Two hypotheses have been advanced to explain the appearance of microvascular complications in diabetic patients with glycemic control. The genetic hypothesis suggests that the development of diabetic complications is genetically determined and independent of diabetic control, whereas the metabolic hypothesis suggests that long-term hyperglycemia causes the subsequent development of small-blood-vessel complications. We review data that either support or reject these hypotheses and suggest a third unifying hypothesis.

The pathophysiology of functional adenomas of the anterior pituitary gland can be understood in the context of the central neural control of anterior pituitary secretion and by the fact that the cell types of the anterior pituitary gland generally express a single polypeptide hormone. Functional pituitary adenomas arise de novo from one or more of these cell types, but a defect in hypothalamic regulation can contribute to tumorigenesis and sometimes result in persistent tumor recurrence despite local surgical cure. The recent advances in molecular biology, radioimmunoassay, neuroradiology, and transsphenoidal microneurosurgery techniques have greatly improved our understanding of the pathophysiology of these tumors, enhanced diagnostic accuracy, and led to newer medical and surgical therapeutic approaches. This conference reviews the molecular and cellular pathophysiology, causes, diagnosis, clinical features, and medical and surgical management of the two common functional pituitary adenomas, prolactinoma and somatotropinoma.

In the last 20 years, serum enzyme and isoenzyme levels have become the final arbiters by which acute myocardial infarction is diagnosed or excluded. We review the characteristics of these enzymes, the methods and limitations of commonly used assays, and data on diagnostic accuracy and clinical implications of enzyme levels in various settings and offer recommendations on their optimal use. Because of the poor sensitivity of single measurements of cardiac enzyme levels, these assays should not be used in the emergency room to exclude myocardial infarction. If myocardial infarction is suspected, levels of creatine kinase and its MB fraction should be measured at admission and about 12 and 24 hours later. If a myocardial infarction may have occurred more than 24 hours before evaluation, then lactate dehydrogenase isoenzyme measurements may increase diagnostic accuracy. Used properly, these assays are remarkably sensitive, but like all tests, optimal interpretation requires insight into technical pitfalls and other causes of misleading results.

Clinical studies using mitoxantrone, an anthraquinone, were begun in the United States in 1979. Subsequent phase II and III trials have shown that mitoxantrone has significant clinical activity in patients with breast cancer, acute leukemia, and lymphoma. The drug has antiviral, antibacterial, antiprotozoal, immunomodulating, and antineoplastic properties and is mutagenic in some animal systems. Its mechanism of action seems to involve both DNA intercalation and nonintercalative electrostatic interactions. The dose-limiting toxicity is myelosuppression when the drug is given on a single-dose, every-3-week schedule and mucositis when it is given daily for 5 days. Other toxicities include gastrointestinal and cardiac effects, the gastrointestinal toxicity being less severe and less frequent than that with the anthracycline anticancer drugs. Because of its low incidence of serious toxicities and effectiveness in treating certain solid tumors and leukemias, mitoxantrone is a promising new agent in the treatment of cancer.

Drugs used to treat portal hypertension cause constriction of mesenteric arterioles, reducing inflow to the portal venous system, portal pressure, and flow through portasystemic collaterals (such as esophageal varices). Vasopressin and somatostatin are direct vasoconstrictors. Propranolol acts by blocking vasodilatory beta 1 receptors and reducing cardiac output. A major side effect of vasopressin therapy is impaired cardiac performance secondary to coronary vasoconstriction and increased work against high arterial pressure. Infusion of vasopressin together with a cardiac inotrope or a vasodilator, and administration of vasopressin as an inactive "hormonogen" which is slowly released in vivo, may lessen adverse effects. Somatostatin appears to act selectively in the mesenteric circulation. Controlled trials indicate that vasopressin may be useful for controlling hemorrhage from esophageal varices and that somatostatin works at least as well as vasopressin. Propranolol treatment has been used to prevent variceal bleeding; however, controlled trials of its effectiveness have produced conflicting results.

The blood-brain barrier separates brain interstitial space from blood and is formed by brain capillary endothelial cells that are fused together by epithelial-like tight junctions. Study of the blood-brain barrier traditionally has been a relatively arcane field, even for neurobiologists. However, advances over the last 10 years in understanding the transport physiology and cell biology of the brain capillary endothelial cell now provide insights into the pathogenesis of such problems as brain glucopenia, hepatic encephalopathy, therapeutic efficacy of alpha-methyldopa, brain edema in diabetic ketoacidosis, Alzheimer's disease, brain tumors, and lupus cerebritis.

The spinal tap, or lumbar puncture, has indisputable value; opinions differ, however, on the amount of that value. The procedure has variable utility depending on the clinical indications and the results of tests on the cerebrospinal fluid. Its greatest value is in the evaluation of infectious or malignant meningitis; for most other diseases, it provides additional, but not essential, information. Because of the potential risk of the spinal tap, decisions about when to do the procedure must be made carefully. A probability analysis is provided to elucidate the usefulness of data from cerebrospinal fluid tests.

Drug-induced injury to the liver can mimic any form of acute or chronic liver disease. Acute injury to the liver frequently is due to the action of cytochrome P450, which breaks down drugs into electrophiles or free radicals; these reactive metabolites can covalently bind to protein and unsaturated fatty acids or induce lipid peroxidation, respectively. These events may impair vital functions of the cell, such as maintenance of calcium homeostasis, leading to death; or hypothetically they may elicit a hypersensitivity reaction directed mainly at the liver. Glutathione and tocopherol play critical roles in cellular defense. Cholestatic disease caused by drugs results from a selective disturbance in bile secretion. Agents such as estrogens, chlorpromazine, and monohydroxy bile acids alter the chemical and physical properties of membranes, leading to impaired activity of carriers and pumps for bile acids and electrolytes. Certain drugs produce chronic liver disease that is pathologically identical to chronic active hepatitis, biliary cirrhosis, or alcoholic liver disease.

The increasing availability of noninvasive methods for measuring bone mass raises the issue of whether perimenopausal women should routinely have such measurements to identify those at risk for osteoporotic fractures of the hip, wrist, and spine. Although the mortality and morbidity caused by hip fractures would warrant routine screening, measurement of bone mass has uncertain value in assessing the risk for hip fracture. Wrist fractures generally cause only transient disability, and measurement of bone mass may not reliably predict risk. Measurements of bone density of the spine might be better able to assess a woman's risk for vertebral fractures, but the value of screening depends on whether the findings would affect a woman's decision about using estrogen therapy after menopause. Serial measurements of bone mass to estimate a woman's rate of bone loss are relatively imprecise, increase the cost of screening, and have at best a limited role in screening women to assess risk for osteoporotic fractures.

Recent progress has been made in diagnosing and tracing the natural history of intracardiac thrombi by echocardiography. Left ventricular thrombi occur and cause emboli in three clinical conditions: acute myocardial infarction, left ventricular aneurysm as a sequel to infarction, and idiopathic dilated cardiomyopathy. Echocardiographic studies have shown that one third of patients with acute anterior myocardial infarction have left ventricular thrombi; only a small percentage of these patients have emboli. Administration of anticoagulants decreases the prevalence of left ventricular thrombi and the frequency of embolization in this group. Thrombi that are protruding and mobile are most likely to embolize. Anticoagulation treatment decreases the prevalence of embolization in idiopathic dilated cardiomyopathy and should be instituted regardless of whether atrial or ventricular thrombi are detected by two-dimensional echocardiography. In patients with chronic left ventricular aneurysm, thrombi occur commonly, but emboli, infrequently. Therefore, data are insufficient to suggest that anticoagulation treatment is indicated, even if left ventricular thrombi are detected by two-dimensional echocardiography.

Although admission and preoperative chest radiography has been done for many years in various settings, existing data do not support its utility in enhancing patient care. Calculations based on estimates of the accuracy of chest radiographs and the likelihood of disease suggest that routine chest radiography may result in many more misleading than helpful results. Patients in whom chest radiographs are likely to improve outcome are best identified by a careful history and physical examination. We recommend that the practice of doing routine chest radiographs on admission and preoperatively be stopped and that the procedure be reserved for patients with clinical evidence of chest disease and patients having intrathoracic surgery.

Obesity is commonly considered a surgical risk factor, but the degree of risk has been imprecisely quantified. There is little evidence that excessive body weight in itself should contraindicate general surgery. However, obesity is often associated with abnormal cardiorespiratory function, metabolic function, and hemostasis, which may predispose to morbidity and mortality after surgery. We review pertinent data and offer guidelines to minimize the risks of surgery in obese patients.

Disorders determined wholly or in part by genetic factors constitute a substantial number of human diseases. This realization has grown during the past 2 decades with the recognition of many specific heritable conditions and the identification of familial risk factors for common disorders. New technologies, such as fetal visualization, chorionic villus sampling, molecular cloning methods, and gene transfer technology, provides a framework for dealing with genetically determined illness in unprecedented ways. Several current and potential applications of these methods are examined, as is the use of restriction fragment length polymorphisms to survey the variability within the genome and to generate markers permitting the prospective detection of genetic disorders. The promise and limitations of chorionic villus biopsy sampling are considered for early prenatal diagnosis. The future of gene therapy in hereditary diseases is examined, and some of the substantial social and ethical considerations engendered by these new developments are explored.

The American Heart Association has updated its recommendations for prevention of bacterial endocarditis. The major changes are less emphasis on administration of parenteral agents and a reduction of the period of prophylaxis. The simplified new recommendations should make compliance easier and should be assiduously implemented by dental and medical practitioners. However, several changes are suggested for possible consideration: Because of the relatively low risk, prophylaxis may not be needed for persons with mitral valve prolapse (unless there is a holosystolic murmur) or for most gastrointestinal endoscopic procedures. Consideration should be given to using a single oral 3-g dose of amoxicillin for dental procedures in all patients at risk and for genitourinary and gastrointestinal tract procedures in patients at risk who have natural cardiac valves. Vancomycin should probably be the agent of choice for prophylaxis in cardiac valve surgery.

Health care is generally unavailable for the homeless. This heterogeneous group of men and women, including long-term street dwellers, residents of shelters, the chronically mentally ill, the economically debased, and alienated youth, are subject to a broad range of acute and chronic diseases, intensified by unsuitable living conditions, stress, and sociopathic behavior. Trauma, pulmonary tuberculosis, infestations, and peripheral vascular disease are common problems among the homeless; incomplete and fragmentary medical care permits exacerbation of chronic disorders. Outreach programs imaginatively constructed by teams of physicians, nurses, and social workers can effectively reestablish and maintain health services for these disenfranchised persons.

We have treated 6 chronic alcoholics and identified an additional 19 reported in the literature who developed severe hepatotoxicity from acetaminophen taken in apparently moderate doses. The clinical disease in these 25 patients had a characteristic pattern: mild to moderate jaundice; mild to severe coagulopathy; and strikingly abnormal aminotransferase levels, values inconsistent with either acute alcoholic hepatitis or viral hepatitis. The possible causes for the injury from ostensibly nontoxic drug levels appear to be either the induction by chronic alcohol intake of the cytochrome P-450 system responsible for converting acetaminophen to a toxic metabolite, or the effect of alcoholism and the associated malnutrition in reducing the glutathione concentration, responsible normally for preventing hepatotoxicity by conjugation with the toxic metabolite. The research data pertaining to the apparent enhanced toxicity from chronic alcoholism are reviewed. Despite the low frequency of ethanol-potentiated acetaminophen hepatotoxicity, alcoholics should be cautioned about the use of acetaminophen while they persist in heavy consumption of alcohol.

Aspirin often causes acute gastric mucosal damage that can be seen endoscopically or assessed indirectly (for example, by measuring increased gastrointestinal blood loss). The occurrence of most adverse effects is apparently related to the dose administered. This dose-response effect, evident in both endoscopic and microbleeding studies done after acute or short-term aspirin administration, is also associated with the risk of developing chronic gastric ulcer. The occurrence of gastric adaptation, or lessening injury with continued treatment, obscures the interpretation of results from studies of acute administration. Moreover, evidence of dose-response effects has frequently been ignored when lists of complications and side effects are compiled. The absence of symptoms does not correlate with acute or chronic mucosal damage and appears to have no predictive value. Endoscopic studies linking the extent and degree of acute mucosal injury to various nonsteroidal anti-inflammatory drugs have little or no value in predicting the frequency or severity of chronic gastric ulcer or gastrointestinal bleeding.

Orthotopic liver transplantation is a therapeutic option for patients with end-stage liver disease in whom conventional forms of medical therapy have failed. Since the first successful liver transplantation in 1967, more than 1000 have been done in North America and Europe. Improvements in patient selection, operative technique, and immunosuppression--most importantly, the introduction of cyclosporine--have resulted in an overall 1-year survival rate of 68%. Immediate postoperative problems are ischemic graft injury, acute rejection reactions, and technical problems with biliary and vascular anastomoses. Later complications include sepsis from bacterial, fungal, or viral pathogens due to immunosuppression. Late morbidity and mortality occur primarily because of chronic rejection or recurrence of primary liver disease. Despite the problems, liver transplantation is an exciting, nonexperimental therapy for patients with end-stage liver disease and offers hope to many patients for whom no treatment was previously available.

The syndromes of thyroiditis include five disorders. Hashimoto's thyroiditis, the commonest, is an autoimmune disease whose principal manifestations are goiter and hypothyroidism. Subacute granulomatous thyroiditis is probably viral in origin and usually presents with a tender goiter. Subacute lymphocytic thyroiditis is of unknown pathogenesis, but the postpartum form may be autoimmune. Its principal manifestations are goiter and spontaneously reversible hyperthyroidism. Acute suppurative thyroiditis results from bacterial or fungal infection causing abscess. Riedel's struma, a disease of unknown cause, presents with a goiter and thoracic inlet obstruction. Thyroiditis may require differentiation from other diseases. The goiter may resemble that of Graves' disease or thyroid lymphoma. Thyroid nodules may resemble neoplasms. Hyperthyroidism may suggest Graves' disease or other hyperthyroid syndromes with low radioactive iodine uptake. Neck pain can also occur with some thyroid malignancies. Local abscess is usually infectious but may be undifferentiated thyroid carcinoma. Finally, hypothyroidism may be transient or permanent.