Search PubMed⌕ Search

Biomedical subjects

P F Weller

Publications and source records attributed to P F Weller.

At least 19 recordsLinked to original sources
PubMed2003

RNA is closely associated with human mast cell lipid bodies.

Both novel and multiple ultrastructural studies based on different principles show relationships of cytoplasmic lipid bodies and ribonucleic acid (RNA) of potential importance to RNA metabolism in human mast cells. The methods include general ultrastructural morphological observations, imaging of RNA with an EDTA regressive stain, imaging of the incorporation of radio labeled uridine by ultrastructural autoradiography, postembedding immunogold labeling of uridine, ribosomes and small nuclear ribonuclear proteins and ultrastructural in situ hybridization detection of poly(A)-positive messenger RNA. Altogether these studies implicate human mast cell lipid bodies in RNA metabolism and are analogous to earlier similar studies which showed that human mast cell granules also curtain RNA.

Edetic Acid↗
PubMed2002

NS-398: cyclooxygenase-2 independent inhibition of leukocyte priming for lipid body formation and enhanced leukotriene generation.

Because the induction of new lipid body formation in leukocytes correlates with and likely contributes to their enhanced 'primed' prostaglandin and leukotriene formation, we evaluated two selective cyclooxygenase (COX)-2 inhibitors. Three types of stimuli, cis -unsaturated fatty acids, platelet activating factor and protein kinase C activators, stimulate lipid body formation. NS-398 (0.1-10 microM), but not another COX-2 inhibitor, SC58125 (0.1- 10 microM), blocked leukocyte lipid body formation elicited by all three types of stimuli and also blocked priming for enhanced LTB(4) production and PGE(2) production. The effect of NS-398 on lipid body formation was independent of its inhibitory effects on COX-2 since arachidonate-induced lipid body formation in COX-2-deficient mouse leukocytes was also inhibited by NS-398. By means of its ability to inhibit leukocyte lipid body formation, NS-398 may exert actions independent of its COX-2 inhibition and more broadly contribute to the suppression of formation of COX-1 and lipoxygenase-derived eicosanoids.

Animals↗
PubMed2001

Travel vaccines and elderly persons: review of vaccines available in the United States.

Aging is associated with alterations in immune responses and may lead to clinically significant changes in the safety, immunogenicity, and protective efficacy of certain vaccines. This review summarizes published data regarding the effects of age on responses after immunization with vaccines generally administered before travel. The specific vaccines discussed in detail include hepatitis A, typhoid, yellow fever, Japanese encephalitis, and rabies vaccines. There is some evidence of diminished serological responses to hepatitis A and rabies vaccines in older individuals. In addition, increased toxic effects following yellow fever vaccination in elderly recipients have recently been reported. However, many travel-related vaccines have never been studied specifically in elderly populations. Consideration of potential age-related differences in responses to travel vaccines is becoming increasingly important as elderly persons more frequently venture to exotic destinations.

Aged↗
PubMed2001

Imported Fasciola hepatica infection in the United States and treatment with triclabendazole.

Infection with Fasciola hepatica, a liver trematode, is not frequently reported in the United States. We describe 2 patients, both originally from Cape Verde, who illustrate the spectrum of clinical presentations of F. hepatica as well as the means of treating infection with this parasite. Patient 1 had extensive disease and underwent multiple diagnostic procedures before the correct diagnosis was reached. Patient 2, who had few symptoms, had fascioliasis diagnosed by a noninvasive evaluation. Both patients were treated with triclabendazole without experiencing significant side effects. Fascioliasis that has been imported to the United States may elude prompt or accurate diagnosis. Obtaining a detailed travel history and recognizing the clinical presentation early in the course of infection may permit timely and noninvasive identification of infection. Triclabendazole is now the recommended drug for treating for fascioliasis because of its efficacy, safety, and ease of use.

Adult↗
PubMed2001

Cutting edge: eotaxin elicits rapid vesicular transport-mediated release of preformed IL-4 from human eosinophils.

IL-4 release is important in promoting Th2-mediated allergic and parasitic immune responses. Although human eosinophils are potential sources of IL-4, physiologic mechanisms to elicit its release have not been established. By flow cytometry and microscopy, eosinophils from normal donors uniformly contained preformed IL-4. In contrast to cytolytic IL-4 release from calcium ionophore-activated eosinophils, eotaxin and RANTES, but not IFN-gamma, elicited IL-4 release by noncytotoxic mechanisms. With a dual Ab capture and detection immunofluorescent microscopic assay, IL-4 was released at discrete cell surface sites. IL-5 enhanced eotaxin-induced IL-4 release, which was mediated by G protein-coupled CCR3 receptors, detectable as early as 5 min and maximum within 1 h. IL-4 release was not diminished by transcription or protein synthesis inhibitors, but was suppressed by brefeldin A, an inhibitor of vesicle formation. Thus, CCR3-mediated signaling can rapidly mobilize IL-4 stored preformed in human eosinophils for release by vesicular transport to contribute to immune responses.

Chemokine CCL11↗
PubMed2001

Extranuclear lipid bodies, elicited by CCR3-mediated signaling pathways, are the sites of chemokine-enhanced leukotriene C4 production in eosinophils and basophils.

Eosinophils and basophils, when activated, become major sources of cysteinyl leukotrienes, eicosanoid mediators pertinent to allergic inflammation. We show that the C-C chemokines, eotaxin and RANTES (regulated upon activation normal T cell expressed and secreted), activate eosinophils and basophils for enhanced leukotriene C(4) (LTC(4)) generation by distinct signaling and compartmentalization mechanisms involving the induced formation of new cytoplasmic lipid body organelles. Chemokine-induced lipid body formation and enhanced LTC(4) release were both mediated by CCR3 receptor G protein-linked downstream signaling involving activation of phosphoinositide 3-kinase, extracellular signal-regulated kinases 1 and 2, and p38 mitogen-activated protein kinases. Chemokine-elicited lipid body numbers correlated with increased calcium ionophore-stimulated LTC(4) production; and as demonstrated by intracellular immunofluorescent localization of newly formed eicosanoid, lipid bodies were the predominant sites of LTC(4) synthesis in both chemokine-stimulated eosinophils and chemokine-primed and ionophore-activated eosinophils. Eotaxin and RANTES initiated signaling via phosphoinositide 3-kinase and mitogen-activated protein kinases both elicits the formation of lipid body domains and promotes LTC(4) formation at these specific extranuclear sites.

Basophils↗
PubMed2001

Ultrastructural immunolocalization of basic fibroblast growth factor to lipid bodies and secretory granules in human mast cells.

Isolated human lung mast cells were used to identify subcellular sites of basic fibroblast growth factor using a postembedding immunogold method. The factor was present in quantity in secretory granules and cytoplasmic lipid bodies. Cisterns of smooth endoplasmic reticulum and ribosome clusters, closely associated with lipid bodies, contained the factor as did the nuclear matrix. Factor-positive lipid bodies were adjacent to nuclear pores and often indented perinuclear cisternae. Altered secretory granules with reduced density, characteristic of secretion by piecemeal degranulation in mast cells, showed reduced gold label for basic fibroblast growth factor; small, electron-lucent (80-100 nm) transport vesicles near altered granules were labelled for the factor. Since these mature mast cells do not display extensive arrays of classical secretory organelles, such as rough endoplasmic reticulum and Golgi structures, these new subcellular localizations for basic fibroblast growth factor suggest several possible alternative release routes for a cytokine devoid of a signal sequence characteristic of regulated secretory proteins.

Fibroblast Growth Factor 2↗
PubMed2001

The relationship of asthma therapy and Churg-Strauss syndrome: NIH workshop summary report.

The Churg-Strauss syndrome (CSS) is a distinct form of vasculitis that is notable for its eosinophilia and frequent associations with asthma and sinusitis. Because there has been an increasing recognition that CSS can develop in patients with asthma and that CSS might be associated with specific asthma treatments, the National Heart, Lung, and Blood Institute, the National Institute of Allergy and Infectious Diseases, the Office of Rare Diseases, National Institutes of Health, and the US Food and Drug Administration jointly sponsored a workshop to consider interrelationships among CSS, asthma, and asthma therapeutics and to assess what is known about underlying mechanisms of CSS. Issues related to the criteria for defining and diagnosing CSS were reviewed, including the contemporary understanding that diagnostic biopsies need only reveal eosinophilic perivascular infiltrates and that asthma need not be present when CSS develops. From published reports and reports to the US Food and Drug Administration, treatment of patients with asthma with any of 3 cysteinyl leukotriene receptor antagonists, a 5-lipoxygenase inhibitor, and inhaled corticosteroids has been associated with CSS development. It is unknown whether these agents were eliciting CSS. A variety of physiologic and study design issues might lead to the reported associations of these drugs with CSS. Because many asthma patients receiving these therapies were able to diminish their systemic corticosteroid therapy, it is possible that incipient CSS was unmasked by lessened steroid use. The underlying pathophysiologic mechanisms of CSS, however, are unknown, and there is no means of identifying which patients with asthma might be at risk for CSS. Accordingly, investigations with the goals of defining the underlying pathophysiologic processes of CSS and establishing the relationships of asthma and its therapies to CSS are needed.

Adrenal Cortex Hormones↗
PubMed2001

A report from the International Eosinophil Society: eosinophils in a tug of war.

The International Eosinophil Symposium in Banff was a timely gathering of leading experts to discuss the precise role of eosinophils in allergic asthma. The meeting followed hard on the heels of a report suggesting that eosinophils might be redundant in late-phase responses in asthma, inasmuch as treatment of asthmatic patients with humanized anti-IL-5 in clinical trials failed to modify bronchial hyperresponsiveness. Mouse models of allergic asthma were also cited for failing to show a consistent proinflammatory role for the eosinophil in asthma. Presentations at this meeting included a reevaluation of murine models of asthma, which exhibit substantial differences from human disease. The inability of murine eosinophils to degranulate either in vivo or in vitro was shown to present a major obstacle in asthma research; this is in sharp contrast to human eosinophils, which readily degranulate in response to stimuli. Degranulation from eosinophils was proposed to be a crucial event in human airway hyperresponsiveness. Major advances were presented in the understanding of molecular and intracellular pathways regulating eosinophil priming, activation, and mediator secretion. Recruitment and activation of eosinophils might be regulated by other immunoregulatory agents as well as IL-5, including eotaxin. Future clinical trials might benefit from focusing on dual inhibition of IL-5 and eotaxin to ensure the removal of the effects of activated eosinophils from the body.

Animals↗
PubMed2001

Induction of endothelial cell cytoplasmic lipid bodies during hypoxia.

Lipid bodies (LBs), lipid-rich cytoplasmic inclusions found in many cell types, seem to act as nonmembrane sites of eicosanoid formation. Because alterations in eicosanoid products have been demonstrated in endothelial cells (ECs) during hypoxia, we investigated induction of LBs in systemic and pulmonary ECs exposed to acute and/or chronic hypoxia. LBs in ECs were O(2)-concentration dependent, increasing approximately fivefold during acute exposure to 0% O(2) in both cell types. During chronic exposure to 3% O(2), LBs were induced only in systemic ECs. LBs were not induced by other cellular stresses (heat shock or glucose deprivation). Subsequent studies suggested that protein kinase C-dependent and tyrosine kinase-dependent pathways are important in LB induction during hypoxia. PGH synthase was demonstrated in LBs in every case in which they were induced. These are the initial studies to demonstrate induction of LBs in ECs and to demonstrate LB induction during exposure to hypoxia in any cell type. These results imply that in ECs, LBs are structurally distinct inducible sites for synthesis of eicosanoid mediators.

Animals↗
PubMed2001

Worm burden and host responsiveness in Wuchereria bancrofti infection: use of antigen detection to refine earlier assessments from the South Pacific.

A population from the Wuchereria bancrofti-endemic island of Mauke was reevaluated retrospectively by use of the Og4C3 circulating antigen (CAg) enzyme-linked immunosorbent assay to assess active infection in relation to host responses by age and gender. Use of microfilaremia (Mf) alone misclassified approximately 50% of infected people, although CAg and Mf levels were positively correlated. Levels of CAg peaked between those aged 31-60 years; men aged > 60 years had a significantly higher CAg prevalence (> 90%) than women. Filaria-specific immunoglobulin (Ig) G4 reached maximum levels in both genders at age 51-60 years. By analysis of variance, both age and gender significantly influenced CAg and IgG4, with men having higher levels of both in the total population. Individuals positive for CAg had significantly lower lymphocyte proliferation responses to parasite antigen than did CAg-negative people, regardless of clinical status. This study reemphasizes the importance of CAg measurements for accurately assessing filarial prevalence and clinical status and demonstrates the relationship between active infection and immune responsiveness.

Adolescent↗
PubMed2000

Benefits of negative penicillin skin test results persist during subsequent hospital admissions.

For an initial series of 38 patients with negative skin test results, we reviewed retrospectively all subsequent admissions over a 2-year period. For 38 patients with negative initial skin test results, there were 48 subsequent readmissions to our institution, of which 35 required antibiotics. beta-lactams were prescribed for 86% of admissions; a penicillin for 37%, and a cephalosporin for 51%. All infections were cured, and there were no allergic drug reactions during any of the admissions that were reviewed.

Anti-Bacterial Agents↗
PubMed2000

EliCell: a gel-phase dual antibody capture and detection assay to measure cytokine release from eosinophils.

Eosinophils contain many preformed cytokines and chemokines, which are stored in specific granules along with cationic granule proteins. Mobilization and release of these granule contents can be selective and mediated by vesicular transport. We have developed a sensitive method to detect and quantitate eosinophil vesicular transport-mediated release of specific eosinophil proteins. Our EliCell assay is based on microscopic observations of individual viable eosinophils embedded in an agarose matrix that contains immobilized antibody to the protein of interest. Following stimulation of eosinophils, released protein is bound by the capture antibody at its site of release and is detected by a fluorochrome-conjugated detection antibody. We have validated this assay by evaluating interferon-gamma-induced release of RANTES from eosinophils. Extracellularly released RANTES was visualized as focal immunoflourescent staining and was quantitated by scoring the numbers of eosinophils releasing RANTES and by measuring the fluorescent intensity over individual eosinophils. In comparison with ELISA assays of RANTES released into supernatant fluids by interferon-gamma-stimulated eosinophils, EliCell assays were more sensitive enabling detection of RANTES release at earlier times and at lower levels of interferon-gamma stimulation. The EliCell assay provides a sensitive method to study the regulated release of eosinophil-derived cytokines, chemokines and other granule proteins.

Antibodies↗
PubMed2000

Phosphatidylinositide 3-kinase localizes to cytoplasmic lipid bodies in human polymorphonuclear leukocytes and other myeloid-derived cells.

Phosphatidylinositide 3-kinase (PI3K) is a key enzyme implicated in intracellular signaling of diverse cellular responses including receptor-mediated responses and neutrophil activation. Several PI3K subunits have been cloned and shown to be localized to plasma membrane receptors, the cytosol, or intracellular vesicles or caveolae. We report the localization of PI3K to a distinct intracellular site, cytoplasmic lipid bodies, in leukocytes. In U937 monocyte cells, PI3K p85 regulatory and p110beta catalytic subunits were localized to lipid bodies by immunocytochemistry and/or immunoblotting and enzyme assays of subcellular fractions. In RAW murine macrophages, p55, p85alpha, and p85beta PI3K subunits were present at isolated lipid bodies. PI3K p85 was also shown to colocalize and, by co-immunoprecipitation, to be physically associated with phosphorylated Lyn kinase in lipid bodies induced to form in human polymorphonuclear leukocytes. These findings, therefore, indicate a novel site for PI3K compartmentalization and suggest that PI3K-mediated signaling is active within cytoplasmic lipid bodies in leukocytes.

Animals↗
PubMed2000

Eosinophilia and helminthic infections.

Among microbial agents, helminths are the most common cause of eosinophilia. An approach to the evaluation of a patient with eosinophilia is outlined, with particular emphasis on clues in the history, examination and routine laboratory data that can help with the diagnosis. Multiple helminthic infections have been associated with eosinophilia, and the characteristic modes of spread, clinical manifestations, diagnostic tests and therapeutic considerations of these infections are discussed.

Animals↗
PubMed2000

Lymph node trafficking and antigen presentation by endobronchial eosinophils.

Because eosinophils recruited into the airways in allergic diseases are exposed to inhaled allergens, we evaluated whether eosinophils within the endobronchial lumen can function in vivo as antigen-presenting cells for inhaled antigens. We recovered eosinophils from the airways after aerosol antigen challenge in sensitized mice or from the peritoneal cavities of IL-5 transgenic mice and fluorescently labeled these cells ex vivo. These labeled cells, instilled intratracheally into normal mice, migrated into draining paratracheal lymph nodes and localized to T cell-rich paracortical areas. The homing of airway eosinophils to lymph nodes was not governed by eotaxin, because CCR3(-/-) and CCR3(+/+) eosinophils migrated identically. Airway eosinophils, recovered after inhalational antigen challenge in sensitized mice, expressed MHC class II and costimulatory CD80 and CD86 proteins and functioned in vitro as CD80- and CD86-dependent, antigen-specific, antigen-presenting cells. Moreover, when instilled into the airways of antigen-sensitized recipient mice, airway eosinophils recovered after inhalational antigen challenge stimulated antigen-specific CD4(+) T cell proliferation within paratracheal lymph nodes. Thus, eosinophils within the lumina of airways can process inhaled antigens, traffic to regional lymph nodes, and function in vivo as antigen-presenting cells to stimulate responses of CD4(+) T cells.

Animals↗