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Biomedical subjects

H Donabedian

Publications and source records attributed to H Donabedian.

23 records · Page 2Linked to original sources

Two inhibitors of neutrophil chemotaxis are produced by hyperimmunoglobulin E recurrent infection syndrome mononuclear cells exposed to heat-killed staphylococci.

Mononuclear cells from normal volunteers and from patients with the hyperimmunoglobulin E recurrent infection syndrome (HIE) were cultured for 18 h with and without opsonized, heat-killed Staphylococcus aureus (OS). The supernatants from normal mononuclear cell cultures without OS revealed no inhibitory activity for neutrophil chemotaxis, whereas those from HIE patients revealed the previously reported 61,000-dalton factor. However, when normal cells were cultured with OS, they produced a proteinaceous, 56 degrees C-stable, 30,000- to 45,000-dalton factor which preferentially inhibited neutrophil versus monocyte chemotaxis. When HIE cells were exposed to OS, they produced the same 30,000- to 45,000-dalton factor as normal cells, as well as the 61,000-dalton factor that they produced spontaneously. Assay of 1,000-fold dilutions of supernatants from cultures of normal mononuclear cells with OS revealed a mean production of 7.8 +/- 5.4% inhibition of chemotaxis, whereas assay of 1,000-fold dilutions of supernatants from cultures of HIE mononuclear cells (spontaneously producing the 61,000-dalton factor) with OS revealed a 26.6 +/- 3.6% inhibition (P less than 0.02). The data indicate that in short-term culture both normal and HIE mononuclear cells produce an inhibitor of neutrophil chemotaxis when exposed to particulate heat-killed staphylococci but that HIE cells produce qualitatively and quantitatively more inhibitory activity.

Cells, Cultured↗

Mononuclear cells from patients with the hyperimmunoglobulin E-recurrent infection syndrome produce an inhibitor of leukocyte chemotaxis.

The chemotactic responsiveness of the neutrophils of 10 patients with the hyperimmunoglobulin E-recurrent infection syndrome (HIE) were compared with neutrophils from normal volunteers over a 10-mo period. HIE neutrophils as a group displayed significantly less chemotactic motility than control neutrophils. The data from individual patients were variable, being normal or abnormal on different days. Mononuclear cells from HIE patients, when cultured for 24 h in the absence of serum or a mitogen, produced a factor that inhibited normal neutrophil and monocyte chemotaxis. Mononuclear cells from normal volunteers with and without atopy or from patients with parasites or bacterial infections did not produce such an inhibitory factor. The production of this chemotactic inhibitory factor in vitro was variable over time, but it correlated with the presence of an in vitro neutrophil chemotactic defect. The chemotactic inhibitory factor was partially purified and was found to contain protein, to be stable at 56 degrees C, and to have a molecular weight of approximately 61,000. Irreversible inhibitors of serine esterases do not inactivate the factor. The factor is produced by esterase-negative mononuclear cells and is not toxic to neutrophils. This chemotactic inhibitory factor may be the basis of the variable chemotactic defect in HIE neutrophils.

Adolescent↗

Deactivation of human neutrophil chemotaxis by chemoattractants: effect on receptors for the chemotactic factor f-Met-Leu-Phe.

Normal human peripheral blood PMN were exposed to varying concentrations of partially purified chemotactic complement fragments (C5fr) and a chemotactic peptide N-formyl methionylleucylphenylalanine (f-Met-Leu-Phe). This exposure resulted in a decreased chemotactic response termed deactivation of chemotaxis. Deactivation was found to be nonpreferential for the deactivating stimulus when high concentrations of either f-Met-Leu-Phe (10(-6) M) or C5fr (20 micrograms/ml) were used. When PMN were incubated with lower concentrations of C5fr (10 micrograms/ml), there was preferential deactivation towards C5fr. Similarly, preferential deactivation of chemotaxis was observed when PMN were incubated with 10(-6) M f-Met-Leu-Phe, but this was transient and cells were nonpreferentially deactivated 60 min after the initial exposure to f-Met-Leu-Phe. The availability of receptors for tritiated f-Met-Leu-Phe was examined by Scatchard analyses and measurement of reversible f-Met-Leu-[3H]Phe binding to C5fr and f-Met-Leu-Phe-deactivated PMN. When PMN f-Met-Leu-Phe receptors were studied immediately after exposure to concentrations of C5fr causing either preferential or nonpreferential deactivation, there was increased receptor availability compared with control PMN. In contrast, PMN deactivated with high concentrations of f-Met-Leu-Phe 10(-6) M) had a transient decrease in the number of receptors followed 1 hr later by an increase in the number of receptors. This was similar to the functional correlate of preferential deactivation of chemotaxis immediately after incubation with f-Met-Leu-Phe followed by nonpreferential deactivation in these same PMN. The data indicate that preferential deactivation of chemotaxis may be associated with a preferential decrease (down-regulation) of chemoattractant receptors and that nonpreferential deactivation is associated with an increase in chemoattractant receptors.

Binding Sites↗

Synergy of vancomycin with penicillins and cephalosporins against pseudomonas, klebsiella, and serratia.

A model of antibiotic synergy based on a molecular mechanism of action which blocked sequential steps in a single metabolic pathway was tested. Twenty-five strains each of Pseudomonas, Klebsiella, and Serratia were tested in vitro against three different two drug combinations of vancomycin, carbenicillin, or cephalothin. Synergy was observed when vancomycin was combined with either carbenicillin or cephalothin against isolates of Pseudomonas or Serratia, whereas the combination of carbenicillin and cephalothin did not result in significant synergy against these isolates. The presence of synergy was not related to the sensitivity or resistance of the isolates to the drugs in the combination. Synergy was also observed with all three antibiotic combinations against Klebsiella isolates which may be related to enzyme inactivation by one of the drugs in the combination. These observations support the hypothetical model of antibiotic synergy based on sequential blocking of one biochemical pathway.

Carbenicillin↗