Tocainide, a newly released class 1B antiarrhythmic agent, has membrane stabilizing and electrophysiologic characteristics similar to those of lidocaine, but it can be prescribed for oral administration. Investigational studies in both animals and humans have shown tocainide's effectiveness for the treatment of ventricular arrhythmias in chronic and acute settings. The drug has nearly 100% bioavailability after oral administration and an effective half-life of 9 to 37 hours (mean, 15 hours). Antiarrhythmic efficacy is similar to that of other class I medications currently in use. Serious side effects most frequently involve the central nervous or gastrointestinal system and occur in 10% to 20% of patients. Tocainide has minimal negative inotropic effects and a tendency to shorten effective refractory periods.

Herpes simplex viruses cause common mucocutaneous infections, but many aspects of their epidemiology and transmission are incompletely defined. Although the incidence of oral herpes remains relatively unchanged, the incidence of genital herpes is increasing significantly. Definitive diagnosis of herpes remains dependent on virus isolation, but techniques involving direct examination of clinical specimens are increasingly sensitive and may simplify and speed diagnosis. With the advent of acyclovir, effective therapy and suppression of infection are feasible for immunodeficient and selected normal patients. Unanswered questions remain regarding the long-term safety of acyclovir and the potential for emergence of clinically significant drug resistance. No effective vaccines are yet available for herpes virus infections. Promising strategies for vaccine development include preparation of immunogenic proteins, engineering of specially attenuated live virus strains, and incorporation of selected herpes genes into live vaccinia virus vectors.

Although biofeedback has been applied to many gastrointestinal disorders, including reflux esophagitis, peptic ulcer disease, and irritable bowel syndrome, the limited number of reports precludes conclusions concerning its safety or efficacy in these disorders. Most studies have used biofeedback in the treatment of fecal incontinence. Uncontrolled trials have shown this procedure can reduce substantially the frequency of incontinence in 70% to 83% of patients at up to 1 to 2 years of follow-up. Biofeedback has been most successful in patients with a surgical cause for fecal incontinence, but recent data suggest the procedure may also be useful in diabetics. The few number of sessions required, its apparent safety, physiological appeal, and apparent success suggest biofeedback is a promising therapy for this disorder, but it remains inadequately tested.

Desmopressin (dDAVP), a synthetic analog of the neurohypophyseal nonapeptide arginine vasopressin, has enhanced antidiuretic potency, markedly diminished pressor activity, and a prolonged half-life and duration of action compared to the natural hormone. Desmopressin is the treatment of choice for central diabetes insipidus and can be administered either intranasally or parenterally. A newly approved indication is treatment of mild classical hemophilia and von Willebrand's disease, in which deficient concentrations of factor VIII and von Willebrand's factor are transiently increased to levels that allow minor surgery.

The human erythrocyte generates high-energy adenosine triphosphate by anaerobic glycolysis and cycles oxidized and reduced nicotinamide adenine dinucleotide phosphate by the aerobic pentose phosphate shunt pathway. Certain enzymopathies of the pentose phosphate shunt are associated with hemolysis resulting from oxidative denaturation of hemoglobin. Glucose-6-phosphate dehydrogenase deficiency, an X-chromosome-linked disorder, is the prototype of these diseases and is genetically and clinically polymorphic. Six enzymopathies of anaerobic glycolysis cause hemolytic anemia; lactate dehydrogenase deficiency does not. In 2,3-diphosphoglycerate mutase deficiency, 2,3-diphosphoglycerate is greatly reduced and asymptomatic polycythemia is noted. Pyrimidine-5'-nucleotidase deficiency, an enzymopathy of nucleotide metabolism, is characterized by intracellular accumulations of pyrimidine-containing nucleotides, marked basophilic stippling on the stained blood film, splenomegaly, and hemolysis. Lead inhibits the nucleotidase and an identical syndrome occurs during severe lead poisoning. Hemolysis also accompanies an unusual enzymopathy characterized by a 40- to 70-fold increase (not decrease) in adenosine deaminase activity.

Vasodilator drugs were initially administered to patients with primary pulmonary hypertension based on the unproven hypothesis that pulmonary vasoconstriction played an important role in the pathogenesis of the disease. There were early reports of hemodynamic and clinical improvement after treatment with various vasodilating agents, but subsequent experience did not confirm these uncontrolled observations, and emphasized the limitations and hazards of this approach. Vasodilator therapy generally fails to reduce pulmonary vascular resistance selectively during long-term administration and frequently leads to systemic hypotension, exacerbation of the pulmonary hypertensive state, worsening of right ventricular failure, and systemic arterial desaturation. Beneficial hemodynamic responses are seen in only 15% to 25% of patients. Vasodilator therapy should not be considered an established treatment of patients with primary pulmonary hypertension.

The exocrine pancreas secretes into the gut on demand more than 20 proteins that are indispensable for digestion. In-vivo autodigestion is prevented by an array of natural safeguards. In acute pancreatitis, inappropriate intrapancreatic activation and release of pancreatic hydrolases occur, but the pathogenetic mechanism of autodigestion is unclear. The release of proteases, lipase and colipase, phospholipase A, vasoactive peptides, and other agents probably accounts for the edema, tissue destruction, fat necrosis, metabolic abnormalities, and complications. Ethyl alcohol abuse, gallstones, trauma, and other common and rare conditions can induce pancreatitis. The patient's outcome can be predicted by certain prognostic signs. Ultrasonography and computerized tomography are invaluable diagnostic tools and magnetic resonance imaging appears promising. Hemodynamic monitoring, intensive care with colloid and crystalloid infusions, correction of electrolyte abnormalities, judicious use of antibiotics, peritoneal lavage, drainage of pancreatic exudation fluids, and surgical intervention require a team approach, especially in patients with multiple complications. Additional research is needed into the pathogenetic mechanism of autodigestion and the design of specific therapies.

Cefamandole and cefoxitin, introduced only 7 years ago, are now the most commonly prescribed parenteral antibiotics in the United States. These drugs are similar to the first-generation cephalosporins in toxicity, but their in-vitro spectrum of activity is greater. Their serum half-lives are longer than those of cephalothin and cephapirin but shorter than that of cefazolin. Although cefamandole has been recommended in empiric therapy for patients with community-acquired pneumonia and as a prophylactic agent for patients having various surgical procedures, other regimens are less expensive and just as effective. Cefamandole should not be used to treat intra-abdominal, enterobacter, or ampicillin-resistant Haemophilus influenzae infections. Cefoxitin is effective in the treatment and prevention of mixed aerobic-anaerobic skin and soft-tissue, intra-abdominal, gynecologic, and penicillinase-producing, spectinomycin-resistant Neisseria gonorrhoeae infections. Cefoxitin represents a greater advance than cefamandole in our continuing search for safe and more effective antimicrobial agents.

Chronic lymphocytic leukemia is a hematologic neoplasm characterized by proliferation and accumulation of mature-appearing lymphocytes. Most cases involve a clonal proliferation of B lymphocytes. The cells typically have low levels of surface immunoglobulin; usually mu or mu and delta heavy chains, and either kappa or lambda light chains. The cells also show receptors for mouse erythrocytes, Fc receptors for IgG, complement receptors, Ia antigens, and B-cell-associated antigens. Although chronic lymphocytic leukemia is usually a stable disease over months to years, transformation of both clinical and biological features may occur. Prognostic factors include the leukemia cell count (greater than 40 X 10(9)/L), anemia, thrombocytopenia, chromosome abnormalities, and the pattern of bone marrow involvement. Alkylating agents, radiation therapy, and corticosteroids are commonly used to treat patients with chronic lymphocytic leukemia. Although these agents are useful, few data show that survival has been substantially improved. Recently, biological response modifiers such as monoclonal antibodies and interferon have been studied.

Cardiac imaging is among the most commonly used diagnostic techniques in cardiovascular medicine. Conventional imaging modes (chest roentgenography, echocardiography, radionuclide imaging, and angiography) allow delineation of cardiac morphology, coronary anatomy, ventricular and valvular function, and cardiac shunts, and permit qualitative evaluation of myocardial perfusion. Four new imaging procedures (digital subtraction angiography, rapid acquisition x-ray computed tomography, emission computed tomography, and magnetic resonance imaging) promise to expand diagnostic capabilities by permitting quantitative analysis of myocardial perfusion, evaluation of myocardial metabolism, and characterization of cardiac tissue composition. These techniques differ widely in cost, availability, and in the additional information they offer. Optimal use will be achieved only through carefully controlled comparative clinical trials directed at specific diagnostic questions.

Patients are considered to have hypercoagulable states if they have laboratory abnormalities or clinical conditions that are associated with an increased risk of thrombosis (prethrombotic states) or if they have recurrent thrombosis without recognizable predisposing factors (thrombosis-prone). The number of specific primary hypercoagulable states that are recognized is growing. These disorders are generally inherited abnormalities of coagulation in which a physiologic anticoagulant mechanism is defective: for example, antithrombin III deficiency, protein C and protein S deficiency, abnormalities of the fibrinolytic system, and dysfibrinogenemias. Secondary hypercoagulable states are generally acquired disorders in patients with underlying systemic diseases or clinical conditions known to be associated with an increased risk of thrombosis: for example, malignancy, pregnancy, use of oral contraceptives, myeloproliferative disorders, hyperlipidemia, diabetes mellitus, and abnormalities of blood vessels and rheology. The complex pathophysiologic features of these secondary hypercoagulable states are discussed, and a framework is provided for the laboratory investigation and systematic clinical approach to the patient.

The acquired immunodeficiency syndrome continues to be a major public health problem in the United States, and recently its spread worldwide has accelerated. The syndrome is caused by a human retrovirus transmitted by sexual contact and via blood or blood products. The virus has been isolated, characterized, and cloned, and in addition to its presence in blood, it has been found in body tissues and fluids including brain, semen, and saliva. Although the syndrome in the United States is still largely confined to male homosexuals and intravenous drug users, there is increasing evidence, particularly from Zaire, that the virus can be spread by heterosexual contact. Attempts at immune reconstitution with lymphocytes and lymphokines have resulted in some transient improvement in immune function but without clinical effect, indicating the need for specific anti-retroviral therapy in combination with immune reconstitution.

Hospital personnel are subject to various occupational hazards. Awareness of these risks, compliance with basic preventive measures, and adequate resources for interventions are essential components of an occupational health program. Physical, chemical, and radiation hazards; important infectious risks; and psychosocial problems prevalent in hospital workers are reviewed. A rational approach to managing and preventing these problems is offered.

The treatment of early (stage I and II) breast cancer over the past 10 years has shown a trend towards conservative use of surgery. The role of mastectomy in achieving local-regional control has been challenged by procedures that preserve the breast, in which tumor excision and axillary node dissection are followed by breast irradiation. Data from retrospective studies as well as prospective randomized trials have shown that in selected patients conservative surgery and radiation achieve results comparable to those of mastectomy in terms of 10-year survival and local-regional recurrence. Studies have shown that conservative surgery, radiation, and adjuvant chemotherapy can be combined effectively in patients at high risk for systemic disease. Although the optimal treatment of early breast cancer remains controversial, the non-mastectomy approach represents major progress.

Immunoglobulin genes responsible for individual antibodies are organized as discontinuous DNA segments in their germline form. As an uncommitted stem cell develops into an antibody-synthesizing plasma cell, rearrangements of these immunoglobulin gene segments serve to activate the genes and to generate the virtually unlimited capacity to synthesize antibodies that recognize potential antigens. The analysis of immunoglobulin gene structure and arrangement has been of immense value in the study of human lymphoid neoplasms. Recombinant DNA technology involving analysis of immunoglobulin gene arrangement has been used to classify neoplasms of previously uncertain lineage, aid in the diagnosis of neoplasms of the B-cell series, and define the state of differentiation of neoplastic B-cell precursors. Furthermore, the demonstration of translocation of a particular transforming gene, the c-myc oncogene, into the immunoglobulin gene locus in Burkitt's lymphoma has provided a major insight into the cause of malignant transformation of these lymphoid cells.

As computer programs are used with increasing frequency in the clinical setting, ethicists, lawyers, computer scientists, clinicians, and patients must confront a group of problems: In what situations is it appropriate to use a medical computer program? Who should use these programs and how should they be used? What is the legal status of a computer program that provides medical advice? Can a proper balance be achieved between confidentiality of patient information and shared access to records by health care personnel? How can regulatory agencies, physicians, and patients determine if a program is safe for human use? Will programs be able to communicate with users well enough to prevent clinically harmful misunderstandings? Because few if any definitive answers are yet available, these questions remain the subject of much discussion.

As more people with mild hypertension are treated, non-drug therapies should be used more frequently and effectively. These therapies include weight reduction; sodium restriction; potassium, calcium, and magnesium supplementation; other dietary changes; exercise; relaxation; and moderation of alcohol use. Such therapies have been inadequately used, in part because of a lack of confidence in their effectiveness and overconfidence in the effectiveness and safety of drug therapy. Evidence about the effectiveness, mode of action, safety, and patient acceptance of the various non-drug therapies is reviewed, and practical guidelines to their use are provided. Non-drug therapies may provide enough antihypertensive effect to lower blood pressure of many patients with mild hypertension to a safe level without the need for antihypertensive drugs.