The appropriate roles for several diagnostic tests for coronary disease are uncertain.

To review recent advances in the pathophysiology and potential clinical applications of leptin, an adipose tissue-derived hormone.

The autoimmune lymphoproliferative syndrome (ALPS) affords novel insights into the mechanisms that regulate lymphocyte homeostasis and underlie the development of autoimmunity. This syndrome arises early in childhood in persons who inherit mutations in genes that mediate apoptosis, or programmed cell death. The timely deletion of lymphocytes is a way to prevent their accumulation and the persistence of cells that can react against the body's own antigens. In ALPS, defective lymphocyte apoptosis permits chronic, nonmalignant adenopathy and splenomegaly; the survival of normally uncommon "double-negative" CD3+ CD4- CD8- T cells; and the development of autoimmune disease. Most cases of ALPS involve heterozygous mutations in the lymphocyte surface protein Fas that impair a major apoptotic pathway. Detailed immunologic investigations of the cellular and cytokine profiles in ALPS show a prominent skewing toward a T-helper 2 phenotype; this provides a rational explanation for the humoral autoimmunity typical of patients with ALPS. Prospective evaluations of 26 patients and their families show an ever-expanding spectrum of ALPS and its major complications: hypersplenism, autoimmune hemolytic anemia, thrombocytopenia, and neutropenia. Defective apoptosis may also contribute to a heightened risk for lymphoma.

Acute heroin overdose is a common daily experience in the urban and suburban United States and accounts for many preventable deaths. Heroin acts as a pro-drug that allows rapid and complete central nervous system absorption; this accounts for the drug's euphoric and toxic effects. The heroin overdose syndrome (sensitivity for diagnosing heroin overdose, 92%; specificity, 76%) consists of abnormal mental status, substantially decreased respiration, and miotic pupils. The response of naloxone does not improve the sensitivity of this diagnosis. Most overdoses occur at home in the company of others and are more common in the setting of other drugs. Heroin-related deaths are strongly associated with use of alcohol or other drugs. Patients with clinically significant respiratory compromise need treatment, which includes airway management and intravenous or subcutaneous naloxone. Hospital observation for several hours is necessary for recurrence of hypoventilation or other complications. About 3% to 7% of treated patients require hospital admission for pneumonia, noncardiogenic pulmonary edema, or other complications. Methadone maintenance is an effective preventive measure, and others strategies should be studied.

To review clinical data on raloxifene hydrochloride, a selective estrogen receptor modulator that was recently approved for the prevention of osteoporosis in postmenopausal women.

Biliary sludge was first described with the advent of ultrasonography in the 1970s. It is defined as a mixture of particulate matter and bile that occurs when solutes in bile precipitate. Its composition varies, but cholesterol monohydrate crystals, calcium bilirubinate, and other calcium salts are the most common components. The clinical course of biliary sludge varies, and complete resolution, a waxing and waning course, and progression to gallstones are all possible outcomes. Biliary sludge may cause complications, including biliary colic, acute pancreatitis, and acute cholecystitis. Clinical conditions and events associated with the formation of biliary sludge include rapid weight loss, pregnancy, ceftriaxone therapy, octreotide therapy, and bone marrow or solid organ transplantation. Sludge may be diagnosed on ultrasonography or bile microscopy, and the optimal diagnostic method depends on the clinical setting. This paper proposes a protocol for the microscopic diagnosis of sludge. There are no proven methods for the prevention of sludge formation, even in high-risk patients, and patients should not be routinely monitored for the development of sludge. Asymptomatic patients with sludge can be managed expectantly. If patients with sludge develop symptoms or complications, cholecystectomy should be considered as the definitive therapy. Further studies of the pathogenesis, natural history, and clinical associations of biliary sludge will be essential to our understanding of gallstones and other biliary tract abnormalities.

Coccidioidomycosis is an increasingly important health problem because of the migration of large numbers of persons to portions of the southwestern United States in which the disease is endemic and because of the increasing numbers of immunosuppressed patients. Most infections due to Coccidioides immitis, although causing significant illness, are self-limited and resolve over a period of weeks to months without specific treatment. It is not known whether antifungal treatment of early infections hastens resolution of the primary illness or prevents complications. Even so, diagnosis of early infections is of value for allaying patient anxiety, lessening the need for further diagnostic studies, decreasing empirical use of antibacterial agents, and facilitating early identification of patients with complications that are more serious. Patients who develop chronic coccidioidal pneumonia or extrapulmonary infection often have complicated courses that require the involvement of various medical, surgical, and radiologic subspecialties for management. Improvement of the ability to control the problem of coccidioidomycosis will require research into the molecular and cellular biology of C. immitis, vaccine development to prevent coccidioidal infection, a better understanding of the soil ecology that supports the fungus in its endemic regions, and discovery of new antifungal drugs. In addition, government agencies, colleges, the military, and employers could improve public health by initiating education programs about the most common manifestations of the disease among persons at risk for infection.

Alternative medicine has a major presence and persuasive attraction in the industrialized western world. The extent to which these practices have clinical efficacy according to biomedical criteria is a matter of ongoing research and debate. It may be that independent of any such efficacy, the attraction of alternative medicine is related to the power of its underlying shared beliefs and cultural assumptions. The fundamental premises are an advocacy of nature, vitalism, "science," and spirituality. These themes offer patients a participatory experience of empowerment, authenticity, and enlarged self-identity when illness threatens their sense of intactness and connection to the world. A discussion of these themes may enable conventionally trained clinicians to better understand their patients' attraction to and acceptance of alternative medical therapies.

To review the pathobiology and clinical implications of vulnerable coronary atherosclerotic plaques and to discuss the identification of vulnerable plaques and mechanisms of plaque stabilization.

This paper describes the role of venous ultrasonography in the diagnosis of suspected deep venous thrombosis and pulmonary embolism. Inability to compress the common femoral or popliteal vein is usually diagnostic of a first episode of deep venous thrombosis in symptomatic patients (positive predictive value of about 97%). Full compressibility of both of these sites excludes proximal deep venous thrombosis in symptomatic patients (negative predictive value of about 98%). In patients with suspected deep venous thrombosis or in those who present with suspected pulmonary embolism but have a nondiagnostic lung scan, the subsequent risk for symptomatic venous thromboembolism is very low (<2% during 6 months of follow-up) provided that ultrasonography of the proximal veins remains normal in the course of 1 week (suspected deep venous thrombosis) or 2 weeks (suspected pulmonary embolism). Anticoagulation and further diagnostic testing can usually be safely withheld in these situations. Venous ultrasonography is much less reliable for the diagnosis of asymptomatic, isolated distal, and recurrent deep venous thrombosis than for the diagnosis of a first episode of proximal deep venous thrombosis in symptomatic patients. Clinical evaluation of the probability of deep venous thrombosis or pulmonary embolism, preferably by using a validated clinical model, complements venous ultrasonographic findings and helps to identify patients who would benefit from additional (often invasive) diagnostic testing. Thus, venous ultrasonography is thought to be a very valuable test for the diagnosis and management of patients with suspected deep venous thrombosis or pulmonary embolism.

Internal medicine has witnessed astounding developments in our understanding of the immune system's role in the pathophysiology of many diseases. The present challenge is to harness this knowledge to develop more effective therapies for immune-related illness. Guidelines for the care of common illnesses such as asthma may encourage appropriate clinical application of advances in our armamentarium against immune disease.

As part of the Iron Overload, Public Health and Genetics conference, sponsored by the Centers for Disease Control and Prevention in March 1997, a working group was convened to consider strategies to increase early case detection of hemochromatosis. This group emphasized that the primary public health goal should be to diagnose hemochromatosis before symptoms appear. To reach this goal, education and action need to be targeted to physicians and other health care workers, laboratorians, administrators, payers, and the public. Strategies to disseminate updated information and increase early case detection were prioritized according to expected effectiveness. Strategies targeting physicians are 1) to identify national and local physician-leaders and 2) to educate physicians about hemochromatosis in basic, graduate specialty, and continuing medical education. Strategies aimed at the health system are 1) to encourage laboratories to provide the transferrin saturation test as part of routine laboratory panels and 2) to work with policymakers and payers to allow reimbursement for case detection. Finally, public education is recommended to increase lay support for the early diagnosis of hemochromatosis. Attempts to educate the public should be aimed first at persons who receive diagnoses of hemochromatosis in order to ensure that they are properly treated and then at asymptomatic persons who could be screened as part of health appraisals. Although identifying physician-leaders and educating physicians are the highest priorities, physicians should not be targeted at the exclusion of payers and the public. Simultaneous efforts to reach all groups in appropriate ways should be initiated to provide the interest and infrastructure necessary to decrease morbidity and mortality from hemochromatosis.

The recent realization that hemochromatosis is a common condition has created opportunities to develop unified public health surveillance for this disorder and its complications and to design programs to prevent unnecessary illness and death resulting from this disorder. Public health surveillance for hemochromatosis can be used to measure the magnitude of the problem (for example, to establish the number of persons with evidence of early iron overload); identify research needs; reveal the natural history of the disease; detect changes in health care practices, such as use of screening tests; and evaluate interventions, such as phlebotomy. Existing surveillance has been limited to periodic measurement of morbidity and mortality done by using hospital discharge records, health examination surveys, vital statistics, and data from small research registries. The improvement of surveillance will entail the ongoing collection of information from population-based surveys, such as the Behavioral Risk Factor Surveillance System; the collection of data on provider practices (for example, through the National Ambulatory Medical Care Survey); and the establishment of population-based registries. Creating population-based registries requires consensus on case definitions; strategies to encourage case ascertainment and reporting; policies and procedures for protecting privacy and ensuring confidentiality; and partnerships among providers, researchers, and public health officials. Longitudinal data from population-based registries will provide insight into determinants of disease expression, such as pattern or degree of iron overload. This information is critical for developing evidence-based recommendations for population screening, monitoring changes in medical practices, and assessing the effect of preventive measures.

Population screening for hemochromatosis done by using the transferrin saturation test has been advocated by experts to permit the initiation of therapeutic phlebotomy before the onset of clinical disease. The discovery of a gene associated with hemochromatosis has made DNA testing another option for screening and diagnosis. In this paper, U.S. Preventive Services Task Force criteria are used to evaluate the evidence for the usefulness of population screening done by using iron measures or genetic testing. Published clinical research offers little evidence to suggest that population screening for hemochromatosis done by using genetic testing improves clinical outcomes. Although one recently discovered mutation, C282Y, accounts for 60% to 92% of cases of the disease in series of patients with hemochromatosis, uncertainties remain about the clinical penetrance of various genotypes; the accuracy of genetic testing; and the ethical, legal, and social effects of genetic testing. Before population screening for hemochromatosis done by using transferrin saturation testing can be recommended, laboratory standardization needs to be addressed and questions about risk for clinical disease in asymptomatic persons with mutations or early biochemical expression of disease require resolution. Evidence from case series suggests that hemochromatosis may be associated with liver cancer, other liver disease, diabetes, bradyarrhythmias, and arthritis. In all studies but one, however, estimation of the magnitude and significance of this risk is limited by lack of adequate comparison groups. The need for population data to answer questions about penetrance among asymptomatic persons should not impede efforts to increase the detection and treatment of hemochromatosis in persons found to have elevated iron measures a family history of hemochromatosis, or consistent early signs and symptoms of the disease.

Interest in including screening for hemochromatosis in the routine medical care of adults has grown in recent years. In March 1997, at a meeting on iron overload at the Centers for Disease Control and Prevention, the directors of four hemochromatosis screening programs described the major challenges that they faced and the lessons that they learned in implementing their programs. Seven issues were consistently described as important challenges: 1) changes in case definitions of hemochromatosis, 2) selection of screening threshold values and identification of false-positive cases, 3) variability and lack of standardization in screening test measurements, 4) physician education, 5) informed consent and concerns about medical and genetic discrimination, 6) patient compliance with screening and therapy, and 7) incidental detection of iron deficiency. The two programs that have been completed report a prevalence of iron overload from hemochromatosis of 4.2 to 4.5 per 1000 persons screened; this is consistent with findings in the recent literature. All programs report that screening is feasible and propose that hemochromatosis be defined by repeated elevated serum transferrin saturation values(with or without DNA test results) rather than by the clinical outcome of excessive iron in tissue. The goal of screening programs is to diagnose iron status disorders, particularly hemochromatosis, before they lead to iron overload and chronic disease states. Further research is needed on the ability of genetic and phenotypic tests to predict the clinical expression of hemochromatosis. The experiences outlined in this report highlight practical issues that need to be addressed when iron status screening for hemochromatosis is implemented. It is hoped that this information will facilitate similar efforts in other health care settings.

The complications of iron overload in hemochromatosis can be avoided by early diagnosis and appropriate management. Therapeutic phlebotomy is used to remove excess iron and maintain low normal body iron stores, and it should be initiated in men with serum ferritin levels of 300 microg/L or more and in women with serum ferritin levels of 200 microg/L or more, regardless of the presence or absence of symptoms. Typically, therapeutic phlebotomy consists of 1) removal of 1 unit (450 to 500 mL) of blood weekly until the serum ferritin level is 10 to 20 microg/L and 2) maintenance of the serum ferritin level at 50 microg/L or less thereafter by periodic removal of blood. Hyperferritinemia attributable to iron overload is resolved by therapeutic phlebotomy. When applied before iron overload becomes severe, this treatment also prevents complications of iron overload, including hepatic cirrhosis, primary liver cancer, diabetes mellitus, hypogonadotrophic hypogonadism, joint disease, and cardiomyopathy. In patients with established iron overload disease, weakness, fatigue, increased hepatic enzyme concentrations, right upper quadrant pain, and hyperpigmentation are often substantially alleviated by therapeutic phlebotomy. Patients with liver disease, joint disease, diabetes mellitus and other endocrinopathic abnormalities, and cardiac abnormalities often require additional, specific management. Dietary management of hemochromatosis includes avoidance of medicinal iron, mineral supplements, excess vitamin C, and uncooked seafoods. This can reduce the rate of iron reaccumulation; reduce retention of nonferrous metals; and help reduce complications of liver disease, diabetes mellitus, and Vibrio infection. This comprehensive approach to the management of hemochromatosis can decrease the frequency and severity of iron overload, improve quality of life, and increase longevity.

If untreated, hemochromatosis can cause serious illness and early death, but the disease is still substantially under-diagnosed. The cornerstone of screening and case detection is the measurement of serum transferrin saturation and the serum ferritin level. Once the diagnosis is suspected, physicians must use serum ferritin levels and hepatic iron stores on liver biopsy specimens to assess patients for the presence of iron overload. Liver biopsy is also used to establish the presence or absence of cirrhosis, which can affect prognosis and management. A DNA-based test for the HFE gene is commercially available, but its place in the diagnosis of hemochromatosis is still being evaluated. Currently, the most useful role for this test is in the detection of hemochromatosis in the family members of patients with a proven case of the disease. It is crucial to diagnose hemochromatosis before hepatic cirrhosis develops because phlebotomy therapy can avert serious chronic disease and can even lead to normal life expectancy.