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Biomedical subjects

D C Hooper

Publications and source records attributed to D C Hooper.

At least 109 records · Page 6Linked to original sources
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↗
PubMed1990

Comparative bacterial clearances of muscle and skin/subcutaneous tissues with and without dead bone: a laboratory study.

Seventeen New Zealand White rabbits underwent implantation of three different concentrations of bacteria and a sterile saline control solution with and without dead autologous bone in eight separate muscular and eight separate subcutaneous sites. Following a period of 1 week, each site was surgically explored and samples of tissue were taken for histology and quantitative culture. Results reveal that final bacterial concentrations in the subcutaneous sites were significantly lower than in the muscle sites (p less than or equal to 0.0001) for each concentration of bacteria, with and without dead bone. Dead bone resulted in very significantly greater bacterial concentrations in both subcutaneous and muscle sites. Clinically, these results indicate that a thorough bony wound debridement is more important than the type of tissue used to close the wound. Flap tissue should be selected with regard to the perfusion, contour, and appearance of the recipient site.

Abscess↗
PubMed1990

Mutants of Escherichia coli K-12 exhibiting reduced killing by both quinolone and beta-lactam antimicrobial agents.

Norfloxacin, ofloxacin, and other new quinolones, which are antagonists of the enzyme DNA gyrase, rapidly kill bacteria by largely unknown mechanisms. Earlier, we isolated, after mutagenesis, Escherichia coli DS1, which exhibited reduced killing by quinolones. We evaluated the killing of DS1 and several other strains by quinolones and beta-lactams. In time-killing studies with norfloxacin, DS1 was killed 1 to 2 log10 units compared to 4 to 5 log10 units for the wild-type parent strain KL16, thus revealing that DS1 is a high-persistence (hip) mutant. DS1 exhibited a similar high-persistence pattern for the beta-lactam ampicillin and reduced killing by drugs that differed in their affinities for penicillin-binding proteins, including cefoxitin, cefsulodin, imipenem, mecillinam, and piperacillin. Conjugation and P1 transduction studies identified a novel mutant locus (termed hipQ) in the 2-min region of the DS1 chromosome necessary for reduced killing by norfloxacin and ampicillin. E. coli KL500, which was isolated for reduced killing by norfloxacin without mutagenesis, exhibited reduced killing by ampicillin. E. coli HM23, a hipA (34 min) mutant that was isolated earlier for reduced killing by ampicillin, also exhibited high persistence to norfloxacin. DS1 differed from HM23, however, in the map location of its hip mutation, lack of cold sensitivity, and reduced killing by coumermycin. Results of these studies with strains DS1, KL500, and HM23 demonstrate overlap in the pathways of killing of E. coli by quinolones and beta-lactams and identify hipQ, a new mutant locus that is involved in a high-persistence pattern of reduced killing by norfloxacin and ampicillin.

Anti-Bacterial Agents↗
PubMed1990

Murine epidermal antigen-presenting cells in primary and secondary T-cell proliferative responses to a soluble protein antigen in vitro.

The capacity of epidermal cells (EC) to present antigen to primed and non-immune T cells was investigated using a culture system that supports antigen-specific primary and secondary proliferative responses. Although both naive and bovine serum albumin (BSA)-immune T cells reacted against BSA in the presence of either splenic or epidermal antigen-presenting cells (APC), important differences were noted in the kinetics and the magnitudes of the various responses. Most conspicuous was the relatively poor primary response supported by EC which evidently elicited very few BSA-immune T-helper cells. Despite this, the primed antigen-specific T cells recovered were phenotypically similar to those resulting from the stronger primary responses induced by spleen cells. In contrast to this disparity in the ability to prime, EC and spleen cells stimulated secondary reactions of comparable magnitude. We therefore consider that, in comparison with splenic APC, EC may require some additional stimulus to acquire the capacity to prime.

Animals↗
PubMed1989

Bacterial resistance to the quinolone antimicrobial agents.

Bacterial resistance to the newer quinolones occurs less frequently than to the older analogue nalidixic acid. Single-step mutations conferring greater than eightfold increases in minimal inhibitory concentration occur at frequencies of less than 10(-10) for many bacterial species and at 10(-8) for Pseudomonas aeruginosa. Passage on increasing concentrations of quinolones, however, results in highly resistant strains of many species. Chromosomal mutations have been shown to produce two mechanisms of resistance, alterations in the A subunit of the target enzyme, DNA gyrase, and decreased drug accumulation associated with altered porin outer membrane proteins and pleiotropic resistance. For some mutants reduced accumulation appears to depend on active quinolone efflux across the inner membrane. Resistance developing during quinolone therapy of infections has been infrequent to date and reported most often with P. aeruginosa and Staphylococcus aureus, and at sites with poor quinolone penetration or foreign bodies. Resistance should be monitored, and the means for limiting its development studied.

4-Quinolones↗
PubMed1989

Comparative pharmacokinetics of ofloxacin and ciprofloxacin.

Review of publications in which the pharmacokinetics of ofloxacin and ciprofloxacin were compared directly indicates that although similar in many respects, these fluoroquinolones exhibit three differences that may be important clinically. First, ofloxacin is more completely absorbed, achieves higher peak serum concentrations, and has a longer terminal elimination half-life, which result in a fivefold greater area under the curve than that of ciprofloxacin when similar doses are orally administered. Ofloxacin's more favorable pharmacokinetic profile seems to compensate at least in part for the greater activity of ciprofloxacin against gram-negative bacilli in vitro. Second, ofloxacin is eliminated almost entirely via the kidneys, whereas ciprofloxacin is eliminated via both the kidneys and non-renal routes. This suggests that ciprofloxacin may be preferable for patients with variable renal function, whereas ofloxacin may be preferable for patients receiving dialysis because of the need for less frequent administration. Third, concomitant use of ciprofloxacin with either theophylline or caffeine decreases elimination and thereby results in elevated serum concentrations of these methylxanthine derivatives. Because ofloxacin does not cause clinically significant alterations in the pharmacokinetics of either theophylline or caffeine, it may be preferable for patients using these concomitantly.

Biological Availability↗
PubMed1989

Altered immune response patterns in murine syngeneic pregnancy: presence of natural null suppressor cells in maternal spleen identifiable by monoclonal antibodies.

Expression of certain autologous lymphocyte-activating antigenic determinants on the developing embryo is known to provide a stimulus for maternal anti-fetal autoproliferative responses. If left unregulated these responses could exert negative influences on the reproductive process by converting to autoaggressive forms of immune reactivity. In normal circumstances, immunological reactions of this nature are therefore likely to be under the control of pregnancy-associated immunoregulatory elements found within the maternal/fetal environment. In the present investigation we describe a naturally occurring splenic inhibitory cell type devoid of conventional T, B, and macrophage surface markers associated with syngeneic murine pregnancy that is capable of exerting potent immunosuppressive effects on an in vitro expression of fetal/newborn T cell autoreactivity, namely the autologous mixed lymphocyte reaction (AMLR). Maternal spleen cells inhibitory for AMLR were found to be highly resistant to cytotoxic pretreatment with a panel of conventional antisera directed against T cell-specific antigenic determinants. The non-T nature of the natural splenic suppressor cell was further indicated by experiments showing that purified spleen T cells had no inhibitory activity. Pregnancy spleen cell populations that were effectively depleted of macrophages retained full ability to inhibit AMLR. Maternal suppressor activity could be localized to the spleen cell population bearing receptors for the B cell-specific lectin, soybean agglutinin (SBA). A panel of monoclonal antibodies prepared against enriched populations of suppressor cells was screened and selected for specific reactivity using an ELISA against glutaraldehyde-fixed SBA+ spleen cell subpopulations from pregnant versus virgin animals. Several of the monoclonals developed against suppressor-enriched spleen cell populations from isopregnant as well as allopregnant animals were effective in reducing or eliminating suppressor cell activity following cytotoxic pretreatment in the presence of complement. The novel set of anti-suppressor monoclonal antibodies described here should prove useful in furthering the isolation and characterization of pregnancy-associated suppressor cells and in determining their relationship to natural suppressor cell populations described in other systems.

Animals↗
PubMed1989

Anti-proliferative action of murine alpha-fetoprotein on activated T-lymphocytes.

Alpha-fetoprotein (AFP) is the dominant serum glycoprotein of fetal life but is expressed only in low nanogram levels in adult sera. A possible explanation for this is that AFP has immunoregulatory properties which may be essential during early ontogeny but unnecessary, if not harmful, in adulthood. The current study shows that the interleukin 2 (IL-2)-dependent division of Lyt 2- T blast cells previously activated in autologous mixed lymphocyte reactions (AMLR) or by stimulation with concanavalin A (Con A) is susceptible to inhibition by AFP. This anti-proliferative activity appears to be independent of any competitive interaction with either IL-2 or I-A antigens and is therefore likely to result from a direct action of AFP on the T cells. These findings support the hypothesis that naturally occurring elevated levels of AFP may be involved in the protection of the conceptus from potentially harmful maternal anti-fetal reactivity and in the establishment and maintenance of T-helper cell tolerance to antigens encountered during early life.

Adjuvants, Immunologic↗