular oncogenes from one chromosome to another may all be associated with the induction of malignant change in cells. In some of these situations altered oncogene products are made. Knowledge about the biology of oncogenes may lead to improved techniques for cancer detection and perhaps new approaches to cancer treatment.

Use of digitalis for the treatment of patients with congestive heart failure and sinus rhythm remains controversial. To ascertain the proper therapeutic role of digitalis, we have critically appraised the published clinical evidence of digitalis efficacy using standardized methodologic criteria. A search of the English literature from 1960 to 1982 identified 736 articles, of which 16 specifically addressed the clinical evaluation of digitalis therapy for patients with congestive heart failure and sinus rhythm. Only two double-blind, placebo-controlled trials provided clinically useful information. One study showed that digoxin therapy could be withdrawn successfully in elderly patients with stable congestive heart failure. The other showed that patients with chronic heart failure and an S3 gallop benefited from digoxin therapy.

Commonly used antibacterial agents may be associated with various neurotoxic reactions. Central nervous system toxicities include seizure disorders, encephalopathy, bulging fontanelles, and neuropsychiatric symptoms. These abnormalities have been associated with the use of the penicillins, cephalosporins, sulfonamides, tetracyclines, chloramphenicol, colistin, aminoglycosides, metronidazole, isoniazid, rifampin, ethionamide, cycloserine, and dapsone. Cranial nerve toxicities, such as myopia, optic neuritis, deafness, vertigo, and tinnitus, have been associated with the use of erythromycin, sulfonamides, tetracyclines, chloramphenicol, colistin, aminoglycosides, vancomycin, isoniazid, and ethambutol. Peripheral nerve symptoms consisting of paresthesias, motor weakness, or sensory impairment have been associated with the use of the penicillins, sulfonamides, chloramphenicol, colistin, metronidazole, isoniazid, ethionamide, and dapsone. Neuromuscular blockade has been associated with the use of the tetracyclines, polymyxins, lincomycin, clindamycin, and aminoglycosides. Management generally consists of supportive therapy and immediate discontinuation of therapy with the offending drug.

Tissues of the eye affected by diabetes are the lens, cornea, and retina. The lens becomes cataractous through osmotic swelling of its cortical fibers. Sorbitol, formed in the presence of aldose reductase, accumulates in the lens during hyperglycemia. Dulcitol similarly accumulates in the presence of galactosemia. Cataractogenesis in both cases can be prevented by inhibitors of aldose reductase. The efficacy of synthetic inhibitors differs in various tissues and species, but they react with aldose reductase at a common structural site. The most promising inhibitor is sorbinil . Diabetic retinopathy is similarly related to sorbitol accumulation and may be prevented or reversed by inhibition of aldose reductase. Healing of corneal wounds in diabetes is facilitated by enzyme inhibition. Retinal vasculopathy of diabetes is due to selective loss of the intramural pericytes that normally form structural elements in the retinal capillary walls. The vulnerability of these cells is due to their aldose reductase content. Whether inhibition of aldose reductase will prevent retinopathy is being tested in a randomized trial conducted by the National Eye Institute.

Advances have recently been made in understanding the pharmacokinetics of theophylline. To correlate the new knowledge of theophylline pharmacokinetics with the drug's current status in therapy, we have critically reviewed the relevant investigations of the last 5 years. We consider data on its presumed mechanisms of action, factors affecting its clearance, its use in pregnancy, treatment of overdoses, and important drug interactions. Theophylline clearance is decreased by concomitant use of erythromycin, cimetidine, high-dose allopurinol, oral contraceptives, and caffeine. Clearance is increased by concomitant use of phenobarbital and phenytoin. Newly discovered actions of theophylline include dose-dependent improvement of diaphragmatic contractility, augmentation of ventilatory response to hypoxia, and sleep disturbances (especially with high-dose treatments). Points clinically relevant to the daily use of theophylline derivatives and the importance of sustained-release preparations are discussed. Theophylline continues to play a major role in therapy for reactive airways disease.

Ergoloid mesylates has been used for 30 years to treat patients with senile dementia. Indications for this drug include hypertension, peripheral vascular disease, and senile dementia of the Alzheimer type. Formerly classified as a cerebral vasodilator, ergoloid mesylates is now considered a metabolic enhancer, but how this action pertains to treatment of senile dementia is uncertain. Prescribed doses of the drug range from 1.5 mg/d to as much as 12 mg/d, but the optimal dose is unknown. Although there is evidence of the short-term efficacy of ergoloid mesylates from numerous controlled trials, many clinicians still consider it to be a placebo. No alternative drug treatments have been proved better. The crucial decision a physician must make is whether to try specific drug therapy or rely solely on supportive care and symptomatic drug treatment. The increasing prevalence of senile dementia has renewed interest in discovering more effective drug treatments for this condition.

Trimethoprim-sulfamethoxazole has excellent microbiologic activity against most pathogens that produce meningitis; both components of this drug have high penetration into tissues, including the cerebrospinal fluid. Clinical experience shows that trimethoprim-sulfamethoxazole may be beneficial in the treatment of gram-negative bacillary meningitis caused by organisms only moderately susceptible to third-generation cephalosporins (Enterobacter cloacae, Serratia marcescens) or resistant to these antibiotic agents (Pseudomonas cepacia, Acinetobacter). The success of trimethoprim-sulfamethoxazole in the treatment of four patients with Staphylococcus aureus and two patients with Listeria monocytogenes meningitis shows that this drug may also be useful in treating infrequent types of gram-positive meningitis.

The herpesviruses that infect humans characteristically establish a latent infection that may be reactivated later. The consequences of reactivation range from asymptomatic shedding to severe disseminated infection. Varicella-zoster and herpes simplex viruses are both highly neurotropic, establishing nonreplicating infections in sensory ganglia. Latent herpes simplex virus is known to reside in neurons, and the virus-cell interactions involved have been defined to an extent. Cytomegalovirus and Epstein-Barr virus interact with peripheral blood leukocytes. Latent cytomegalovirus infection of human leukocytes has not been proved, although studies in a murine model have implicated B lymphocytes as a repository of latent virus. Epstein-Barr virus is known to persist in a non-replicating state as extrachromosomal DNA in B lymphocytes and to cause "immortalization" of the infected cell; persistence of the viral genome in epithelial cells may also result in malignant transformation, such as nasopharyngeal carcinoma.

Systemic lupus erythematosus is a multisystem, antibody-mediated, autoimmune disorder that occurs spontaneously in humans and mice. Genetic factors appear to play an important predisposing role in the disorder: The presence of certain genes may produce a generalized immune abnormality, whereas others may lead to specific autoantibodies. Environmental triggers increase autoantibody production and augment the expression of illness. Bacterial and viral illnesses can provide stimulation by activating macrophages and T cells that, in turn, stimulate B cells. In the absence of normal control mechanisms, the stimulatory process is not suppressed, and excessive stem cell proliferation results in abnormal B-cell proliferation. A trigger for the disease is the signaling of the proliferating B cells to differentiate into antibody-forming cells. Most autoantibody-producing B cells can be eliminated from mice with lupus erythematosus by virtue of the presence of the gene, xid. In addition, administration of an analog of arachidonic acid is an effective treatment for murine lupus erythematosus.

Cisplatin is a metal coordination compound that was approved for clinical use in treating testicular cancer 5 years ago. Although early trials showed marked gastrointestinal and renal toxicities, treatment-related morbidity has been significantly alleviated with modern antiemetic therapy and adequate pretreatment hydration. More recent clinical studies of cisplatin have shown a broad range of activity and provide a better understanding of the drug's pharmacology, mechanism of action, and toxicity. Variations in the dosage and mode of administration as well as development of cisplatin analogues are being currently studied.

Hepatic metastases of colorectal origin are resistant to radiation and immunotherapy. Traditional intravenous chemotherapy produces responses in 10% to 30% of patients, and surgical resection is feasible in approximately 20% of patients who have a solitary or unilobar lesion. Infusion of cytotoxic agents into the hepatic artery, introduced 2 decades ago, is the most promising form of therapy for unresectable hepatic metastases. Fluorouracil, floxuridine, and mitomycin have been most commonly administered by hepatic arterial infusion. The recent development of a totally implantable pump has allowed prolonged ambulatory infusion of chemotherapeutic agents into the hepatic artery. We review the recent data on the pharmacology, therapeutic outcome, administration techniques, and complications of hepatic arterial chemotherapy. Future trials in this area should use uniform stratification variables and standardized criteria for evaluating response, time to progression, and survival.

Anxiety commonly accompanies serious illness. However, in some patients anxiety is the primary manifestation of illness. Diagnostic criteria for these "primary" anxiety disorders have been redefined in the most recent revision of the American Psychiatric Association's Diagnostic and Statistical Manual. We discuss these new diagnostic categories; review the theoretical basis for the psychodynamic, behavioral, and physiologic manifestations of each of these disorders; and critically examine the treatments offered for each.

Heparin-associated thrombocytopenia is a relatively common complication of heparin therapy occurring in approximately 5% of the patients who receive this drug. The incidence is higher with bovine heparin then with porcine heparin. Onset of heparin-associated thrombocytopenia usually occurs 6 to 12 days after initiation of treatment and by itself has a low morbidity. Heparin-associated thrombocytopenia plus arterial thrombosis can cause major complications including stroke, heart attack, and death. The incidence of heparin-associated thrombocytopenia plus arterial thrombosis is lower than that for heparin-associated thrombocytopenia alone. The diagnosis of heparin-associated thrombocytopenia remains one of exclusion, but testing for the presence of a heparin-dependent platelet-aggregating factor may prove to be useful. Analysis of the time of onset suggests a strategy for prevention. Oral anticoagulants could be started concomitantly with the heparin so that it could be discontinued in several days. This approach may prevent most episodes of heparin-associated thrombocytopenia.

Human T-cell leukemia/lymphoma virus is a unique family of T-cell tropic, human, type-C retroviruses. The discovery of this class of retroviruses provides the first proven link between retroviruses and cancer in humans. This virus is endemic in certain parts of the world, including the southeastern United States, and is associated with the development of adult T-cell leukemia/lymphoma, a fulminant lymphoproliferative disorder frequently accompanied by opportunistic infections and hypercalcemia. Over the last few years, major advances have been made in understanding the clinical, epidemiologic, molecular biologic, and immunologic features of this unique class of human RNA tumor viruses.

After heart disease and cancer, alcoholism is America's third largest health problem; it affects 10 million people, costs $ 60 billion, and is implicated in 200 000 deaths annually. Alcohol is involved in 50% of deaths by motor vehicle and fire, 67% of murders, and 33% of suicides. It contributes to morbidity in certain malignancies and to many diseases of the endocrine, cardiovascular, hematopoietic, gastrointestinal, and nervous systems. The fetal alcohol syndrome occurs in a third of the infants born to women who drink more than 150 g of ethanol daily during pregnancy; another third of the infants become mentally retarded. The prevalence of alcoholism is lower in elderly than in middle-aged persons, but detection is difficult and vulnerability to harm is great in the elderly, due to both pharmacokinetic factors and increased tissue sensitivity. Alcohol and aging are additive in their harmful effects. Although modern medical treatment is helpful, alcoholics are frequently misdiagnosed and mismanaged by health professionals. Total abstinence from alcohol should be a primary goal of treatment.

Because of recent findings, a reassessment is needed of the concept that rest angina associated with ST-segment depression is due to a spontaneous, transient increase of blood pressure or heart rate, or both, in the presence of critical coronary artery stenosis. Continuous hemodynamic and electrocardiographic recordings done before and during attacks of rest angina and thallium-201 scintigrams done during pain indicate that a transient reduction of flow is the immediate cause of ischemia in most, but not all, instances. Flow reduction, in turn, appears to be due to coronary arterial spasm or platelet aggregation, or both, acting at a site of atherosclerotic narrowing. Therapy for unstable rest angina should include measures to prevent both transient reductions of flow and increases of myocardial oxygen consumption. A combination of long-acting nitrates, a beta-blocker, a calcium-channel blocker, and aspirin or heparin is suggested for this purpose. Intravenous nitroglycerin is useful when angina occurs despite this therapy or when frequent attacks of ischemia are occurring at the time of admission.

In hospitalized patients, the commonest causes of acute insomnia are the effects of illness, environmental sleep disruption, medication, anxiety, and depression. Treatment should correct underlying medical disorders; reduce environmental sleep disruptions; and lower anxiety with psychological interventions, sedative or hypnotic medication, and relaxation training. Special clinical problems include chronic pain, delirium, and insomnia in the elderly.

In the United States, the weight associated with the greatest longevity tends to below the average weight of the population under consideration, if such weights are not associated with a history of significant medical impairment. Overweight persons tend to die sooner than average-weight persons, especially those who are overweight at younger ages. The effect of being overweight on mortality is delayed and may not be seen in short-term studies. Cigarette smoking is a potential confounder of the relationship between obesity and mortality. Studies on body weight, morbidity, and mortality must be interpreted with careful attention to the definitions of obesity or relative weight used, preexisting morbid conditions, the length of follow-up, and confounders in the analysis. The terminology of body weight standards should be defined more precisely and cited appropriately. An appropriate database relating body weight by sex, age, and possibly frame size to morbidity and mortality should be developed to permit the preparation of reference tables for defining the desirable range of body weight based on morbidity and mortality statistics.