Metoclopramide antagonizes the effect of dopamine in the central nervous system and other organ systems. Metoclopramide's effect on the medullary chemoreceptor trigger zone makes it useful as a routine anti-emetic and in preventing vomiting induced by antineoplastic drugs, particularly cisplatin. Metoclopramide's gastrointestinal smooth muscle stimulatory effects are related to its ability to antagonize the inhibitory neurotransmitter, dopamine; to augment acetylcholine release and sensitize the muscarinic receptors of the gastrointestinal smooth muscle; and to coordinate gastric-pyloric-small intestinal motor function. The indications for which metoclopramide is approved in the United States are reviewed. Adverse effects, which may occur in up to 20% of patients, include drowsiness, lassitude, and akathisia; all are usually mild, transient, and reversible. Tremor, dystonic reactions, and extrapyramidal effects are infrequent; breast enlargement, galactorrhea, and menstrual irregularities are related to prolactin release.

Eighty-five patients with Wegener's granulomatosis were studied for 21 years at the National Institutes of Health. Patients were treated with a protocol consisting of cyclophosphamide, 2 mg/kg body weight d, together with prednisone, 1 mg/kg body weight d, followed by conversion of the prednisone to an alternate-day regimen. Complete remissions were achieved in 79 of 85 patients (93%). The mean duration of remission for living patients was 48.2 (+/- 3.6) months. Twenty-three patients are off all therapy for a mean duration of 35.3 (+/- 6.3) months without therapy. This study provides a prospective experience with Wegener's granulomatosis and shows that long-term remissions can be induced and maintained in an extremely high number of patients by the combination of daily cyclophosphamide and alternate-day prednisone therapy.

Over the last few years the approach to managing patients with the Zollinger-Ellison syndrome has changed dramatically. The establishment of gastrin hypersecretion by a non-beta islet cell tumor as responsible for the gastric acid hypersecretion, and the subsequent development and widespread availability of gastrin radioimmunoassays have changed the criteria generally used for diagnosis and have led to an increased understanding of syndromes that can mimic Zollinger-Ellison syndrome. With the availability of histamine H2-receptor antagonists, gastric acid hypersecretion can be controlled medically in almost all patients with Zollinger-Ellison syndrome, obviating routine total gastrectomy. With the reduced mortality from gastric acid hypersecretion, increased attention is being focused on the natural history of the gastrinoma. Newer methods of localizing tumors are being investigated with a view to surgical removal of the gastrinoma, and the importance of developing an affective chemotherapeutic regimen is becoming increasingly apparent.

Endomyocardial biopsy has been used more frequently over the past 10 years in an increasing number of centers in this country and abroad. When done by an experienced physician, it is as safe as routine cardiac catheterization. Although biopsy is not yet applicable in all cases of myocardial disease, many investigators have found this procedure valuable in specific circumstances, including cardiac allograft rejection, anthracycline-induced cardiomyopathy, and myocarditis. With this technique diagnoses can be made for various disorders including cardiac amyloidosis, sarcoidosis, hemochromatosis, and endomyocardial fibrosis. Although helpful in detecting an unsuspected condition or in formulating prognosis in some patients, biopsy is not diagnostically specific in patients with dilated or hypertrophic cardiomyopathy, because these diseases have no completely pathognomonic features under current examination methods. The proper practice of endomyocardial biopsy requires both technical proficiency and expert pathologic interpretation. As a research tool, biopsy will continue to yield new knowledge about myocardial disease and its treatment.

Neuroblastoma, the second commonest solid tumor in children, is a neoplasm of the peripheral autonomic nervous system that usually occurs before children are 6 years old. Therapy of localized tumor (clinical stage I and II) and of a special form of metastatic tumor (clinical stage IV-S) is usually successful, but treatment of widespread regional (clinical stage III) or metastatic (clinical stage IV) neuroblastoma is almost uniformly unsuccessful. Unfortunately, two thirds of children have stage III or IV disease at diagnosis. Several clinical trials are in progress. Preclinical investigations with monoclonal antibodies and retinoic acid may lead to new therapies. Monoclonal antibodies that react relatively selectively with neuroblastoma cells may be useful for diagnosis and therapy. Neuroblastoma cells have cytoplasmic retinoic-acid-binding proteins; treatment of cultured cells with retinoic acid induces morphologic maturation and markedly inhibits proliferation.

Indirect noninvasive neurovascular tests provide information on hemodynamic changes cephalad to the carotid bifurcation, whereas direct tests measure anatomic or physiologic changes at the bifurcation itself. Batteries of tests are often done and should combine both indirect and direct methods. Results with two ultrasonic techniques and digital subtraction intravenous angiography suggest a larger role for these methods. Carotid arteriography is the definitive procedure for evaluating the carotid artery, although it should only be done when carotid endarterectomy is contemplated. The relative risks and benefits of other diagnostic and therapeutic management strategies should guide the decision to do noninvasive neurovascular tests, or to proceed directly to arteriography.

Urinary incontinence is a problem affecting 5% of 10% of the elderly in the community and up to 50% of the elderly in institutions. Despite complex factors governing normal micturition, the causes of urinary incontinence can be classified into detrusor instability, overflow incontinence, sphincter insufficiency, functional illness, and iatrogenic causes. An accurate pathophysiologic diagnosis is a prerequisite to successful treatment. A decision sequence is presented to help design a reasonable diagnostic approach. With appropriate therapy, most incontinent elderly patients can expect significant improvement or cure.

Approximately 200 million persons are infected with schistosomes. Of those infected, a small proportion develop serious chronic disease, usually after years of intensive exposure and infection. Schistosoma mansoni and Schistosoma japonicum reside in the mesenteric veins and produce liver fibrosis, which results in portal hypertension and bleeding esophageal varices but little hepatocellular dysfunction. Schistosoma haematobium resides primarily in the pelvic veins and produces mass lesions in the bladder and ureters, which lead to hydroureter and hydronephrosis. The intensity of infection is a major factor determining development of disease, but differences in worm strain and host response may also be important. In acute schistosomiasis there is an intense response to the parasite, which is suppressed as the infection becomes chronic. The marked inflammatory response seen in early and acute schistosomiasis becomes less intense and fibrotic lesions predominate. The recent advent of safe, effective, and easily administered chemotherapeutic reagents will aid in the control of schistosomiasis.

Total joint replacement surgery has revolutionized the management of chronic arthritis. Careful patient selection, medical follow-up, patient education, and rehabilitation management produce the best results. The indications, contraindications, and results of total knee and hip replacement are reviewed.

Numerous adverse reactions have been attributed to cimetidine, which is understandable in view of the attention and scrutiny the drug has received, its widespread use, and its systemic effects. The reported frequency of side effects has differed considerably but is surprisingly low in all studies. The drug has caused an array of central nervous system disturbances, gynecomastia, and, rarely, hepatotoxicity, interstitial nephritis, bradycardia, hypotension, and even cardiac arrest. The last complication has occurred with rapid-bolus intravenous injection. Blood dyscrasias have also been rare and usually associated with serious underlying disease or multiple drugs, making it difficult to establish cause and effect in most cases. The drug is used widely to treatment conditions for which it is not approved. Some of these conditions are now believed to respond to cimetidine (gastric ulcer); others are known not to respond (acute upper gastrointestinal bleeding and acute pancreatitis).

Three new broad-spectrum penicillins--azlocillin, mezlocillin, and piperacillin--will soon be available for clinical use. Azlocillin and piperacillin are more active than carbenicillin or ticarcillin against Pseudomonas aeruginosa. Piperacillin and mezlocillin demonstrate significant activity against the Enterobacteriaceae, including many strains of Klebsiella pneumoniae against which the older penicillins carbenicillin, ticarcillin, and ampicillin are ineffective. All three new drugs show substantial activity against anaerobes and ampicillin-susceptible gonococci and Haemophilus influenzae. Because these agents are inactivated by various beta-lactamases, most Staphylococcus aureus isolates and a number of gram-negative organisms, including some important nosocomial pathogens, will be resistant to these antibiotics. The new penicillins appear to be relatively safe and have been used successfully to treat patients with various infections; however, comparative trials have not yet established the superiority of these drugs over conventional therapeutic agents.

Recent advances in the diagnosis of epilepsy include the development of a clinically useful classification of epileptic seizures and the recognition of specific epileptic disorders. These advances have been aided by the advent of x-ray computed tomography, long-term electroencephalographic telemetry, and video monitoring. Techniques for functional imaging of the human brain promise even greater diagnostic capabilities. New antiepileptic drugs have improved medical management, and technical and theoretical advances in pharmacokinetics have permitted physicians to design balanced dosing for individual patients. Although currently underused, surgical treatment of partial complex epilepsy can be safe and effective when used appropriately. Operant conditioning of electroencephalography may become another practical alternative therapy. Contributions of basic research to understanding the complications of status epilepticus have influenced treatment protocols and greatly improved the prognosis of this potentially lethal condition.

Cimetidine therapy has proved to be effective in healing most duodenal ulcers and in reducing the frequency of reulceration. It is unclear if low-dose maintenance therapy is superior to intermittent full-dose therapy in managing patients whose ulcers recur. Cimetidine is the preferred treatment for patients with the Zollinger-Ellison syndrome, and current evidence indicates efficacy in healing benign gastric ulcers. Some patients with reflux esophagitis improve with cimetidine treatment, but the drug cannot be regarded as first-time therapy. Largely circumstantial evidence suggests a role in preventing bleeding from acute gastric erosions and in preventing the acid aspiration syndrome. Cimetidine therapy has not been found to be useful in controlling acute upper gastrointestinal hemorrhage, acute pancreatitis, or several other conditions for which H2 blockade has been advocated.

Pseudotumor cerebri, a disorder of intracranial pressure regulation, is characterized by elevated cerebrospinal fluid pressures. The symptoms and signs are those of elevated intracranial pressure alone. Extensive endocrine studies in patients with the primary disease have generally been normal. The major threat to the patient with pseudotumor cerebri is loss of vision; severe deficits occur in 4% to 12% of patients. The causative mechanism is not known. There are no controlled studies of treatment and interpretation of uncontrolled studies is limited by the high rate of spontaneous remission. A short course of steroid therapy is recommended for the patient with significant symptoms that have not remitted after 7 to 10 days of observation and serial lumbar punctures. Shunting is considered in refractory patients or when loss of vision is threatened.

The milk-alkali syndrome was first identified in 1923, and continues to occur in patients ingesting large amounts of calcium and absorbable alkali, particularly as calcium carbonate. Hypercalcemia, alkalosis, and renal impairment remain hallmarks of the syndrome, which may occur in acute, subacute, and chronic forms. Although the pathophysiology of the milk-alkali syndrome has not been completely studied, it appears to involve complex interactions between ingested calcium and alkali resulting in an impairment in renal calcium and bicarbonate excretion. The diagnosis of the milk-alkali syndrome is based on a history of calcium and alkali ingestion, the presence of characteristic clinical and laboratory features, and the exclusion of other causes of hypercalcemia. Conservative treatment, including discontinuing calcium and alkali ingestion and supportive measures, is usually effective.

The graying of America will be accompanied by an epidemic of major proportions--dementia or intellectual impairment--that will have an impact on all aspects of the helath care system, particularly on the institutional component of the long-term care system. Health professionals; federal, state, and local health planners; families; and others must recognize that many ameliorable or curable physical and emotional diseases in the elderly are associated with intellectual impairment that may be difficult to distinguish from irreversible brain disease of the Alzheimer type. We present information on the cause, physiopathologic mechanism, clinical presentation, appropriate laboratory studies, and anticipated outcomes in the various forms of intellectual impairment found in the elderly. Important new developments will occur in the next decade that will address the cause, pathogenesis, further refinement of laboratory investigation, and specific therapeutic intervention in dementia.

The idiopathic hypereosinophilic syndrome (HES) represents a heterogeneous group of disorders with the common features of prolonged eosinophilia of an undetectable cause and organ system dysfunction. Fifty patients with the idiopathic HES were studied over 11 years of the National Institutes of Health. Multiple organ systems were involved; bone marrow hypereosinophilia was common to all patients, but the most severe clinicopathologic involvement was of the heart and nervous system. Postmortem gross pathologic examination of the hearts of patients with idiopathic and nonidiopathic HES suggested that the common mechanism of cardiac disease is the eosinophilia. Endomyocardial biopsy findings showed that the endothelial cells in the endocardium and of the microvasculature were the primary targets of the tissue damage. This damage initiates thrombosis; endocardial fibrosis and restrictive endomyocardopathy may follow. In-vitro culture of circulating eosinophil colony-forming units showed some normal studies, some studies showing increased progenitor cells committed to eosinophil development, and others showing an excess production of eosinophil colony-stimulating factor. Chemotherapy to lower the eosinophil counts has resulted in marked improvement of HES prognosis, as have agressive medical and surgical approaches to cardiovascular complications.

Barrett's esophagus denotes the presence of columnar epithelium in the esophagus instead of the usual stratified squamous epithelium. Barrett's esophagus had been thought to represent a mediastinal extension of the stomach in patients with a congenital short esophagus. Subsequent clinical and experimental data have established the abnormality as an acquired condition resulting from chronic gastroesophageal reflux. Although roentgenographic studies may show a mild-esophageal stricture or an esophageal ulcer, definitive diagnosis requires endoscopy with directed biopsy of erythematous mucosa in the esophagus, or manometrically guided biopsies for showing the presence of columnar epithelium above the lower esophageal sphincter. Although the origin of the cells causing this epithelium is still unclear, three distinct epithelial types have been found: atrophic gastric-fundic, junctional, and specialized columnar. Esophageal strictures and esophageal ulcers are complications associated with Barrett's esophagus, but its major significance is the association with the development of adenocarcinoma of the esophagus. Treatment of Barrett's esophagus is aimed at preventing gastroesophageal reflux with the additional need for close endoscopic surveillance for the development of dysplasia or early adenocarcinoma. Whether the diagnosis of Barrett's esophagus mandates anti-reflux surgery (fundoplication) remains controversial.

In recent years, considerable new information has become available on the pathogenesis, diagnosis and therapy of gastroesophageal reflux. Gastric contents, mucosal resistance, esophageal acid clearance, and gastric emptying are now recognized, along with incompetency of the lower esophageal sphincter, as contributing factors to gastroesophageal reflux disease. The potential tests for reflux are reviewed and the diagnostic accuracy of each is evaluated. A diagnostic approach to the patient with reflux symptoms is outlined that considers the sensitivity and specificity of these various tests as well as their availability to the generalist and gastrointestinal specialist. Finally, an overview of the current therapy for reflux disease summarizes the controlled studies in the medical literature.