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Biomedical subjects

G L Mandell

Publications and source records attributed to G L Mandell.

At least 19 recordsLinked to original sources
PubMed1998

Fellowship training in infectious diseases: a report from the regional and national meetings of infectious diseases division chiefs and program directors.

During the 2-year period April 1995 to April 1997, six regional meetings and one national meeting of division chiefs and program directors of adult infectious diseases programs in the United States were held to review fellowship training. Herein, we report data on job availability and job selection for recently graduated fellows. We summarize discussions on decreasing the number of fellows in training, and we outline suggested components of a core clinical curriculum and of three training tracks--clinician track, clinical investigator track, and basic investigator track.

Adult↗
PubMed1997

The new antibiotics, 1997.

Some of the antimicrobial agents released in the past few years possess characteristics suggesting real advantages over older agents (see Table I). These advantages include broader spectrum of activity, favorable pharmacokinetic profile allowing for infrequent dosing, low toxicity and lower pricing. Although older agents and agents with narrower spectra should be considered first-line in most circumstances, there may be some clinical scenarios in which these newer agents should be contemplated as reasonable alternatives.

Anti-Bacterial Agents↗
PubMed1996

The role of molecular techniques in the understanding of emerging infections.

Emerging infections are defined as infections that are newly identified or recognized, or those whose incidence in humans has significantly increased over the past 20 years. The interaction of several factors contributes to the emergence of infectious disease, including changes in human behavior, technological advances, economic development, increased international travel, microbial adaptation and lapses in public health measures. Biomedical research has allowed us to identify and classify previously uncultured pathogens, characterize microbial virulence factors, create new diagnostic tests and develop vaccines. Here, we highlight a few emerging infections and illustrate the role that molecular medicine has played in furthering our understanding of these diseases.

Bartonella Infections↗
PubMed1996

Interaction of tumor necrosis factor-alpha and granulocyte colony-stimulating factor on neutrophil apoptosis, receptor expression, and bactericidal function.

Infected patients are likely to have increased levels of tumor necrosis factor-alpha (TNF-alpha) and may be treated with recombinant human granulocyte colony-stimulating factor (G-CSF). Recombinant human TNF-alpha activates polymorphonuclear neutrophil (PMN) inflammatory activity. We examined the effect of exposure to TNF-alpha and G-CSF alone and in combination on PMN apoptosis, receptor expression, phagocytosis, and bactericidal function. The results were compared to those obtained with a promoter of PMN apoptosis, cycloheximide. After 24 hr, 27% of PMNs were nonapoptotic, and TNF-alpha (1 unit/ml) showed no change. Cycloheximide (10 micrograms/ml) decreased the number of nonapoptotic cells to 10% of the initial PMN. In contrast, G-CSF (30 ng/ml) decreased apoptosis (57% nonapoptotic PMN after 24 hr). Both G-CSF and TNF-alpha (but not cycloheximide) induced preservation of PMN Fc gamma RIII (467% and 167% of 24-hr controls, respectively) and beta 2-integrin expression (150% and 168% of 24-hr controls, respectively). G-CSF (but not TNF-alpha or cycloheximide) stimulated expression of Fc gamma RI (191% of 24-hr control) and Fc gamma RII (267% of 24-hr control). G-CSF (but not TNF-alpha) maintained the ability of PMN to ingest and kill opsonized Staphylococcus aureus. TNF-alpha decreased the effect of G-CSF on apoptosis, expression of Fc gamma RIII and Fc gamma RI, and bactericidal function. Thus, TNF-alpha promoted expression of Fc gamma RIII and beta 2-integrin receptors, which are important for phagocytic activity, and G-CSF diminished apoptosis, increased Fc gamma receptor expression, and maintained bactericidal function. TNF-alpha counteracted some effects of G-CSF. Interactions of these cytokines in vivo serve to regulate the PMN inflammatory response and bactericidal capacity.

Apoptosis↗
PubMed1995

Adenosine modulation of tumor necrosis factor-alpha-induced neutrophil activation.

We hypothesized that adenosine, known to be release from inflammatory sites, could lessen the potentially damaging activity of neutrophils (PMN) primed by tumor necrosis factor-alpha (TNF alpha) at sites of infection. We investigated the effect of adenosine on PMN primed with cell-free medium from mononuclear leukocytes (MNL) that had been treated with lipopolysaccharide (LPS) yielding a conditioned medium rich in TNF alpha and on PMN primed with recombinant human TNF alpha (rhTNF alpha). LPS (10 ng/mL) minimally primed PMN, but LPS-MNL-conditioned medium increased PMN chemiluminescence in response to f-Met-Leu-Phe (fMLP) 1242% compared with unprimed PMN. LPS-MNL-conditioned medium contained adenosine (approximately 30 nM). Converting the adenosine in the LPS-MNL-conditioned medium to inosine with adenosine deaminase (ADA) or blocking adenosine binding to PMN with the adenosine receptor antagonist 1,3-dipropyl-8-(phenyl-p-acrylate)-xanthine (BW A1433U) resulted in a near doubling of chemiluminescence. The LPS-MNL-conditioned medium contained TNF alpha (836 pg/mL; approximately 1 U/mL). Recombinant human TNF alpha (1 U/mL) primed PMN for a 1033% increase in chemiluminescence. Added adenosine decreased rhTNF alpha-primed PMN chemiluminescence (IC50 approximately 100 nM), and adenosine (100 nM) decreased both superoxide and myeloperoxidase release from rhTNF alpha-primed fMLP-stimulated PMN. The activity of adenosine was counteracted by ADA and BW A1433U, and the modulating effect of adenosine was on the primed response rather than on priming per se. Thus, physiological concentrations of adenosine reduce the effects of recombinant human TNF alpha and native human TNF alpha (released from LPS-treated MNL) on PMN activity. Endogenous adenosine may preclude or minimize damage to infected tissue by damping the TNF alpha-primed PMN oxidative response.

Adenosine↗
PubMed1995

Methylxanthines with adenosine alter TNF alpha-primed PMN activation.

Methylxanthines are best known as phosphodiesterase inhibitors that cause a rise in intracellular cAMP. One would expect the two methylxanthines, caffeine and pentoxifylline, to have similar actions on neutrophils (PMN). However, caffeine stimulated and pentoxifylline inhibited PMN oxidative activity. Micromolar concentrations of pentoxifylline decreased native and recombinant tumor necrosis factor-alpha (TNF alpha)-primed formyl met-leu-phe (fMLP)-stimulated PMN chemiluminescence, superoxide production and myeloperoxidase (MPO) release. In contrast, equal concentrations of caffeine increased chemiluminescence and MPO release with no effect on superoxide production. These activities of the methylxanthines were only observed in the presence of physiological concentrations of adenosine, and were abolished by the treatment of the PMN with adenosine deaminase. The activities of adenosine, pentoxifylline and caffeine on PMN activity could not be readily explained by changes in PMN [cAMP]. Thus for TNF alpha-primed PMN, pentoxifylline decreases PMN activity by enhancing the effect of adenosine on degranulation and superoxide production; whereas caffeine increases PMN activity by counteracting the effect of adenosine on degranulation.

Adenosine↗
PubMed1995

The specific type IV phosphodiesterase inhibitor rolipram combined with adenosine reduces tumor necrosis factor-alpha-primed neutrophil oxidative activity.

Monocytes and macrophages produce tumor necrosis factor-alpha (TNF alpha) in response to microbial products including endotoxin. TNF alpha is a potent primer of neutrophil (PMN) oxidative activity. Certain xanthine phosphodiesterase (PDE) inhibitors such as pentoxifylline have been shown to inhibit stimulated oxidative activity in PMN. In the present study, the non-xanthine PDE type IV inhibitor rolipram (4-[3'-cyclopentyloxy-4'-methoxyphenyl]-2-pyrrolidone) alone and in combination with adenosine is examined as a potential modulator of TNF alpha-primed PMN oxidative activity. Attainable in vivo concentrations of rolipram and physiological concentrations of adenosine alone and together synergistically decreased rhTNF alpha-primed suspended PMN oxidative activity stimulated by the chemoattractant f-met-leu-phe. The rolipram effect was reversible by washing, and rolipram had a comparable effect if added before or after priming, indicating that its effect was on the primed response rather than on priming per se. In addition, rolipram especially when combined with adenosine, decreased rhTNF alpha-stimulated PMN adherence to a fibrinogen-coated surface, and the oxidative burst of rhTNF alpha-stimulated adherent PMN. The specific adenosine A2a receptor agonists CGS 21680 and WRC-0474 had comparable activity to adenosine in these experiments. Adenosine (or CGS 21680) combined with rolipram synergistically increased f-met-leu-phe-stimulated PMN cAMP content. The effects of both adenosine and rolipram with adenosine could be only partly counteracted by treatment of the PMN with the protein kinase A inhibitor KT 5720, indicating that protein phosphorylation is only partially involved. Rolipram activity was about 1000 x (by molar concentration) greater than pentoxifylline in comparable assays. Thus, rolipram, especially when combined with adenosine, has potent modulating effects on PMN activation and may be useful in decreasing inflammatory tissue damage in patients with sepsis.

Adenosine↗
PubMed1995

Cytokines, phagocytes, and pentoxifylline.

Phagocytic cells, such as polymorphonuclear neutrophils, monocytes, and macrophages, are essential for defense against infection caused by a variety of microorganisms. The mechanisms used by these cells to destroy microbes comprise a potent oxidative armamentarium including superoxide, hydrogen peroxide, and hypochlorous acid. In addition, granule contents such as proteolytic enzymes, lysozyme, lactoferrin, and myeloperoxidase are released into the phagosome to destroy ingested microorganisms. Inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and IL-6, enhance the phagocytic and microbicidal activity of the cells and increase their stickiness. It has been demonstrated in a variety of animal and clinical studies that activated phagocytes can damage the host they are designed to protect, using the mechanisms described above. Alkylxanthines, including pentoxifylline, are potent inhibitors of this inflammatory damage by two major actions: (a) reduction of the production of inflammatory cytokines (especially TNF) by phagocytes stimulated with a variety of microbial products (e.g., endotoxin); and (b) reversal of the effect of these cytokines on phagocytes. Thus, pentoxifylline counteracts the following effects of inflammatory cytokines on phagocytes: increased adherence, shape change resulting in larger size and rigidity, increased oxidative burst, priming for an enhanced oxidative burst, increased degranulation, and decreased chemotactic movement. In addition, these activities synergize with the normal anti-inflammatory mediator adenosine. Alkylxanthines have the potential to be effective therapy for conditions in which inflammatory cytokines and phagocytes cause damage, including the sepsis syndrome, ARDS, AIDS, and arthritis.

Animals↗
PubMed1995

Adjuncts to antibacterial therapy.

Strategies of augmenting or attenuating the immune system's response to infection are promising potential methods to enhance antibacterial therapy. Many of these new therapies are natural cytokines, such as the hematopoietic growth factors and interferons, which upregulate the immune response. Other examples include replacement therapies, such as immune globulin, and downregulators of the immune response, such as corticosteroids. In the near future it may be possible to adjust the host response to microbial infection to maximally inhibit the microbe while minimizing inflammatory damage.

Adrenal Cortex Hormones↗
PubMed1994

Delivery of antibiotics by phagocytes.

Mobile phagocytes, especially polymorphonuclear neutrophils, accumulate at the site of many infections. This homing activity of phagocytes can be exploited as a mechanism for the delivery of antibiotics. To be effectively transported by neutrophils, antibiotics must be concentrated in neutrophils, must not interfere with the function of neutrophils, must remain present at high concentration long enough to be transported, and must be released in active form at the site of infection. Experimental studies have demonstrated that these criteria are fulfilled by azithromycin and, to a lesser extent, by rifampin.

Animals↗
PubMed1994

Inhibition of phospholipase D blocks activation of fibrinogen-adherent neutrophils by tumor necrosis factor.

Tumor necrosis factor stimulates fibrinogen-adherent neutrophils to produce a dramatic oxidative burst; the resulting superoxide and other products may contribute to tissue damage in severe infection. Inhibitors of the phospholipase D pathway blocked this activation without affecting cell adherence or nonspecific activation by phorbol myristate acetate. The phospholipase D pathway appears to be involved in the activation of adherent neutrophils by tumor necrosis factor, and this pathway may be a target for modulation of tumor necrosis factor's effects.

Cell Adhesion↗
PubMed1993

The effect of three human recombinant hematopoietic growth factors (granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, and interleukin-3) on phagocyte oxidative activity.

Hematopoietic growth factors not only modulate blood progenitor cell activity but also alter the function of mature phagocytes. Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; 1 ng/mL for 60 min) did not stimulate luminol-enhanced chemiluminescence of polymorphonuclear leukocytes (PMNs) in suspension but primed PMN for as much as a 15-fold increase in chemiluminescence in response to f-met-leu-phe (fMLP). Mixed mononuclear leukocytes (monocytes [approximately 20%] and lymphocytes [approximately 80%]; MNL) chemiluminescence was very low even after rhGM-CSF priming, but MNLs added to the PMNs (PMN-MNL) resulted in near doubling of rhGM-CSF-primed PMN fMLP-stimulated chemiluminescence. The enhancing factor(s) from MNLs were inherent rather than induced by the GM-CSF, and purified lymphocytes increased GM-CSF-primed PMN chemiluminescence equal to mixed MNLs. We could not detect cell-free "enhancing factor(s)," but cell-to-cell contact further enhanced rhGM-CSF-primed fMLP-stimulated PMN-MNL oxidative activity by 40%. Polyclonal rabbit anti-tumor necrosis factor (TNF) (but not preimmune serum) decreased both fMLP-stimulated rhGM-CSF-primed PMNs and PMN-MNL chemiluminescence, suggesting that TNF on the PMN surface is enhancing GM-CSF-primed chemiluminescence. GM-CSF priming markedly increased PMN superoxide release (sevenfold), but PMN superoxide release was not further enhanced by the presence of MNLs. Recombinant human granulocyte colony-stimulating factor (rhG-CSF) and interleukin-3 (rhIL-3) displayed much smaller effects on pure PMNs and mixed PMN-MNL chemiluminescence and superoxide release than rhGM-CSF. rhGM-CSF primes PMNs for increased oxidative activity more than rhG-CSF and rhIL-3. Maximal oxidative activity was observed when mixed PMN-MNL were primed with GM-CSF in a cell pellet-promoting cell-to-cell contact. This enhanced activity can be attributed, in part, to both inherent enhancing factor(s) on lymphocytes and PMN-associated TNF induced by GM-CSF.

Animals↗
PubMed1993

Obstetric and anesthetic considerations in the May-Hegglin anomaly. A case report.

The obstetric and anesthetic considerations in the management of a patient with the May-Hegglin anomaly, an autosomal dominant platelet deficiency, are discussed. A review of the medical literature notes three previous case reports of May-Hegglin anomaly in pregnancy. In addition to the two successful pregnancies reported in this paper, there are four infant survivors among the five reported pregnancies. Anesthetic managements included general and spinal anesthesia: the latter employed following platelet transfusion. A successful pregnancy should be anticipated when management includes a well-informed patient and coordinated obstetric and anesthetic care.

Adult↗
PubMed1992

A wave of elevated intracellular free calcium spreads through human neutrophils during phagocytosis of zymosan.

The cytosolic concentration of free calcium ([Ca2+]i) plays an important role in the control of many neutrophil functions. In this study, we characterize the early rapid subcellular changes in [Ca2+]i that occur in adherent neutrophils during phagocytosis of zymosan particles, using both dual- and single-excitation wavelength Fura-2 ratio imaging. We observed a wave of elevated cytosolic calcium that began shortly after zymosan contact and propagated from the region of neutrophil contact with the zymosan throughout the cell at a rate of approximately 17 microns/s at 31 degrees C. The wave was initiated by both opsonized and unopsonized zymosan and occurred independently of extracellular calcium. Multiple characteristics of the [Ca2+]i signal (including the absolute and regional [Ca2+]i and wave properties such as amplitude, frequency, duration, and topography) may be responsible for the differential regulation of cellular functions in the neutrophil.

Calcium↗