Neutrophils, the predominant phagocytes of circulating blood, are the first cells to arrive at sites of infection. Although neutropenia has long been recognized to predispose to infection, recently other syndromes marked by frequent infections have been shown to be caused by an underlying neutrophil dysfunction. Efforts to define the molecular pathology of such disorders have helped delineate the molecular basis of normal neutrophil function. Advances have been made in defining the roles of the neutrophil's varied receptors in recognition, movement, and adhesive phenomena. Progress in establishing the pathogenesis of chronic granulomatous disease has provided important insights into the enzymatic machinery that normal neutrophils use to produce antimicrobial oxidants. The identification and precise characterization of antimicrobial components, such as defensins, have outlined the potential roles of "natural antibiotics" in neutrophil-mediated host-defense functions. These areas of neutrophil function will be reviewed and placed in a clinical context to guide physicians in evaluating children and adults with frequent or unusual infections.

During the last 2 years, the use of pulsed Doppler echocardiography for assessing left ventricular diastolic function has received increased attention. This method is based on measurements derived from a waveform that reflects the velocity of blood flow through the mitral valve during ventricular filling. The technique is particularly attractive because it is noninvasive and relatively simple. Technically satisfactory recordings can be obtained in most patients. In a relatively short period, numerous studies using the Doppler technique to assess diastolic function in children and adults with cardiac disease have been published. This review appraises the current status of applications of Doppler echocardiography and critically examines the strengths, limitations, and ultimate potentials of this new method.

In patients with end-stage renal disease, nervous system dysfunction remains a major cause of disability. Patients with chronic renal failure who have not yet received dialysis may have symptoms ranging from mild sensorial clouding to delirium and coma. Dialysis itself is associated with at least three distinct disorders of the central nervous system, including the dialysis disequilibrium syndrome, dialysis dementia, and progressive intellectual dysfunction. Peripheral neuropathy is also a major cause of disability in uremic patients. Aluminum probably contributes to the pathogenesis of dialysis dementia. Parathyroid hormone, the levels of which are elevated in patients with renal failure, also may be a uremic neurotoxin. Biochemically, brain calcium levels are elevated in renal failure, possibly because of the action of parathyroid hormone. Studies on synaptosomes have also shown that parathyroid hormone can affect calcium transport in the brain. Intellectual dysfunction, dialysis dementia, uremic neuropathy, and the dialysis disequilibrium syndrome can be diagnosed when the characteristic clinical findings are present and other causes of nervous system dysfunction have been excluded.

There are no uniform diagnostic criteria for congestive heart failure. To determine the pattern of diagnostic criteria used, reports of 51 randomized, double-blind, placebo-controlled, clinical drug trials published between 1977 and 1985 were reviewed. Only 23 (45%) of the trials specified objective diagnostic criteria beyond treatment history, clinical diagnosis, or functional class. Of these, there were two trials each for digoxin, hydralazine, amrinone, and metoprolol; for each pair, only one study showed therapy beneficial. Of the amrinone pair, the positive study required a lower ejection fraction (less than 30% compared with less than 45%) and selected patients with more clinical severity. Conversely, for metoprolol, the positive study specified a higher ejection fraction (less than 49% compared with less than 35%) and selected patients with clinically milder disease, suggesting that conflicting results may relate to differences in study population. Many studies of congestive heart failure are done without explicit diagnostic criteria. Criteria lack uniformity, and such discrepancies may explain conflicting results.

Clinicopathologic features of Alzheimer disease, the commonest cause of presenile or senile dementia, are presented. Several of the microscopic brain lesions found in patients with this dementia share the staining properties of amyloid and at least two of these lesions (senile plaque cores and amyloid angiopathy) are biochemically identical. Theories pertinent to the origins of brain amyloid and its role in the pathogenesis of Alzheimer disease are discussed in relation to theories of the cause of this dementia. Possible treatments for Alzheimer disease developed from our knowledge of brain amyloid processing and biochemistry are considered.

With the increasing recognition of relatively mild hypertension, asymptomatic patients are being started on life-long therapy with antihypertensive agents. Before the diagnosis is made or therapy instituted, elevated blood pressure must be verified. To provide maximal protection against premature cardiovascular disease and coronary disease, various non-drug therapies should be used that lower both blood pressure and other risk factors. Drugs should be chosen to provide maximal efficacy, long-term safety, and multifaceted convenience, providing the greatest protection with the least interference with quality of life. These goals can be best achieved by substituting commonly used drugs such as diuretics, central agonists, and beta-blockers with vasodilators, such as alpha-blockers, angiotensin-converting enzyme inhibitors, and calcium blockers.

Dyspepsia, defined as chronic or recurrent upper abdominal pain or nausea, is a common occurrence. Dyspepsia without an ulcer (non-ulcer dyspepsia) is diagnosed in patients at least twice as often as peptic ulceration. Diseases that may present with similar symptoms include gastroesophageal reflux, biliary tract disease, chronic pancreatitis, and irritable bowel syndrome. A careful history and physical examination, supplemented by selected tests, usually lead to a correct diagnosis. The pathogenesis of non-ulcer dyspepsia remains unknown. Gastric acid secretion, duodenogastric reflux, psychological factors, environmental exposures, and heredity probably do not play a major role. Some patients may have motility disturbances, but whether these disturbances cause dyspepsia is unknown. Campylobacter pylori infection and associated gastritis are common in non-ulcer dyspepsia, but their etiologic role is controversial, as is the importance of chronic duodenitis. By recognizing the heterogeneity of patients who present with non-ulcer dyspepsia, more rational management may be possible. Although an empiric trial of antacids or H2 blockers has been recommended to treat dyspepsia, most controlled trials show that although these substances reduce severity of symptoms, they are no more effective than placebos in non-ulcer dyspepsia.

Experimental studies in animals have shown that therapy with high-dose interleukin-2 either alone or in combination with lymphokine-activated killer cells can reduce established pulmonary and hepatic metastases. Based on these experiments, recent clinical trials have shown that therapy with high-dose interleukin-2 alone or in combination with lymphokine-activated killer cells can mediate the regression of established metastatic disease in selected patients with advanced malignancy. Of 221 patients with advanced cancer treated with this immunotherapy, 16 have had a complete regression of all metastatic cancer, and an additional 26 have had a partial regression (greater than 50% reduction) of cancer. Toxicity from treatment was primarily due to increased capillary permeability, which led to fluid extravasation and organ dysfunction. Based on these findings, new approaches are being explored, including the use of tumor-infiltrating lymphocytes and combinations of lymphokines. These studies show that the regression of established growing cancer can be mediated by manipulating the immune system.

Travel to the developing world by U.S. citizens has been increasing. Exposure to illnesses such as travelers' diarrhea, malaria, and vaccine-preventable diseases challenges the internist to provide pre-travel advice. Each traveler's itinerary, duration of stay and medical history, including previous immunizations, should be reviewed. Immunizations that may be required by individual countries, such as yellow fever and cholera, may then be administered. Immunizations for diseases such as hepatitis, typhoid fever, and meningococcal disease can be given according to the type of exposure within each country. Restricting a traveler's diet to cooked foods and purified, carbonated, or heated beverages may prevent travelers' diarrhea and other enteric infections. Most travelers will want to carry medications to treat diarrhea promptly. Malaria is prevented by avoiding mosquitos, taking safe and appropriate anti-malarials and treating malaria if it occurs. Preparation before travel may prevent medical complications.

A new antimetabolite, 2'-deoxycoformycin (pentostatin), has striking antitumor activity in several lymphoid neoplasms. Isolated from cultured soil organisms, this purine analogue is a potent inhibitor of adenosine deaminase (ADA), and is thus selectively toxic to lymphocytes. Early clinical trials showed that high doses of pentostatin caused severe and unpredictable toxicity, but responses in refractory lymphoid malignancies were encouraging. Careful pharmacologic studies led to the definition of a safe and effective low weekly dose, at which protracted ADA inhibition occurs in neoplastic cells. The most sensitive tumor identified is hairy cell leukemia, in which durable remissions are achieved in more than 90% of patients with a relatively brief course of treatment. Other responsive diseases include chronic lymphocytic leukemia, prolymphocytic leukemia, mycosis fungoides, and acute T-cell lymphoma or leukemia. Response has been seen in acute lymphocytic leukemia, but the higher doses required are substantially more toxic. Pentostatin is valuable for treatment of indolent lymphoid malignancies and may be useful in non-cancer-related lymphocyte research.

The rapid growth of the elderly population has increased the need for improved geriatric care and prevention of disability. For example, the prevalence and severity of osteoporosis can be reduced significantly by the use of estrogen, with or without added progestin, in postmenopausal women. A common and devastating problem of frail elderly persons is urinary incontinence, most cases of which can be classified without referral for urologic services. Appropriate treatment can improve nearly half of all cases of persistent incontinence. Comprehensive geriatric assessment is effective in guiding the treatment of frail elderly patients and leads to significantly improved outcomes under appropriate conditions. The advent of the teaching nursing home has shed light on the medical problems of elderly residents of nursing homes, including malnutrition, dysregulation of water and electrolyte balance, falling, cognitive and affective illnesses, behavior disturbances, infections, and pathogenic drug use. The future application of advanced technology may revolutionize nursing home care.

The lack of a widely available diagnostic test for genital infections with Chlamydia trachomatis, coupled with their often nonspecific clinical nature, have been important factors contributing to the increasing incidence of these infections. Recent studies have more clearly defined the clinical manifestations of C. trachomatis infections, especially mucopurulent cervicitis and pelvic inflammatory disease. In addition, methods for the direct detection of chlamydial antigen in genital secretions have been developed. Although less sensitive than traditional cultural methods, these noncultural methods are more widely available than cultures and can facilitate the earlier recognition and more specific diagnosis of chlamydial genital infections. This article reviews these recent developments and outlines specific applications of tests for diagnostic purposes and for screening of high-risk populations.

Angioimmunoblastic lymphadenopathy with dysproteinemia is a disorder characterized by a sudden onset of constitutional symptoms and lymphadenopathy. Patients often have hypergammaglobulinemia, autoantibodies, rashes, thrombocytopenia, or hemolytic anemia. Diagnosis requires a lymph node biopsy that shows architectural effacement, absence of germinal centers, arborization of postcapillary venules, and a polymorphous infiltrate that includes immunoblasts. Early in the disease, activated T cells in blood and lymph nodes stimulate B cells to proliferate and produce antibody. However, late in the disease, immune suppression may result from increased suppressor function. Clonal rearrangements, which are seen in all patients with regard to either the T-cell receptor beta-chain gene or immunoglobulin genes, have been followed by malignant transformation and frank lymphoma in some patients. Thus, this disorder stands partway between benign lymphoid proliferation and clonal lymphoid transformation. The prognosis of this disorder is poor; 75% of patients die within 2 years or develop a lymphoid malignancy. The rest usually go into a sustained remission. Current treatment with corticosteroid and immunosuppressive agents is unsatisfactory, especially because of late immunosuppression and predisposition to infections.

The response of human breast cancer to drugs and radiation is dose-dependent, with higher doses producing increased response rates. However, dose escalation of several agents active against breast cancer is limited by bone marrow toxicity. This limitation can be overcome in some instances by transplantation of bone marrow cells. We evaluated 27 trials of bone marrow autotransplants in 172 patients who received single or multiple drug chemotherapy, radiation, or both. The overall response rate was 58%. Response rates were highest in trials involving multiple alkylating agents (76%) or previously untreated patients (81%). These data suggest that high-dose therapy and bone marrow autotransplants can produce remissions in patients with advanced breast cancer unresponsive to conventional therapy. A critical evaluation of this approach will require controlled trials in high-risk persons.