Mark S. Klempner

The Effect of Dietary Supplementation with n—3 Polyunsaturated Fatty Acids on the Synthesis of Interleukin-1 and Tumor Necrosis Factor by Mononuclear Cells

We examined whether the synthesis of interleukin-1 or tumor necrosis factor, two cytokines with potent inflammatory activities, is influenced by dietary supplementation with n-3 fatty acids. Nine healthy volunteers added 18 g of fish-oil concentrate per day to their normal Western diet for six weeks. We used a radioimmunoassay to measure interleukin-1 (IL-1 beta and IL-1 alpha) and tumor necrosis factor produced in vitro by stimulated peripheral-blood mononuclear cells. With endotoxin as a stimulus, the synthesis of IL-1 beta was suppressed from 7.4 +/- 0.9 ng per milliliter at base line to 4.2 +/- 0.5 ng per milliliter after six weeks of supplementation (43 percent decrease; P = 0.048). Ten weeks after the end of n-3 supplementation, we observed a further decrease to 2.9 +/- 0.5 ng per milliliter (61 percent decrease; P = 0.005). The production of IL-1 alpha and tumor necrosis factor responded in a similar manner. Twenty weeks after the end of supplementation, the production of IL-1 beta, IL-1 alpha, and tumor necrosis factor had returned to the presupplement level. The decreased production of interleukin-1 and tumor necrosis factor was accompanied by a decreased ratio of arachidonic acid to eicosapentaenoic acid in the membrane phospholipids of mononuclear cells. We conclude that the synthesis of IL-1 beta, IL-1 alpha, and tumor necrosis factor can be suppressed by dietary supplementation with long-chain n-3 fatty acids. The reported antiinflammatory effect of these n-3 fatty acids may be mediated in part by their inhibitory effect on the production of interleukin-1 and tumor necrosis factor.

The Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America

Evidence-based guidelines for the management of patients with Lyme disease, human granulocytic anaplasmosis (formerly known as human granulocytic ehrlichiosis), and babesiosis were prepared by an expert panel of the Infectious Diseases Society of America. These updated guidelines replace the previous treatment guidelines published in 2000 (Clin Infect Dis 2000; 31[Suppl 1]:1-14). The guidelines are intended for use by health care providers who care for patients who either have these infections or may be at risk for them. For each of these Ixodes tickborne infections, information is provided about prevention, epidemiology, clinical manifestations, diagnosis, and treatment. Tables list the doses and durations of antimicrobial therapy recommended for treatment and prevention of Lyme disease and provide a partial list of therapies to be avoided. A definition of post-Lyme disease syndrome is proposed.

An inherited abnormality of neutrophil adhesion. Its genetic transmission and its association with a missing protein.

Neutrophils from a five-year-old boy with recurrent bacterial infections failed to spread on surfaces, leading to a severe defect in chemotaxis and a mild impairment in phagocytosis. Failure to spread was also seen in a fraction of the neutrophils from the patients mother and sister, but cells from his father and brother were normal. Gel electrophoresis revealed that a protein with a molecular weight of 110,000 daltons (designated gp 110) present in the particulate fraction of normal neutrophils was absent from the patients cells, and that its levels were below normal in cells from his mother and sister but normal in neutrophils from his father and brother. These findings suggest that gp 110 is necessary for the spreading of neutrophils onto surfaces, that the functional abnormality in the patients cells is caused by its absence, and that deficiency of gp 110 is an X-linked congenital disease.

Central nervous system disease in systemic lupus erythematosus: Therapy and prognosis

The effect of corticosteroid therapy in 28 patients with 52 episodes of neuropyciatric disease in systemic lupus erythematosus (SLE) was elevated. Categories of organic central nervous system disease were seizures (eight patients), organic brain syndromes (nine patients), aseptic meningitis (four patients) and a variety of focal neurologic findings (seven patinets). Fourteen pateints had 15 episodes of functional psychosis without other evidence of neurologic disease. Although there was a general correlation between clinical and serologic evidnce of active SLE and the development of organic neurolgic disease, there was no evidence that therapy with very large doses of corticosteroids was beneficial. Of the deaths in this series, two were due to probable active SLE involving the central nervous system wheras five were attributable to complications of therapy. The long-term morbidity, likewise, was high in the patients who recieved large doses of corticosteroids. In all, 12 patients had major complications of corticosteroid therapy. Functional psychosis was usually preciptated by corticsoteroid therapy and respond to a reduction in steroid dosage and administration of psychotropic drugs.

Human leukocytic pyrogen induces release of specific granule contents from human neutrophils.

The ability of highly purified human leukocytic pyrogen (LP) to induce neutrophil lysosomal protein release is described. Human peripheral blood neutrophils isolated by Ficoll-Hypaque and dextran sedimentation were exposed to purified human LP. The specific granule-associated proteins, lysozyme and lactoferrin were selectively released, whereas primary granule (beta-glucuronidase) and cytoplasmic (lactic dehydrogenase) enzyme markers were not. Optimum release was observed after 45 min in the presence of Ca++ and Mg++. Cytochalasin B (5 microgram/ml) had no effect on LP-induced lysosomal enzyme release. Since the pyrogenicity of LP is dependent on prostaglandin synthesis, the effect of two potent inhibitors of prostaglandin synthesis on lysozyme release was studied. Both indomethacin and naproxen failed to inhibit specific granule protein release. These observations suggest that the concommitance of fever, elevated serum or urine lysozyme and hypoferremia may, in part, be explained by the interaction of LP and peripheral blood neutrophils.

An Acquired Chemotactic Defect in Neutrophils from Patients Receiving Interleukin-2 Immunotherapy

Bacterial sepsis is a frequent complication in patients with cancer who are receiving high doses of interleukin-2. We evaluated the function of neutrophils from such patients to determine whether there was any abnormality in this form of host defense. Before interleukin-2 therapy, neutrophils from 31 patients with metastatic cancer were normal in assays of random migration and chemotaxis. Superoxide production, phagocytosis, secretion of granule proteins, and bactericidal activity were also normal. Neutrophils from the patients near the end of the first course of interleukin-2 had severely impaired chemotaxis in response to a formylated peptide stimulus (mean [+/- SEM], 49.6 +/- 7.4 percent of base line; P less than 0.001). The detect in chemotaxis improved 5 to 10 days after patients completed the first course of interleukin-2 therapy but recurred toward the end of the second course of such therapy (35.3 +/- 6.9 percent of base line; P less than 0.001). The chemotactic response to a second stimulus (zymosan-activated serum) was also abnormal, but random migration, superoxide production, bactericidal activity, and the secretion of neutrophil granule constituents remained normal or increased throughout treatment with interleukin-2. We conclude that patients who receive interleukin-2 immunotherapy acquire an acute, profound, and reversible defect in neutrophil chemotaxis that may contribute to the high morbidity resulting from bacterial infections in these patients.

Chronic Granulomatous Disease Presenting in a 69-Year-Old Man

CHRONIC granulomatous disease is a rare inherited disease characterized by severe recurrent bacterial and fungal infections beginning in childhood.1 Phagocytes from patients with chronic granulomat...

Disorders of phagocyte chemotaxis.

Recent advances in understanding the physiologic and biochemical bases for recruitment of phagocytes to inflammatory sites has led to the recognition of patients who have recurrent infections because of abnormalities of phagocyte chemotaxis. In some of these patients there is abnormal chemoattractant mediator production or regulation, whereas in others there are defects in phagocytic cell function. The cellular defects in chemotaxis can be characterized as either intrinsic defects of the cellular motility apparatus or acquired defects from mediators influencing cell function or from shifts in circulating phagocyte subpopulations. Systematic study of these defects has resulted in functional, biochemical, and ultrastructural characterization of abnormal phagocyte chemotaxis in certain patients, and in some patients study has led to rational approaches for treatment. Clinical trials assessing the efficacy of such pharmacologic agents are underway.

Identification of a human neutrophil angiotension II-generating protease as cathepsin G.

A human neutrophil protease, initially termed neutral peptide-generating protease, has been shown to cleave angiotensin II directly from angiotensinogen and has been identified as leukocyte cathepsin G. When purified neutrophils were disrupted by nitrogen cavitation and fractionated by differential centrifugation, 44 and 24% of the angiotensin II-generating activity was in the lysosomal and undisrupted cell fractions, respectively. Cytochalasin B-treated human neutrophils stimulated with N-formyl-L-methionyl-L-leucyl-L-phenylalanine released beta-glucuronidase, lysozyme, and angiotensin II-generating protease in a dose-dependent fashion, consistent with localization of this protease to the neutrophil granule. Individually purified angiotensin II-generating protease and cathepsin G had similar proteolytic and esterolytic activity for angiotensinogen and N-benzoyl-L-tyrosine ethyl ester on a weight basis, exhibited identical mobilities by SDS-gradient polyacrylamide gel electrophoresis and pH 4.3 disc-gel electrophoresis, and gave precipitin lines of antigenic identity on Ouchterlony analysis with goat antibody to the angiotensin II-generating protease. Thus, the angiotensin II-generating protease of human neutrophils has been identified as cathepsin G on the basis of subcellular localization, substrate specificity, physicochemical characteristics, and antigenic identity.

Stimulation of neutrophil oxygen-dependent metabolism by human leukocytic pyrogen.

The ability of highly purified human leukocytic pyrogen (LP) to stimulate neutrophil oxygen-dependent metabolism was studied. Human peripheral blood neutrophils exposed to leukocytic pyrogen in vitro demonstrated an increase in the percentage of neutrophils reducing nitroblue tetrazolium (NBT) dye and a marked stimulation of superoxide dismutase inhibitable reduction of ferricytochrome c. LP stimulation of neutrophil oxygen-dependent metabolism was dose and time dependent. Procedures that destroyed the pyrogenicity of LP also abolished the effects on neutrophil metabolism. Neutrophil hexose monophosphate shunt activity was also stimulated by LP. In a rabbit model, the effect of in vivo LP on neutrophil superoxide generation was also studied. There was a consistent increase in the percent and absolute number of NBT positive neutrophils. Peak stimulation of neutrophil metabolism occurred after defervescence suggesting several possible mechanisms. The observations reported here may, in part, explain the nonspecificity of the NBT test in febrile, noninfected patients and provide further understanding of neutrophil physiology during acute inflammation.