The widespread emergence of chloroquine-resistant Plasmodium falciparum led to the formulation of an effective, fixed combination of two antimalarial agents, pyrimethamine and the long-acting sulfonamide sulfadoxine, for prophylaxis and treatment. These drugs act at sequential steps to inhibit the formation of tetrahydrofolate in the parasite. Recently, their use for malaria prophylaxis has been associated with severe, at times fatal, cutaneous reactions including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. These reactions have necessitated a major reassessment of the indications for pyrimethamine-sulfadoxine use and increased the search for pharmacologic, immunologic and behavioral approaches to the prophylaxis and treatment of infection with P. falciparum. Pyrimethamine-sulfadoxine may be effective in preventing recurrent pneumonia caused by Pneumocystis carinii in patients with the acquired immunodeficiency syndrome, but life-threatening cutaneous reactions have also been reported in this setting.

High-level resistance to gentamicin among clinical isolates of enterococci has been found with increasing frequency in recent years. In this issue, Zervos and colleagues report findings from a prospective study in which they assessed the frequency of colonization and infection with such organisms at a university medical center, demonstrating probable person-to-person spread. Their findings suggest that hospitals should conduct systematic screening for enterococci with high-level resistance to gentamicin, that antimicrobial treatment habits be modified to limit the emergence of such organisms, and that rigorous infection control be practiced to minimize their spread. These observations are particularly timely because it has become clear that enterococci are extremely versatile pathogens which are both well suited for survival and capable of causing serious illness, especially in hospitalized patients treated with some of the newer broad-spectrum antibiotic agents. Enterococci with high-level resistance to gentamicin are also of growing concern because their resistance to many antibiotic agents severely limits the clinician's options for treatment.

All five sleep disorders reviewed in this article can be adequately evaluated in the physician's office by taking a sleep history and conducting a careful general medical and psychiatric assessment. Insomnia, the commonest sleep disorder, is more prevalent among women and elderly and psychosocially disadvantaged persons. Personality factors such as a tendency toward the internalization of emotions and the occurrence of stressful life events also play a major role in the development of chronic insomnia. A multidimensional approach is indicated for the treatment of chronic insomnia; hypnotic drugs should be used only as an adjunct to this treatment. In children, sleepwalking and night terrors (two manifestations of the same pathophysiologic substrate), nightmares, and enuresis are commonly related to developmental factors; counseling and reassurance of the parents is indicated. Psychopathologic disorders are usually present in secondary enuresis, as well as in sleepwalking, night terrors, and nightmares that occur in adulthood. Psychotherapy and the occasional use of psychotropic drugs may be necessary in the treatment given adults with these disorders.

Patients with the acquired immunodeficiency syndrome (AIDS) die of overwhelming infections as a consequence of the destruction of the T4 subset of lymphocytes. Approaches to the treatment of AIDS have involved attempts to reestablish immune competence as well as treat opportunistic infections. The discovery of the human T-lymphotropic virus type III, which causes AIDS, has provided a specific target for screening antiviral drugs. There are many potential screening targets, from surface-binding proteins to viral integration and assembly, but most of the recent efforts have been aimed at developing drugs to inhibit the unique viral DNA polymerase (reverse transcriptase). The early studies with 3'-azido-3'-deoxythymidine (AZT) have provided encouraging results.

Symptoms of obstructive sleep apnea, a potentially life-threatening disorder, include excessive daytime sleepiness and sleep attacks, nocturnal breath cessation, and snorting and gasping sounds. These symptoms usually become manifest before age 40 and cluster within a few years. Most patients are obese, hypertensive men who eventually develop cardiovascular abnormalities. If sleep apnea is suspected based on clinical information, a sleep laboratory evaluation is indicated. For severe obstructive sleep apnea, tracheostomy is the most effective treatment. Narcolepsy, another sleep disorder, is a life-long and usually disabling condition. In most narcoleptic patients the first symptoms develop during childhood or adolescence, yet many years pass before the proper diagnosis is made. The presence of sleep attacks together with auxiliary symptoms, particularly cataplexy, is diagnostic. Treatment of narcolepsy includes stimulants in combination with therapeutic naps for sleep attacks and tricyclic drugs for cataplexy.

A major difficulty limiting the use of immunomodulators in clinical medicine has been the complexity of the immunoregulatory network in which modulation of one component usually perturbs the entire system, thus diminishing the specificity of the approach. Lymphokine-activated killer cells infused with interleukin-2 have proved effective in inducing remissions in several advanced cancers, particularly metastatic renal cell carcinomas. The interferons have shown direct antiproliferative effects as well as specific effects on immune function. Alpha-interferon has shown impressive antitumor effects in hairy cell leukemia and significant antiviral effects in papillomavirus infection of the genital tract. Interleukin-2 has multifaceted effects on various limbs of the inflammatory and immune responses and may be the critical common denominator in the adjuvant effects of several other compounds. Monoclonal antibodies have assumed an increasing role in diagnostic and therapeutic approaches to neoplastic and immune-mediated diseases. Finally, several immunomodulators are currently being tested in the treatment of the immune defect of the acquired immunodeficiency syndrome.

Since its introduction into medicine 15 years ago, decision analysis has been applied to difficult clinical problems. Several important advances have made the process more practical and acceptable: computer programs that eliminate the need for burdensome calculations, improved techniques for designing analytic models, the ability to carry out sensitivity analyses over several dimensions simultaneously, and the elaboration of clinically relevant measures of utility. Using these techniques, analysts have addressed many important clinical issues including screening for and prevention of disease, tradeoffs among tests and treatments, and the interpretation of clinical data under conditions of uncertainty. Problems with the approach remain and applications have not been extensive, but decision analysis is evolving as a powerful clinical tool and gradually is gaining acceptance in medical practice.

Three therapeutic areas of clinical immunology that have seen active development recently are immunopharmacology of immunosuppressive drugs; clinical use of the alpha-, beta-, and gamma-interferons and interleukin-2; and monoclonal antibody applications in marrow transplantation and antitumor therapy. Understanding of the immune regulatory systems and of the soluble factors that convey information between immune and related cells (for example, lymphokines and cytokines and their receptors) has improved substantially. New information about established immunosuppressive drugs and the introduction of new drugs are providing new opportunities for effective treatment of autoimmune diseases and improved effectiveness of organ transplantation. Clinical trials are evaluating the use of interleukin-2 in immunodeficiency disorders and neoplastic disease. Monoclonal antibodies, which have been successfully applied to diagnostic procedures, have been shown to be useful for therapeutic applications in marrow transplantation and antitumor treatment.

Excess body hair, or hirsutism, is usually only a problem in women and can cause considerable psychological distress. The disorder is usually androgen mediated. Because androgens come only from the adrenal glands or gonads or by conversion in peripheral tissues of precursor steroids from these organs, the causes of hirsutism are found in these two organs. Adrenal causes include Cushing's disease, adrenal tumors, and congenital adrenal hyperplasia. Ovarian causes include tumors, polycystic ovarian syndrome, and most cases of idiopathic hirsutism. The clinical evaluation is designed to differentiate between these diagnostic possibilities. When an underlying abnormality can be identified, such as an ovarian tumor, the treatment course is clear. When the diagnosis is idiopathic hirsutism, however, the best treatment is uncertain and several available regimens are possible.

The complete blood count and leukocyte differential count have no value in screening asymptomatic members of the general population. The complete blood count may be useful for screening infants in the first year of life, institutionalized elderly persons, pregnant women, and recent immigrants from Third World countries, if poor nutrition or inadequate iron intake is suspected. These tests are not useful for hospitalized patients, unless an abnormality is suspected or surgery with major blood loss is anticipated. It is appropriate to obtain the tests when a hematologic or infectious disorder is suspected, but they may not affect decision making if the diagnosis is clinically evident. The leukocyte differential count is unnecessary to confirm an infection in most cases in which leukocytosis is present. Repeat tests should be limited to situations where the clinical course is unclear, and at intervals long enough such that the results might affect clinical decision making.

Two hypotheses have been proposed to explain the pathogenesis and cause of the increased subepithelial collagen deposition that occurs in patients with collagenous colitis, a rare disease of unknown cause. One hypothesis considers an inflammatory origin, and the other, a local abnormality of collagen synthesis. An analysis of clinical, endoscopic, and histologic findings from one of our patients and from previously published cases suggests that collagenous colitis is a form of inflammatory bowel disease characterized by localization of the initial injury to the superficial subepithelial zone and with subsequent fibrosis in that area. The data show a spectrum of clinical and histologic changes that represent different stages in the evolution of the inflammatory process.

Primary (essential) hypertension has recently been related to calcium deficiency, rather than excess. The evidence used to support this hypothesis includes surveys showing lesser dietary intake of calcium, lower levels of ionized calcium in the blood, and reduction of blood pressure with calcium supplements. This critique examines each of these points and the theoretical construct used to explain the hypothesis. We conclude that the theoretical construct is based on the use of only a portion of available experimental data and the clinical evidence remains inconclusive. Until the hypothesis is supported further, calcium deficiency should not be accepted as a mechanism responsible for hypertension and calcium supplements should be used with caution.

Several new beta-lactam antibiotics impair normal hemostasis. Hypoprothrombinemia has occurred frequently with cephalosporins that possess a methylthiotetrazole substitution (cefamandole, moxalactam, and cefoperazone). The incidence ranges from 4% to 68%, and the risk is greatest in debilitated patients with cancer, intra-abdominal infection, or renal failure. Impaired platelet function caused by perturbation of agonist receptors on the platelet surface has occurred primarily with beta-lactam antibiotics having an alpha-carboxyl substitution (moxalactam, carbenicillin, and ticarcillin). These antibiotics often cause the template bleeding time to be markedly prolonged (greater than 20 minutes). Acylureidopenicillins, which lack the alpha-carboxyl marker, impair platelet function less frequently and only modestly prolong the bleeding time. If serious hemorrhage occurs, hypoprothrombinemia associated with methylthiotetrazole-substituted cephalosporins should be treated with fresh frozen plasma. Likewise, dangerous bleeding due to impaired platelet aggregation requires treatment with platelet concentrates.

Although in practice computed tomography (CT) has nearly replaced standard tomography in the evaluation of chest diseases, an analysis of the literature shows that standard tomography may be preferred in some settings. After a detailed review of studies on test performance, we calculated overall sensitivity and specificity values. Using Bayesian analysis, we then developed guidelines for choosing between computed and standard tomography. A test is recommended if its results might obviate the need for an invasive procedure. Standard tomography is recommended in the detection of mediastinal metastases from lung cancer. In the detection of hilar metastases, standard tomography is recommended for patients who have low pretest probabilities of metastases to this site, and computed tomography is recommended for patients who have high pretest probabilities. Computed tomography is recommended for the detection of calcification in solitary pulmonary nodules. Tomographic procedures are not recommended when the pretest probability is intermediate. The discrepancy between current practice and these guidelines highlights the need for carefully designed, multi-institutional comparative studies of radiographic procedures.

Collagen, the major extracellular matrix component, comprises a family of closely related, yet genetically distinct proteins that provide physiologic tensile properties to the tissues. The recent progress made in understanding the normal biochemistry and biology of collagens has permitted us to identify different levels at which errors might be introduced into the structure and metabolism of this protein. Several acquired and heritable diseases are now known to involve distinct abnormalities in collagen. This conference reviews some of the latest discoveries in the biochemistry of collagen and highlights some disease entities in which definitive information on molecular alterations in collagen is available.

Infection with the human immunodeficiency virus (HIV) (formerly HTLV-III/LAV) is transmitted by sexual contact, by blood and blood products, and perinatally. There is no evidence for casual transmission. The risk to health care workers is low but appropriate infection control precautions should be taken. Specimens should be transported to the laboratory in plastic bags labeled with an easily recognized biohazard warning. Placing patients in private rooms is unnecessary unless a patient has an additional illness that requires such an arrangement. Disinfection, sterilization, housekeeping, and waste management must be done according to recommended guidelines. Asymptomatic hospital personnel with HIV antibody can safely engage in direct patient care. Routine HIV serologic screening of personnel or patients is not recommended. Counseling and HIV antibody testing should be offered to pregnant high-risk women. Laboratories that process specimens potentially containing HIV virus should adhere to maximum containment procedures. An intensive and continuing educational program on the epidemiology of HIV infection and appropriate infection control practice is recommended.

The advent of calcium (slow-channel) blockers introduced a potent new pharmacologic tool to cardiovascular therapy. Among these agents, the dihydropyridines have been shown to be the most potent vasodilators and the uses for their clinically available representative, nifedipine, in particular, have expanded. Beyond the standard use of nifedipine to treat various ischemic heart disorders, the drug's potent vasodilatory properties often make it a powerful antihypertensive agent. Although dihydropyridines might be effective in the treatment of other disorders such as central nervous system vascular accidents, some valvular heart disorders, hypertrophic obstructive cardiomyopathy, pulmonary hypertension, and perhaps antiatherogenesis, nifedipine's clinical role remains the treatment of myocardial ischemia and systemic hypertension.

Recurrent duodenal ulcers, treated with cimetidine, 400 mg, or ranitidine, 150 mg, once nightly, or with sucralfate, 1 g twice daily, can be prevented in approximately 75% of patients for up to 1 year. Because these drugs are generally of equal efficacy, the choice is based on the patient's previous drug experience and tolerance, potential side effects, risk of drug interaction, frequency of administration, and cost. These medications do not alter the natural history of duodenal ulcer disease, and therapy may need to continue for longer than 1 year if there are no long-term side effects. Extra efforts should be made to help cigarette smokers discontinue smoking. Patients who have recurrent duodenal ulcers during maintenance therapy can be retreated with full-dose therapy. If optimal drug therapy is unsuccessful in preventing frequent recurrences or complications, surgical treatment is indicated.

The human receptor for interleukin-2 (T-cell growth factor) plays a critical role in the growth of T cells and is required for full expression of the normal immune response. Through hybridoma and recombinant DNA techniques, the interleukin-2 receptor protein has been biochemically characterized and purified; full-length copies of its complementary DNA have been molecularly cloned, sequenced, and expressed in eukaryotic cells; and the receptor gene has been characterized. Transient expression of the interleukin-2 receptor gene occurs during normal T-cell activation, and high- and low-affinity forms of the membrane receptor exist. A naturally occurring, soluble receptor has also been isolated, and its levels in serum correlate with the activity of various diseases. Deregulation of interleukin-2 receptor expression occurs in T-cell leukemias produced by the human T-lymphotropic retroviruses types I and II (HTLV-I and -II) and has been causally linked to the action of the trans-activator (taf) gene of these viruses. Monoclonal antibodies specific for the interleukin-2 receptor are being evaluated in the treatment of HTLV-I-induced leukemias and other conditions involving the inappropriate function of activated T cells.

Cirrhotic ascites occurs via both overflow and underfill mechanisms. Intrahepatic hypertension activates a hepatic baroreceptor reflex that enhances renal sodium absorption; plasma volume is expanded. As cirrhosis progresses, the hepatoportal Starling forces become sufficiently disturbed to sequester this "overflow" in the peritoneal cavity, which results in ascites formation. "Underfill" of the vascular system occurs and eventually dominates the clinical picture. Finally, intrahepatic hypertension also activates the renin-angiotensin system, which causes renal vasoconstriction; the increase in renal prostaglandin synthesis maintains renal blood flow. Although cirrhotic ascites is traditionally classified as a transudate, the serum-ascites albumin gradient may be a better indicator of ascites secondary to portal hypertension than other causes. General management of patients with cirrhotic ascites includes severe restriction of dietary sodium intake and bed rest; diuretics are added if spontaneous diuresis does not occur after 3 to 4 days.