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Biomedical subjects

D C Hooper

Publications and source records attributed to D C Hooper.

13 recordsLinked to original sources
PubMed1992

Synergism of trimethoprim and ciprofloxacin in vitro against clinical bacterial isolates.

For the first time, the effects of combinations of trimethoprim and a fluoroquinolone (ciprofloxacin) against gram-positive and gram-negative bacterial isolates were evaluated in vitro. Synergism was found in 31% (fractional inhibitory concentration, FIC) and 33% (fractional bactericidal concentration, FBC) of 121 clinical isolates of various bacterial strains, most often in Escherichia coli, staphylococci, and enterococci. Antagonism occurred in 1% (FIC) and 3% (FBC). The combination of trimethoprim and ciprofloxacin merits further evaluation for potential usefulness as a clinical regimen.

Ciprofloxacin↗
PubMed1992

Genetics and regulation of outer membrane protein expression by quinolone resistance loci nfxB, nfxC, and cfxB.

Quinolone resistance mutations (cfxB1, marA1, and soxQ1) that reduce porin outer membrane protein OmpF map near 34 min on the Escherichia coli chromosome. Another such mutation, nfxC1, was found in strain KF131 (nfxB, 19 min). nfxC1 and cfxB1 mutants (selected with quinolones) differed slightly but reproducibly from marA1 (selected with tetracycline) and soxQ1 (selected with menadione) mutants in quinolone resistance and linkage to zdd2208::Tn10kan (33.7 min). For nfxB nfxC1 and cfxB1 mutants, as previously shown for marA mutants, resistance and reduced OmpF required the micF locus encoding an antisense RNA complementary to ompF mRNA and were associated with increased micF expression.

4-Quinolones↗
PubMed1992

Primary and secondary human in vitro T-cell responses to soluble antigens are mediated by subsets bearing different CD45 isoforms.

A culture system has been developed which consistently supports in vitro proliferative responses to conventional soluble antigens by human CD4+ T cells from non-immunized donors. T cells exposed to an antigen in primary cultures could be restimulated in vitro in an antigen-specific manner to give secondary responses with greater magnitudes and a more rapid onset than the initial reaction. To characterize further the responding T-cell population in primary compared with secondary reactions, T cells were depleted of CD45RA+ or CD45RO+ cells and stimulated with recall and non-recall antigens. It was found that the soluble non-recall antigen keyhole limpet haemocyanin did not stimulate CD45RO+ T cells, yet induced strong proliferative responses from CD45RA+ T cells. Conversely, it was confirmed that human CD45RO+ T cells respond to the recall antigen-purified protein derivative from Mycobacterium tuberculosis. Cell mixing experiments indicated that CD45RO+ T cells are unlikely to have any suppressive effect on the reactivity of CD45RA+ cells to non-recall antigens. These data provide new support for the hypothesis that CD45RA+ represents the naive and CD45RO+ the memory phenotype of human CD4+ T cells.

Antigens↗
PubMed1992

The effect of neonatal tolerance to bovine gamma globulin (BGG) on BGG-reactive CD4+ T lymphocytes.

Compelling evidence has been presented that tolerance to major histocompatibility complex (MHC) and other antigens expressed on cells of the thymus is due to clonal deletion. However, it has not been determined conclusively how tolerance to diverse antigens, which may initially interact with the immune system in the periphery, is induced and maintained. Considerable evidence exists to suggest that mechanisms other than deletion, such as clonal anergy or immunoregulation, may be involved. We have previously shown that the clonal deletion of CD4+ cells specific for bovine gamma globulin (BGG) does not occur during induction of tolerance to this soluble antigen in adult life. In this study we have extended our previous findings by examining unresponsiveness to BGG which had been established during early ontogeny, when natural tolerance of self-antigens is likely to develop. It is demonstrated here that BGG-reactive, CD4+8- T cells, which proliferate and secrete interleukin-2 on stimulation with BGG in vitro, can be obtained from mice rendered tolerant of BGG as neonates. Even though the mice from which they were derived were unable to respond to BGG, these BGG-reactive T cells, by the parameters tested here, could not readily be distinguished from the corresponding cells in BGG-immune and non-immune animals. It is therefore evident that this tolerant state is not simply the result of clonal deletion of BGG-reactive CD4+ T cells but is more likely to be due to a reversible mechanism which controls their responsiveness in vivo.

Animals↗
PubMed1991

Overview of fluoroquinolone safety.

The safety of the fluoroquinolone antimicrobial agents is reviewed, discussing documented and potential clinical and laboratory adverse effects and drug-drug interactions. In prospective, randomized, double-blind clinical trials comparing fluoroquinolones to nonquinolone drugs or placebo, the fluoroquinolones were not significantly different (22 studies) or were superior (5 studies) to comparison agents but were only rarely more toxic (2 studies). Adverse effects included mild gastrointestinal toxicities and less common but more problematic central nervous system toxicities. Clinically important interactions occurred with coadministration of antacids and all fluoroquinolones and with theophylline and enoxacin and to a lesser extent ciprofloxacin and pefloxacin but not other fluoroquinolones. Potential adverse effects such as cartilage damage, DNA damage, teratogenicity, and crystalluria, while of concern, have not as yet been shown to be of clinical importance. Therapy of bacterial infections in children and adolescents is relatively contraindicated, but growing clinical experience with treatment of these patients has not so far revealed serious bone or cartilage toxicity. The fluoroquinolones thus far have exhibited a favorable safety profile, but our clinical experience is still limited, and monitoring for as yet unappreciated toxicities is warranted.

4-Quinolones↗
PubMed1991

Enterobacter bacteremia: clinical features and emergence of antibiotic resistance during therapy.

OBJECTIVES: To study the effect of previously administered antibiotics on the antibiotic susceptibility profile of Enterobacter, the factors affecting mortality, and the emergence of antibiotic resistance during therapy for Enterobacter bacteremia. DESIGN: Prospective, observational study of consecutive patients with Enterobacter bacteremia. SETTING: Three university tertiary care centers, one major university-affiliated hospital, and two university-affiliated Veterans Affairs medical centers. PATIENTS: A total of 129 adult patients were studied. MEASUREMENTS: The two main end points were emergence of resistance during antibiotic therapy and death. MAIN RESULTS: Previous administration of third-generation cephalosporins was more likely to be associated with multiresistant Enterobacter isolates in an initial, positive blood culture (22 of 32, 69%) than was administration of antibiotics that did not include a third-generation cephalosporin (14 of 71, 20%; P less than 0.001). Isolation of multiresistant Enterobacter sp. in the initial blood culture was associated with a higher mortality rate (12 of 37, 32%) than was isolation of a more sensitive Enterobacter sp. (14 of 92, 15%; P = 0.03). Emergence of resistance to third-generation cephalosporin therapy (6 of 31, 19%) occurred more often than did emergence of resistance to aminoglycoside (1 of 89, 0.01%; P = 0.001) or other beta-lactam (0 of 50; P = 0.002) therapy. CONCLUSIONS: More judicious use of third-generation cephalosporins may decrease the incidence of nosocomial multiresistant Enterobacter spp., which in turn may result in a lower mortality for Enterobacter bacteremia. When Enterobacter organisms are isolated from blood, it may be prudent to avoid third-generation cephalosporin therapy regardless of in-vitro susceptibility.

Adolescent↗
PubMed1991

Mode of action of the new quinolones: new data.

New details of the molecular interactions of quinolones with their target DNA gyrase and DNA have come from the nucleotide sequences of the gyrA genes from resistant mutants of Escherichia coli and wild-type strains of other bacteria and studies of gyrase A tryptic fragments, all suggesting the importance of an amino-terminal domain in quinolone action. Alterations in DNA supertwisting were also associated with altered quinolone susceptibility, possibly by indirect effects on DNA gyrase expression. Specific binding of relevant concentrations of norfloxacin to a complex of DNA gyrase and DNA in the presence of ATP, the cooperativity of DNA binding, and the crystalline structure of nalidixic acid have led to a model in which quinolones bind cooperatively to a pocket of single-strand DNA created by DNA gyrase. Quinolones vary in their relative activity against DNA gyrase and its eukaryotic homolog topoisomerase II, and in some assays increased action against the eukaryotic enzyme was associated with genotoxicity. Inhibition of bacterial DNA synthesis by quinolones may correlate with MICs in some species, but comparisons of drug accumulation and inhibition of DNA synthesis in permeabilized cells among species have been difficult to interpret. The specific factors necessary for bacterial killing by quinolones in addition to interaction with DNA gyrase have remained elusive, but include oxygen and new protein synthesis. The coordinate expression of the SOS proteins appears not to be necessary for quinolone lethality. Two independent mutants with selective reduced killing by quinolones and beta-lactams indicate overlap in the pathways of bactericidal activity of these classes of agents with distinct targets.

4-Quinolones↗
PubMed1991

Pharmacokinetics of quinolones: newer aspects.

Differences in pharmacokinetic properties are emerging as important determinants in distinguishing among clinical uses of individual new quinolone antimicrobial agents. Selected data on pharmacokinetics, new pharmacokinetic studies, and pharmacodynamics are reviewed, with reference to norfloxacin, ciprofloxacin, ofloxacin, pefloxacin, enoxacin, fleroxacin, lomefloxacin, and other new quinolones. Considering pharmacokinetics, oral bioavailability is excellent (greater than 95%) for most quinolones. Differences in peak serum concentrations and beta-half-lives of elimination exist, however, and are reflected in up to ten-fold differences in values of the area under the curve of serum concentration versus time for administration of similar drug doses. As suggested by high apparent volumes of distribution and low binding to serum proteins, penetration into many body tissues and fluids is favorable. Considering new findings, orally administered ciprofloxacin has been found to be absorbed primarily in the duodenum and jejunum. Studies also suggest this drug to be cleared by transepithelial elimination into the bowel lumen as well as by the renal route. Oral bioavailability of quinolones has been demonstrated to be in general good in ill as well as healthy subjects but is reduced on co-administration with magnesium- and aluminum-containing acids, sucralfate (which contains aluminum), or ferrous sulfate. Pharmacodynamic parameters, such as the relationship of serum concentrations and drug potency in vitro to clinical response and suppression of bacterial resistance, have been little studied and merit further investigation.

4-Quinolones↗
PubMed1991

A novel locus conferring fluoroquinolone resistance in Staphylococcus aureus.

Fluoroquinolones such as ciprofloxacin and ofloxacin are potent antimicrobial agents that antagonize the A subunit of DNA gyrase. We selected and mapped a novel fluoroquinolone resistance gene on the Staphylococcus aureus chromosome. Resistant mutants were selected with ciprofloxacin or ofloxacin and were uniformly localized to the A fragment of chromosomal DNA digested with SmaI and arrayed by pulsed-field gel electrophoresis. Several mutants (cfxB, ofxC) were genetically mapped between the thr and trp loci in the A fragment. A majority of A fragment fluoroquinolone resistance mutations were associated with reduced susceptibility to novobiocin, an antagonist of the B subunit of DNA gyrase. Two genes previously associated with fluoroquinolone resistance, the gyrA gene of DNA gyrase and the norA gene (associated with decreased drug accumulation), were localized to the G and D fragments, respectively. Thus, the fluoroquinolone resistance mutations in the A fragment are distinct from previously identified fluoroquinolone resistance mutations in gyrA and norA. Whether mutations in the A fragment after a second topoisomerase or another gene controlling supercoiling or affect drug permeation is unknown.

Anti-Infective Agents↗
PubMed1991

Murine epidermal antigen-presenting cells in primary and secondary T-cell proliferative responses to herpes simplex virus in vitro.

The role of epidermal Langerhans' cells in infection with herpes simplex virus (HSV) was investigated using a culture system that supports antigen-specific primary and secondary T-cell proliferative responses. Epidermal cell suspensions were capable of restimulating the response of in vivo primed T cells to UV-inactivated HSV. This capability was also present in cell suspensions enriched for Langerhans' cells, but was abrogated by the depletion of I-A-bearing cells. The magnitude, kinetics and phenotype of the responding cells were similar to those elicited when HSV was presented to primed T cells by antigen-presenting cells from the spleen. In marked contrast, whereas splenic antigen-presenting cells induced strong antigen-specific proliferation of unprimed T cells (primarily of the helper phenotype), Langerhans' cells failed to invoke any detectable reaction of such cells.

Animals↗
PubMed1990

Bovine gamma globulin-specific CD4+ T cells are retained by bovine gamma-globulin-tolerant mice.

Immunological tolerance is an acquired state of antigen-specific nonresponsiveness which is generally attributed to either the deletion or suppression of tolerogen-specific T helper cell clones. Unresponsiveness to xenogeneic immunoglobulins can be readily induced and has been extensively studied in order to ascertain the means by which tolerance is established and maintained. As an absence of reactivity to foreign immunoglobulin has been noted in situations where suppressor cell activity was minimized, this tolerant state has often been ascribed to clonal deletion. The present study demonstrates that bovine gamma-globulin (BGG)-tolerant mice are unable to generate humoral responses to BGG in vivo and yet harbor BGG-specific CD4+CD8- T cells which can divide and secrete interleukin 2 when stimulated in vitro. Indeed, the in vitro reactivity to BGG of these cells exceeded that of a similar population of non-immune cells. This is in direct opposition to the loss of response that would be expected if clonal deletion were operative. The presence of BGG-specific CD4+ T cells, which appear to be at least partly primed, in mice unresponsive to BGG, indicates that tolerance to BGG is likely to be dependent on unidentified immunoregulatory processes rather than clonal deletion.

Animals↗
PubMed1976

Determination of the subunit composition of haptoglobin 2-1 polymers using quantitative densitometry of polyacrylamide gels.

Human haptoglobin (Hp), a hemoglobin-binding glycoprotein containing two types of polypeptide chains, alpha and beta, in equimolar amounts linked by disulfide bonds, exists in three major phenotypes determined by the properties of the alpha chain: Hp 1-1 (alpha1), Hp 2-2 (alpha2), and Hp 2-1 (alpha1 and alpha2). Hp 2-2 and Hp 2-1 form a series of alpha-disulfide-linked polymers. The subunit composition of the Hp 2-1 series was studied by isolation of single Hp 2-1 polymers by polyacrylamide gel electrophoresis. After reductive disulfide cleavage and alkylation the relative content of alpha2 and alpha1 polypeptide chains was determined by quantitative densitometry of acid/urea polyacrylamide gels stained with Coomassie brilliant blue R250. The molar ratios alpha2/alpha1 for the Hp 2-1 polymers. P1 through P5 (in order of decreasing electrophoretic mobility), were found to be: P1, 0.0 (alpha1 only); P2, 0.48; P3, 0.97; P4, 1.6; P5, 2.0. Since one alphabeta-Hb half-molecule is known to bind to each Hp beta chain, the beta polypeptide chain content of each of the Hp 2-1 polymers could be estimated by by counting the number of Coomassie blue bands formed after electrophoresis of isolated Hp 2-1 polymers fractionally saturated with cyanmethemoglobin (Hb). The number of beta chains present in Hp 2-1 polymers P1 through P4 was determined to be: P1, 2; P2, 3; P3, 4 and P4, 5. Molecular weights of the Hp 2-1 polymers were determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresus using as standards the almost homologous Hp 2-2 polymer series whose molecular weights are known from ultracentrifugation studies. Molecular weights for the first five Hp 2-1 polymers were estimated to be 107,000; 162,000; 217,000, 274,000; and 331,000, respectively. These data are consistent with the previously proposed model for the subunit composition of the Hp 2-1 polymer series when P1 = (alpha1 beta)2 and the subsequent polymers in order are represented as (alpha1 beta)2(alpha2 beta)n where n = 1,2,3,4...

Densitometry↗