Prazosin, an orally active alpha-1 selective adrenergic antagonist, has been of value in treating patients with hypertension and congestive heart failure. In contrast to non-subtype-selective alpha-adrenergic antagonists and direct-acting vasodilators, prazosin's hypotensive action is accompanied by little or no increase in heart, rate, plasma renin, or plasma norepinephrine. Prazosin is a versatile drug that may be used alone or in combination to treat mild, moderate, or severe hypertension. The antihypertensive effect is sustained, and may increase during long-term therapy. The major side effect, postural hypotension after the first drug administration, is related to drug dose and intravascular volume depletion. Other side effects are mild and seldom limit therapy. In patients with congestive heart failure, prazosin results in balanced venous and arterial dilation, similar to that produced by nitroprusside. Attenuation of some or all of prazosin's initial hemodynamic effects has been seen during multiple short-term administrations. However, chronic studies have shown sustained symptomatic and hemodynamic improvement during long-term administration; initial hemodynamic attenuation may be transient or partial, and does not preclude long-term effectiveness, particularly during exercise. Preliminary studies indicate that prazosin may also be effective in treating patients with peripheral vasospasm due to Raynaud's phenomenon or ergotamine overdose.

Four studies assessed the frequency of vaginal Staphylococcus aureus colonization in healthy women and associated risk factors. An association was found between S. aureus vaginal colonization and colonization at the labia minora and the anterior nares. Significant risk factors associated with an increased risk of vaginal S. aureus in at least one study were a history of genital herpes simplex infection, insertion of tampons without an applicator, and the use of Rely (Procter & Gamble) tampons. The use of systemic antibiotics within 2 weeks of the vaginal culture decreased the risk of recovery of S. aureus. The overall frequency of vaginal S. aureus in the 808 women in the four studies was 9.2%.

The role of surgery before the completion of a standard course of antibiotics in endocarditis continues to evolve. The most commonly cited indications for surgery include heart failure, repeated emboli, resistant infection, large vegetations seen by echocardiography, and deep tissue involvement. It has also been suggested that any prosthetic valve infected with a nonstreptococcal pathogen should be considered for early replacement. We discuss the rationale behind surgical intervention, critically review the pertinent literature, and propose guidelines for the clinical management of these patients.

Diabetes mellitus is classified into two major categories: type I, which is insulin dependent, and type II, which is not. Insulin resistance in type II diabetes may be related to impaired receptor binding in some forms of the disorder. In the past, diabetes in pregnant women resulted in high rates of maternal and infant mortality. During the past 10 years, however, better management of maternal diabetes has led to a significant sharp reduction in maternal and fetal morbidity and mortality. The long-term outcome of insulin-dependent diabetes remains gloomy, probably because adequate control of the disease has rarely been achieved. Recently, more stringent efforts have been made to achieve tighter control. Frequent monitoring of blood glucose levels at home and use of constant infusion insulin pumps may help to achieve this end until successful islet transplantation is feasible.

Danazol, approved 5 years ago for the treatment of pelvic endometriosis, has recently been approved for treating cystic disease of the breast. As the mechanisms of action of this drug are made clear, the clinical syndromes that can be treated by this impeded androgen have increased dramatically. Results of controlled prospective clinical studies on the drug have increased our understanding of the pathophysiology of several poorly understood diseases. Danazol is well tolerated by most patients; the side effects are mild and reversible.

Control of Paget's disease of bone has been possible through treatment with agents that decrease bone resorption; calcitonins, diphosphonates, and mithramycin. The pagetic lesion is not, however, cured. Etidronate disodium is one of the diphosphonates. The clinical improvement attained with this drug has to be set against adverse effects, of which pain is probably the most bothersome in practice. Clinical remission can last as long as 2 years after treatment is stopped.

The last 5 to 6 years have witnessed an outburst of renewed interest in the beta-lactam antibiotics. One of the main factors contributing to this was the introduction of the simple and powerful technique of sodium dodecyl sulphate electrophoresis for the identification of bacterial membrane components--penicillin binding proteins--that bind radioactive penicillin and most likely represent the primary biochemical targets of penicillin action in the bacterial cell. Application of this technique has led to a remarkable number of novel observations that have substantially modified our view of the mode of action of beta-lactam antibiotics.

Sexual behavior in humans may be classified according to gender role, gender identity, and gender orientation. Sexually dimorphic behavior in humans is generally felt to be determined by postnatal socialization. Recent work in laboratory animals shows that sexual behavior is a function of circulating steroid hormones, particularly androgens. Testosterone given during a critical period in prenatal or immediate postnatal life causes permanent organizational effects on brain structure and function in laboratory animals. Studies in human patients with testicular feminization, 5-alpha-reductase deficiency, congenital adrenal hyperplasia, or prenatal steroid hormone exposure, provide clinical examples of possible effects of prenatal hormone action in the brain as opposed to postnatal socialization. However, these studies do not permit a clear assessment of the role played by either prenatal steroid hormones or postnatal socialization factors in the ultimate expression of sexual behavior in humans.

Self-regulatory therapies such as relaxation, biofeedback, and meditation have attracted increasing interest as primary or adjunctive treatments for anxiety. In addition to a clinical perspective, this review provides the medical practitioner with the underlying theory and methodologic issues involved in assessing the efficacy of self-regulation.

Colestipol is a safe, effective, cholesterol-lowering, bile-acid sequestrant that lowers low-density-lipoprotein (LDL) and total plasma cholesterol levels without consistently affecting high-density-lipoprotein (HDL) cholesterol levels. Long-term colestipol therapy in conjunction with diet may reduce xanthoma size, arrest progression of coronary artery atherosclerosis, and may reduce mortality from coronary heart disease. Probucol, a bisphenol cholesterol-lowering drug, is an effective cholesterol-lowering agent that reduces levels of HDL cholesterol, HDL cholesterol, and apoprotein A-1, the major apolipoprotein of HDL. Because HDL cholesterol is independently and inversely associated with development of coronary heart disease, the ramifications of simultaneous lowering of LDL and HDL cholesterol levels by probucol treatment need further study. Long-term, placebo-controlled studies of repetitive coronary arteriography, coronary heart disease morbidity and mortality, or both are needed to ascertain the efficacy of long-term probucol use in relation to development of atherosclerosis.

Effective therapy for aerobic gram-negative bacillary meningitis is limited by antibiotic resistance among many pathogens and by poor diffusion of some antibiotics into the subarachnoid space. The host response to suppurative meningitis caused by all encapsulated bacteria is impaired by a deficiency of complement and opsonic activity in infected spinal fluid; consequently, therapy with bactericidal antibiotics is preferred. Chloramphenicol diffuses well into cerebrospinal fluid, but is bacteristatic against enteric gram-negative bacilli. Although aminoglycosides are bactericidal, their use requires daily intralumbar or intraventricular injections. Newer cephalosporin compounds, moxalactam and cefotaxime, are bactericidal at very low concentrations and diffuse well from serum to infected spinal fluid. Clinical trials with moxalactam suggest that it is the most effective regimen for enteric gram-negative bacillary meningitis in adults; Pseudomonas aeruginosa and acinetobacter meningitis are most susceptible to a combination of intravenous ticarcillin and aminoglycoside, plus intrathecal aminoglycoside.

Since disopyramide was introduced 5 years ago, the therapeutic spectrum of this drug in treating patients with ventricular and atrial arrhythmias has been found to be similar to that of the other type I antiarrhythmic drugs, quinidine and procainamide. Disopyramide has the potential to suppress sinus node function and, therefore, must be used cautiously in patients with the sick sinus syndrome. The available data indicate that it can be used safely in patients with bundle branch block and first-degree or type I second-degree atrioventricular block. Disopyramide has been found at times to precipitate ventricular tachycardia or ventricular fibrillation. Because this drug often causes decompensation in patients with congestive heart failure, it must be used very cautiously, if at all, in such patients.

Abnormal autonomic nervous system responsiveness may contribute to the pathogenesis of asthma and other allergic diseases. Therefore, we measured alpha- and beta-adrenergic and cholinergic responsiveness in allergic subjects. Allergic asthmatic subjects had an abnormal adrenergic (alpha = hyperresponsive; beta = hyporesponsive) and cholinergic (hyperresponsive) profile. However, subjects with allergic rhinitis and preallergic subjects (those with positive allergen skin tests without any disease manifestation) had equivalent beta-adrenergic and cholinergic abnormalities. Thus, all allergic subjects showed abnormal beta-adrenergic hyporeactivity and cholinergic hypersensitivity whereas allergic asthma was singularly associated with excessive alpha-adrenergic responsiveness. Autoantibodies against beta-receptors were found predominantly in subjects with beta-adrenergic hyporeactivity. The presence of these autoantibodies and the physiologic abnormalities associated with their presence suggests a causitive relationship.

Primary hyperparathyroidism has become a relatively common endocrine disorder. Greater recognition of this disease has led to earlier detection. Consequently, primary hyperparathyroidism is now characterized frequently by asymptomatic mild hypercalcemia rather than by the more classical presentation with bone or renal involvement. Patients who have hypercalcemia and signs or symptoms should undergo neck surgery and removal of the abnormal parathyroid tissue. For the growing population of asymptomatic patients, however, indications for surgery are not as clear. The natural history of primary hyperparathyroidism is variable, and predicting who will develop complications of this disorder is not possible. Alternatives to surgery are careful and regular observation combined with various general and specific approaches currently receiving attention. Available information on the medical management of asymptomatic, mild primary hyperparathyroidism is summarized.

Streptococcus pneumoniae causes substantial morbidity and mortality. Incidence and severity are increased among populations with some chronic diseases. The currently available polyvalent polysaccharide vaccine induces antibody production among immunologically competent recipients against the 14 serotypes responsible for 80% of pneumococcal bacteremia in the efficacious in clinical trials with healthy young men in epidemic conditions and in patient with sickle cell anemia. Similar trials in two other high-risk populations had inconclusive results. Decisions on vaccine use now largely rest on indirect evidence of efficacy derived from knowledge of disease incidence, severity, and antibody response to vaccination among patient groups. Findings of a literature review suggest vaccinating high-risk patients immunologically competent to produce homotypic antibodies in response to vaccination with polysaccharide antigen, while continuing investigation of disease incidence, severity, serotype distribution, and immunologic response among high-risk groups and postmarketing surveillance efforts among all vaccinated patients.

Interferons are proteins elaborated by infected cells that protect noninfected cells from viral infection. These proteins produce a temporary "antiviral state" by altering nucleotide metabolism and cytoplasmic enzyme induction. Interferons appear early after viral infection locally and systematically to limit spread of viral infection; they also affect cell differentiation, growth, surface, antigen expression, morphologic findings, and immunoregulation. Several human disorders have diminished interferon production. Newborns have normal interferon alpha but deficient interferon gamma production. Infants with congenital infections may also have defects in interferon production. Immunosuppressed patients receiving transplants (marrow, heart, of kidney) have diminished interferon production, particularly immediately after transplant. Deficiencies of interferon have also been noted in Down's syndrome, cellular immunodeficiencies, uremia, malnutrition, and hematopoietic malignancy. Leukocyte interferon has been of therapeutic value in herpes zoster infections, in patients with cancer, and in patients with hepatitis B infection. Interferon has not been proved to help children with congenital cytomegalovirus or rubella. Interferon can shrink lymphoid tumors, particularly non-Hodgkin's lymphoma.

Age-related biologic and physiologic changes in the elderly may lead to altered pharmacokinetics. Volume of distribution, half-life, systemic clearance, and receptor sensitivity have been shown to change with increasing age. Unique features of illness in the elderly may interfere with effective drug therapy more than changed pharmacokinetics in some patients. Physical, psychologic, and socioeconomic considerations often interfere with ability to obtain and comply with health care. Disease is often difficult to recognize in elderly patients. Multiple chronic conditions, many of which may be undetected, may be exacerbated by or alter drug therapy for other illnesses. Cognitive impairment and diminished vision and hearing may make patient education difficult, and compliance poor. The elderly are also more susceptible to adverse drug reactions. The recommendations for clinical practice and directions for future research that are presented should help make drug therapy in the elderly safer and more effective.

Platelets may have a role in the development of animal tumor metastases. Ultrastructural studies in vivo have shown arrested tumor emboli surrounded by platelets. Several tumor cell lines induce thrombocytopenia in vivo. Certain tumor cells aggregate platelets in vitro. Correlations exist between the ability of some tumor cells to aggregate platelets in vitro and their metastatic potential in vivo. Antiplatelet agents have impaired or altered the spread of certain tumor metastases. It is suggested that platelets have a role in the sequestration, adherence, and penetration of tumor cells through the blood vessel endothelial cell barrier, thus preventing their rapid clearance from the circulation and allowing extravascular formation of nests of cells. Antiplatelet agents, particularly prostaglandins, may prove useful in preventing experimental animal metastases when administered before the inoculation of tumor cells. Their potential in human malignancy, where the patient presents with an established tumor, remains to be established.