Pennyroyal is a widely available herb that has long been used as an abortifacient despite its potentially lethal hepatotoxic effects. However, quantitative data for pennyroyal constituents and their metabolites in humans have not been previously reported.

To compare the efficacy, nephrotoxicity, and ototoxicity of once-daily aminoglycoside dosing with those of standard aminoglycoside regimens in immuno-competent adults.

A complex array of multiphasic and multifactorial immunopathogenic mechanisms are involved in the establishment and progression of human immunodeficiency virus (HIV) disease. After primary infection, acute viremia occurs with wide dissemination of HIV. During this early viremic phase, the virus is trapped within the processes of follicular dendritic cells in the germinal centers of lymphoid tissue. Also, during this phase of primary infection, some patients show major expansions of certain subsets of CD8+ T cells that are identified by the expression of a particular variable region of the beta chain of the T-cell receptor. These expansions are manifestations of responses to HIV that may be important in controlling the progression of HIV infection. In addition, inappropriate immune activation and elevated secretion of certain proinflammatory cytokines occur during HIV infection; these cytokines play a role in the regulation of HIV expression in the tissues. Infection of progenitor cells in bone marrow and the thymus contribute to the lack of regeneration of immunocompetent cells. Dendritic cells are involved in the initiation and propagation of HIV infection in CD4+ T cells. In studies of long-term nonprogressors - persons who have stable CD4+ T-cell counts and no HIV disease progression despite years of HIV infection - preserved lymph node architecture, low viral burden, and viral expression were found.

Dietary protein has long been thought to play a role in the progression of chronic renal disease, but clinical trials to date have not consistently shown that dietary protein restriction is beneficial.

The patient population at risk for opportunistic pulmonary infections has increased during the last decade. The spectrum of organisms causing opportunistic infections has also grown. With an ever broader list of potential diagnosis, a specific diagnosis of the cause of pulmonary disease becomes more important. Recent microbiologic advances have helped to facilitate the laboratory diagnosis of some of these agents. Immunoassays are available for the detection of antigen in nasopharyngeal secretions (respiratory syncytial virus, influenza) in serum (Cryptococcus species), and in urine (Legionella or Histoplasma species). Rapid-culture techniques are available for the culture and detection of various viruses, including cytomegalovirus. Molecular probes can now assist in the rapid identification of Mycobacterium tuberculosis and some fungi. In the near future, polymerase chain reaction-based techniques may assist in the detection of Pneumocystis carinii and Legionella, Chlamydia, Mycoplasma, and Mycobacteria species. An expeditious evaluation of pulmonary disease requires an understanding of the differential diagnosis of likely causes of pulmonary disease in specific immunosuppressed patient populations, an understanding of the most appropriate specimens to process for these diagnoses, and an understanding of the limitations (sensitivity and specificity) of these diagnostic tests. An understanding of the most appropriate specimens and tests in a given institution should allow for early, relatively specific treatment of many potentially life-threatening infections.

To assess the role of serum lipid levels as screening tests in adults.

Considerable evidence links elevated blood cholesterol levels to the development of atherosclerosis. The National Cholesterol Education Program (NCEP) has recently published revised guidelines for detecting and treating hypercholesterolemia in adults. Included in these guidelines is the recommendation that all adults older than 20 years of age know their cholesterol levels. Under the NCEP guidelines, knowledge of cholesterol levels, even if the levels are elevated, does not automatically lead to drug therapy; on the other hand, under these guidelines, adults are not automatically excluded from treatment simply on the basis of age or sex. The guidelines presented by the American College of Physicians in this issue differ from the NCEP guidelines in that they recommend only limited screening, primarily for middle-aged men. This recommendation is based in part on the assumption that overuse of cholesterol-lowering drugs will otherwise become a problem. In fact, a major current problem is underuse of cholesterol-lowering medications, even in patients at high risk for coronary events. The guidelines proposed by the College minimize large elements of the database linking cholesterol to atherogenesis and make unwarranted and unproven assumptions about physician behavior. In its rationale, its potential consequences, and the process by which it was derived, this policy is in error and should be rejected.

To summarize recent information about the "new" gastrointestinal protozoal pathogens (cryptosporidia, microsporidia, isospora, and cyclospora) and to help practicing clinicians integrate this information into their clinical databases by emphasizing the similarities among these organisms.

Given the dramatic increase in the incidence of vancomycin resistance among the enterococci and experimental evidence for the transfer of vancomycin resistance from enterococci to Staphylococcus aureus, there is concern that strains of S. aureus will emerge that are resistant to vancomycin. The result would be a highly virulent pathogen for which effective antimicrobial therapy would not be available. To prevent the nosocomial transmission of such an organism, stringent infection control policies need to be developed and implemented. We offer proposals that are based on the limited data available on the transmission and control of S. aureus and that may be used as starting points for the development of formal guidelines for the isolation of colonized and infected patients and for microbiology laboratory precautions.

Chronic hyperglycemia is implicated in the pathogenesis of microvascular, neurologic, and macrovascular complications of diabetes. Recent studies prove that near-normal glycemic control in insulin-dependent diabetes mellitus (IDDM) reduces the risk for the development and progression of microvascular and neurologic complications. With the expectation of comparable benefits, similar glycemic goals have been advocated for the management of non-insulin-dependent diabetes mellitus (NIDDM). However, using intensified insulin therapy to achieve near-normal glycemia in NIDDM may be problematic because of basic differences in pathophysiology of the two types of diabetes. Insulin resistance is a major contributor to the development of hyperglycemia in NIDDM and may prevent attainment of normoglycemia in most patients who are using the conventional approaches of diet, exercise, and oral hypoglycemic therapy. Near-normal glycemia in patients with NIDDM can usually be achieved with exogenous insulin but often requires large doses to overcome the insulin resistance. Intensive insulin therapy normalizes glycemia by decreasing hepatic glucose output and improving peripheral glucose uptake and may also improve insulin resistance and insulin secretion by reducing hyperglycemic glucotoxicity. However, large doses of exogenous insulin are associated with hyperinsulinemia and weight gain, but these effects may be minimized by combining insulin with other forms of therapy, for example, oral antidiabetic agents. When intensive management is instituted, the dose of exogenous insulin should be kept as low as possible. To do this, therapy for NIDDM must be part of a multifaceted approach combining insulin therapy with other effective forms of treatment such as counseling on diet and exercise therapy and the use of oral antidiabetic agents.

To examine the putative pathogenetic mechanisms of the long-term, specific complications of diabetes mellitus.

Feedback control is an important mechanism for reaching a targeted goal. Biologic examples range from achieving the appropriate blood pressure level to glycemia control. Computer-based feedback control systems have many potential applications in medicine. Closed-loop systems directly sense the state of the patient and then deliver an intervention without human action. Closed-loop systems have been used to control postoperative fluid infusion, reduce malignant hypertension to a reasonable range through nitroprusside infusions, and control continuous insulin infusions-in effect, an artificial pancreas. Sensory problems have limited the direct application of closed-loop systems to date; most current medical uses of computer-based feedback control are open loop, where a human is interposed between the suggested intervention and the delivered treatment. Because many variables important to the management of diabetes are objective, many opportunities exist for open-loop control in diabetes management. Open-loop systems have already been used to suggest insulin dosage adjustments and treatment for hypercholesterolemia and to remind physicians of various mellitus. However, existing applications have only scratched the surface. Many more facets of diabetes management could be standardized and assisted by open-loop control systems if the management rules could be more exactly specified, a task requiring substantial time commitments by diabetologists. Efforts to translate existing knowledge bases into precise guidelines will be helpful, but new primary studies and decision analyses are needed to define the optimal use of some interventions.

Care of persons with non-insulin-dependent diabetes mellitus (NIDDM) in the United Kingdom resembles that in the United States. However, health care practice in Europe is being influenced by the Saint Vincent Declaration, the joint European World Health Organization-International Diabetes Federation initiative, which emphasizes prevention of diabetic complications. In recent years, the responsibility for care for NIDDM has shifted in the United Kingdom to general practice teams. The effect of this shift on the quality of care and the coordinating and educational role of local diabetes specialist teams is discussed, as is the importance of an individualized "menu" of care for each patient. This menu aims for optimum blood glucose level control as well as detection and correction of risk factors for diabetic complications. The pervasive and dangerous notion of NIDDM as a "mild" disease must be corrected. The importance of systematic auditing of process and outcomes in diabetes care is emphasized, as is the need for regular data acquisition, aggregation, and analysis to achieve continuous improvement in the quality of care. Although patient-health professional encounters are the core of good diabetes care, the need for larger-scale appraisal on a local, regional, and national basis is now apparent.

A structured treatment and education program for patients with non-insulin-dependent diabetes mellitus (NIDDM) who are not taking insulin was developed, evaluated, and implemented at the primary health care level throughout Germany. The program is based on the definition of individual and pragmatic therapeutic goals for each patient, primarily using nondrug treatment, which includes systematic glycosuria self-monitoring by the patients and four structured sessions of group education held in a general practitioner's office. After documentation of the program's efficacy in a randomized, controlled trial and several pilot projects, the program has been officially incorporated into the general German health care scheme and includes payment to practicing physicians for each patient treated. More than 12,500 primary health care physicians have participated in special 2-day postgraduate courses given by diabetologists; these courses are a precondition to participating in the program. As part of the primary health care scheme, the NIDDM program will be continuously monitored for quality control and efficiency. Currently, similar structured treatment and education programs targeted to primary health care physicians are being introduced for both insulin-treated NIDDM and arterial hypertension.

Cardiovascular disease is a major causes of morbidity and mortality in patients with non-insulin-dependent diabetes mellitus (NIDDM). With an increase in the number of older diabetic persons, an increase in U.S. minority populations with high rates of diabetes, and the proven success of new methods to reduce microvascular complications, the importance of diabetic macrovascular complications will increase. The relative effectiveness of different treatments to reduce the incidence of diabetic cardiovascular complications is poorly understood. In addition to relative efficacy, issues related to patient burden and the economic cost of different treatments must be considered. Some of the information needed to improve therapy therapy will be available soon from ongoing clinical trials. Obtaining definitive answers to other questions, especially those related to the relative benefit of intensive glucose level control compared with control of other known cardiovascular disease risk factors, will require additional studies. Although several questions unique to diabetic patients remain unanswered, results of previous clinical trials done among largely nondiabetic participants can be used to develop interim recommendations for cardiovascular disease prevention. Until definitive guidelines for prevention are established, combining aggressive therapy for known cardiovascular disease risk factors with efforts to normalize the glucose level offers the best chance to reduce the higher risk for cardiovascular disease associated with NIDDM.

Recent evidence suggests that non-insulin-dependent diabetes mellitus (NIDDM) and cardiovascular disease, rather than being related as underlying disease and complication, share common genetic and environmental antecedents, that is, they "spring from the same soil." Fetal and early-life nutritional deficiencies appear to predispose persons to both NIDDM and cardiovascular disease in later life. The insulin resistance syndrome, including abdominal obesity, may constitute the intermediate link between fetal and early-life nutritional deficiency and later disease. The insulin resistance syndrome includes insulin resistance, hyperinsulinemia, abdominal obesity, dyslipidemia with high triglyceride and low high-density lipoprotein cholesterol levels, and hypertension. Each element of the insulin resistance syndrome has been firmly established as a risk factor for development of diabetes. In addition, most of these elements are also well-recognized cardiovascular risk factors, although the weight of evidence now suggests that hyperinsulinemia itself is not. This last point is significant because of concern that aggressive insulinization of diabetic patients, which has been proved to reduce microvascular complications, might paradoxically increase the risk for large-vessel atherosclerosis. Available clinical trials suggest that this fear is unwarranted, but definitive trials are needed to resolve this important clinical question.

It is currently unknown whether intensive insulin treatment of diabetes decreases the risk for cardiovascular complications by lowering glucose levels or increases the risk by postulated direct atherogenic effects. This article reviews published data from two long-term, randomized clinical trials that compared cardiovascular outcomes associated with different exogenous insulin treatment regimens. STUDY SELECTION AND DATA SOURCES: The University Group Diabetes Program (UGDP) and the Diabetes Control and Complications Trial (DCCT) were selected as the only available randomized intervention trials with long-term follow-up results. Data reviewed were from the major publications of these two trials.