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Biomedical subjects

D A Hess

Publications and source records attributed to D A Hess.

At least 19 recordsLinked to original sources
PubMed2003

Coculture and transplant of purified CD34(+)Lin(-) and CD34(-)Lin(-) cells reveals functional interaction between repopulating hematopoietic stem cells.

The human hematopoietic stem cell compartment is comprised of repopulating CD34(+) and CD34(-) cells. The interaction between these subsets with respect to their reconstitution capacity in vivo remains to be characterized. Here, lineage-depleted (Lin(-)) human CD34(+) and CD34(-) hematopoietic cells were isolated from human male and female umbilical cord blood (CB) and transplanted into immune-deficient NOD/SCID EMV(null) mice, thereby allowing the use of human and Y-chromosome-specific DNA sequences to discriminate human reconstitution contributed by CD34(+) vs CD34(-) repopulating stem cells. Although cultured human CB CD34(-)Lin(-) cells transplanted alone possessed only minimal repopulating capacity, with 15% of mice achieving low levels of engraftment, transplantation of cocultured male CD34(-)Lin(-) cells with female CD34(+)Lin(-) cells demonstrated human repopulation with a contribution from CD34(-)Lin(-)-derived progeny in 80% of the recipients. After coculture and transplantation, male CD34(-)Lin(-) cells gave rise to primitive CD34(+)CD38(-) cells isolated in vivo, which demonstrated clonogenic progenitor function into multiple lineages. Taken together, our study indicates that the presence of CD34(+)Lin(-) cells in coculture enhanced the low repopulating function of human CD34(-)Lin(-) cells in vivo. We propose that CD34(+)Lin and CD34(-)Lin cells represent phenotypically distinct, but related cell types that exhibit unique and previously unappreciated functional interaction.

Animals↗
PubMed2003

Ambulatory sentinel node biopsy under local anaesthesia for patients with early breast cancer.

AIMS: Sentinel lymph node biopsy (SLNB) may permit reliable identification of patients with axillary node involvement. The aim of this study was to report our experience with this procedure under local anaesthesia. METHODS: One hundred and sixty-two patients underwent a sentinel node procedure under local anaesthesia without sedation. The SLN was identified by (99m)Tc-nano-colloid and patent blue. Immediate histopathologic examination and immunohistochemistry was performed. Patients with positive SLNs proceded to axillary dissection under general anaesthesia. RESULTS: In all 162 patients the SLN ('s) were found using blue dye and gamma-probe. The SLN was positive in 55/162 patients (34%). Five of these were detected using immunohistochemistry only. CONCLUSIONS: A 100% detection rate of sentinel nodes in early breast cancer harvested under local anaesthesia was achieved without serious morbidity. This allows the surgeon to select preoperatively the treatment given to the patient.

Adult↗
PubMed2000

The human hematopoietic stem cell compartment is heterogeneous for CXCR4 expression.

The chemokine stromal derived factor-1alpha (SDF-1alpha) has been implicated recently in the chemotaxis of primitive human hematopoietic cells, suggesting that pluripotent human stem cells express the SDF-1alpha receptor, CXCR4. By using flow cytometry and confocal microscopy, we have identified and isolated primitive subsets of human CXCR4(+) and CXCR4(-) cells. Distinctions in the progenitor content and response to SDF-1alpha in vitro indicate that CXCR4(+) and CXCR4(-) cells represent discrete populations of primitive blood cells. The i.v. transplantation of these subfractions into immune-deficient mice established that both possess comparable engraftment capacity in vivo. Human myeloid, lymphoid, and primitive CD34(+) CXCR4(+) cells were present in chimeric animals transplanted with either subset, indicating that CXCR4(+) and CXCR4(-) stem cells have equivalent proliferative and differentiative abilities. Our study indicates that the human stem cell compartment is heterogeneous for CXCR4 expression, suggesting that the relationship between CXCR4 expression and stem cell repopulating function is not obligatory.

Animals↗
PubMed1999

Cytotoxicity of sulfonamide reactive metabolites: apoptosis and selective toxicity of CD8(+) cells by the hydroxylamine of sulfamethoxazole.

Treatment with sulfonamide antibiotics in HIV-infected patients is associated with a high incidence (> 40%) of adverse drug events, including severe hypersensitivity reactions. Sulfonamide reactive metabolites have been implicated in the pathogenesis of these adverse reactions. Sulfamethoxazole hydroxylamine (SMX-HA) induces lymphocyte toxicity and suppression of proliferation in vitro; the mechanism(s) of these immunomodulatory effects remain unknown. We investigated the cytotoxicity of SMX-HA via apoptosis on human peripheral blood mononuclear cells and purified cell subpopulations in vitro. CD19(+), CD4(+), and CD8(+) cells were isolated from human peripheral blood by positive selection of cell surface molecules by magnetic bead separation. SMX-HA induced significant CD8(+) cell death (67 +/- 7%) at 100 microM SMX-HA, with only minimal CD4(+) cell death (8 +/- 4%). No significant subpopulation toxicity was shown when incubated with parent drug (SMX). Flow cytometry measuring phosphatidylserine externalization 24 h after treatment with 100 microM and 400 microM SMX-HA revealed 14.1 +/- 0.7% and 25. 6 +/- 4.2% annexin-positive cells, respectively, compared to 3.7 +/- 1.2% in control PBMCs treated with 400 microM SMX. Internucleosomal DNA fragmentation was observed in quiescent and stimulated PBMCs 48 h after incubation with SMX-HA. Our data show that CD8(+) cells are highly susceptible to the toxic effects of SMX-HA through enhanced cell death by apoptosis.

Apoptosis↗
PubMed1997

The role of reactive drug metabolites in immune-mediated adverse drug reactions.

OBJECTIVE: To highlight recent advances in the understanding of adverse drug reactions (ADRs), with a focus on models outlining interactions between drug metabolism, disease processes, and immunity. Specific mechanisms that identify the metabolic pathways responsible for drug bioactivation to reactive drug metabolites (RDMs) involved in the initiation and propagation of specific immune-mediated hypersensitivity reactions are discussed. Drug classes well known to be associated with immune-mediated ADRs are reviewed and the clinical implications of current research are discussed. DATA SOURCES: Original experimental research and immunologic review articles relevant to ADR diagnosis and etiology. DATA EXTRACTION: Results of relevant in vitro experiments and clinical reactions to drug therapy were compiled and reviewed. Critical discoveries concerning the identification of RDMs involved in ADRs were highlighted, with respect to RDM involvement in the production of an immune response to drug haptens. DATA SYNTHESIS: Drug adverse effects are classified according to clinical characteristics, immune interactions, and mechanistic similarities. Cytochrome P450 bioactivation of drug molecules to RDMs is a prerequisite to many ADRs. An electrophilic metabolite may react with cellular macromolecules (i.e., lipids, proteins, nucleic acids), resulting in direct cellular damage and organ toxicity. Covalent binding of an RDM to cellular macromolecules may also result in the formation of a hapten that is capable of eliciting a cellular or humoral immune response against drug or protein epitopes, culminating in the characteristic symptoms of hypersensitivity reactions. Mechanistic details concerning the identification of stable protein-metabolite conjugates and their interaction with the immune system remain unclear. Genetic imbalance between bioactivation and detoxification pathways, as well as reduced cellular defense against RDMs due to disease or concomitant drug therapy, act as risk factors to the onset and severity of ADRs. CONCLUSIONS: Adverse reactions to drug therapy cause significant morbidity and mortality. Identification of the pathways involved in drug bioactivation and detoxification may elucidate the potential of chemical agents to induce immune-mediated ADRs. Understanding the mechanisms of ADRs to current xenobiotics is helpful in the prevention and management of ADRs, and may prove useful in the design of novel therapeutic agents with reduced incidence of severe adverse events.

Drug Hypersensitivity↗
PubMed1997

The hydroxylamine of sulfamethoxazole synergizes with FK506 and cyclosporin A, inhibiting T-cell proliferation.

We previously demonstrated the capacity of the hydroxylamine metabolite of sulfamethoxazole (SMX-HA) to inhibit mitogen-induced T-cell proliferation. We studied the interaction of SMX-HA with the immuno-suppressants cyclosporin A (CsA), FK506 and rapamycin. Human peripheral blood mononuclear leukocytes were treated with SMX-HA and combined in culture with CsA or FK506 or rapamycin. The cells were stimulated with phytohaemaglutinin, and phorbol myristate acetate and proliferation was determined by cellular uptake of 3H-thymidine. Using median-effect analysis and concentration reduction index calculations to assess immunosuppressive drug interactions, we produced synergistic immunosuppression by SMX-HA/CsA and SMX-HA/FK506. Concentration reductions at the 50% inhibitory level of over 46-fold and 64-fold with CsA and FK506, respectively, were observed with 25 microM SMX-HA, and this effect was not associated with reduced cell viability. SMX-HA failed to augment the suppressive capacity of rapamycin in inhibiting mitogen-induced cellular proliferation. SMX-HA at immunosuppressive concentrations also failed to interfere with interleukin-2 mRNA transcription and interleukin-2 protein production, which suggests that signaling events proximal to cytokine production are not affected by the metabolite. Synergy between SMX-HA/FK506 and SMX-HA/CsA suggests that the mechanism(s) of action of reactive sulfonamide metabolites may occur in later stages of lymphocyte activation.

Actins↗
PubMed1990

Integration of clinical and administrative strategies to reduce expenditures for antimicrobial agents.

A comprehensive program of clinical and administrative strategies to reduce expenditures for antimicrobial agents is described. Clinical intervention strategies include the use of antimicrobial order sheets, standardized dosage regimens, restriction policies for certain antimicrobial agents, and position statements on the use of restricted agents. A cornerstone of the program is the support for cost-reduction interventions offered by the pharmacy and therapeutics committee and its subcommittee on therapeutics; that support is demonstrated through endorsement and enforcement of pharmacy programs. Physicians are reminded of the cost-reduction programs through periodic articles in the pharmacy newsletter and an "antibiogram" card supplied by the division of epidemiology. The effectiveness of these interventions has been demonstrated by progressive decreases in expenditures for antimicrobial agents during 1987 and 1988. Antimicrobial agents also account for increasingly smaller percentages of the total drug budget. This combination of clinical and administrative strategies reduced expenditures for antimicrobial agents by more than $700,000 over two years without the use of clinical specialists or any apparent sacrifice in the quality of patient care.

Anti-Infective Agents↗
PubMed1986

Comparison of aspartame- and fructose-sweetened layer cakes: importance of panels of users for evaluation of alternative sweeteners.

Panelists with and without known carbohydrate metabolic diseases evaluated layer cakes sweetened with aspartame, alone or in combination with low levels of fructose, for texture and flavor. Panelists used a 5-point, descriptive rating scale to evaluate flavor and texture of lemon, orange, spice, and chocolate layer cakes baked in conventional and microwave ovens. Panelists judged that aspartame alone was not suitable in layer cakes. In general, healthy panelists evaluated the cakes as sweeter, crust bitterness as greater, and overall eating quality as higher than the panel members with carbohydrate metabolic disorders. Panelists did not differ in their evaluation of textural qualities.

Aspartame↗
PubMed1976

A new experimental approach to assessment of velopharyngeal adequacy: nasal manometric bleed testing.

A new experimental method for assessment of velopharyngeal adequacy/inadequacy, using nasal manometric pressure readings for three types of speech conditions under controlled incremental bleed conditions, is described. Cleft palate speakers (N = 30) tended to have higher nasal pressure readings than non-flect palate speakers (N = 56), with or without bleed conditions. Reduction in nasal pressure under controlled incremental bleed for non-cleft palate speakers and cleft palate adequate (CPA) speakers is compatible with an aerodynamic quadratic equation. Unlike cleft palate inadequate (CPI) speakers, non-cleft palate speakers and CPA speakers exhibit similar ability to achieve 0 cm nasal monometric pressure under a bleed bore diameter of 4 mm for a circular bleed orifice. Results for cleft palate marginal (CPM) speakers are less conclusive. Reliability of nasal manometric bleed testing was limitedly tested but not conclusively established in the present report. Further study of reliability and validity is necessary.

Adolescent↗