Biomedical subjects

A J Henderson

Publications and source records attributed to A J Henderson.

At least 19 recordsLinked to original sources

PubMed2000

A method for bronchoscopic evaluation of salivary aspiration in a disabled child.

Chronic aspiration is a cause of life-threatening respiratory complications and repeated hospital admissions, particularly in children with neurological disabilities. Determining the source of aspiration is important for optimizing treatment. This report describes a simple technique to demonstrate salivary aspiration during fibreoptic bronchoscopy. A child with a history of recurrent pneumonia was given methylene blue orally 2 h prior to fibreoptic bronchoscopy. Bronchoscopy was carried out through a laryngeal mask airway under inhalational anaesthesia. The stained saliva was seen to be pooling in the valleculae and then running down the trachea into the bronchi, confirming salivary aspiration.

Bronchoscopy↗

PubMed1999

Enhanced antitumor activity of paclitaxel in combination with the anticarcinoma immunoconjugate BR96-doxorubicin.

The efficacy of chemotherapy has been improved by regimens that combine several cytotoxic drugs with different mechanisms of action and/or different dose-limiting toxicities. Here we demonstrate clearly, and for the first time, that combined therapy using an anticarcinoma immunoconjugate, BR96-doxorubicin, and the cytotoxic drug paclitaxel results in a significant increase in antitumor activity over that of either agent alone. Synergistic activity was seen at doses of BR96-doxorubicin that were minimally active as single agents. A dramatic increase in regression rates was seen when a regimen that combined BR96-doxorubicin and paclitaxel was used to treat both paclitaxel-sensitive and paclitaxel-insensitive carcinomas. Importantly, combined therapy resulted in increased antitumor activity against lung, colon, and breast tumors xenografted in athymic mice and large, paclitaxel-insensitive colon tumors xenografted in athymic rats that also express the Lewis(y) target antigen in normal tissues.

Adenocarcinoma↗

PubMed1998

Changes in blood-gas tensions during apnoeic oxygenation in paediatric patients.

We report changes in arterial blood-gas tensions for up to 5 min of apnoeic oxygenation in 26 anaesthetized paediatric patients (21 children, five infants). Changes in oxygen and carbon dioxide tension were greatest in the first minute of apnoeic oxygenation. In subsequent minutes, rates of change in gas tension were approximately constant. The rate of decline in oxygen tension (31 (95% confidence interval (CI) 20.1-42.2) mm Hg min-1) was more than three times that reported in studies in adults. The rate of increase in carbon dioxide tension (4.2 (95% CI 3.7-4.7) mm Hg min-1) was similar to that reported in adults. After successful preoxygenation, oxygen tension remained greater than 290 mm Hg in all children (age > 1 yr) throughout the study. This was not the case in infants. We found no correlation between changes in blood-gas tensions and age or weight of patients. The small number of infants studied showed rapid decreases in oxygen tension which if sustained would be expected to limit the safe duration of apnoeic oxygenation, unlike adults where apnoeic oxygenation is limited by hypercapnia. Extrapolation of our results suggests that when preoxygenation has been successful, apnoeic oxygenation could continue safely in children for at least 10 min. Infants may become hypoxic after only 2 min.

Age Factors↗

PubMed1997

CCAAT/enhancer binding protein (C/EBP) sites are required for HIV-1 replication in primary macrophages but not CD4(+) T cells.

The importance of CCAAT/enhancer binding proteins (C/EBPs) and binding sites for HIV-1 replication in primary macrophages, T cell lines and primary CD4(+) T cells was examined. When lines overexpressing the C/EBP dominant-negative protein LIP were infected with HIV-1, replication occurred in Jurkat T cells but not in U937 promonocytes, demonstrating a requirement for C/EBP activators by HIV-1 only in promonocytes. Primary macrophages did not support the replication of HIV-1 harboring mutant C/EBP binding sites in the long terminal repeat but Jurkat, H9 and primary CD4(+) T cells supported replication of wild-type and mutant HIV-1 equally well. Thus the requirement for C/EBP sites is also confined to monocyte/macrophages. The requirement for C/EBP proteins and sites identifies the first uniquely macrophage-specific regulatory mechanism for HIV-1 replication.

Binding Sites↗

PubMed1997

Effect of linker variation on the stability, potency, and efficacy of carcinoma-reactive BR64-doxorubicin immunoconjugates.

The internalizing anti-Le(y) monoclonal antibody (MAb) BR64 was conjugated to the anticancer drug doxorubicin (DOX) using an acid-labile hydrazone bond to the DOX and either a disulfide or thioether bond to the MAb. The resulting disulfide (BR64-SS-DOX) and thioether (BR64-S-DOX) conjugates were evaluated for stability, potency, and antigen-specific activity in both in vitro and in vivo model systems. The BR64-SS-DOX conjugates demonstrated antigen-specific activity both in vitro and when evaluated against antigen-expressing, DOX-sensitive human carcinoma xenografts. However, the stability and potency of disulfide conjugates were poor, and in vivo activity superior to unconjugated DOX was seen only at doses approaching the maximum tolerated dose. Furthermore, BR64-SS-DOX conjugates were not active against antigen-expressing, DOX-insensitive colon tumor xenografts. In contrast, the BR64-S-DOX conjugates demonstrated good stability both in vitro and in vivo. The increased stability of the BR64-S-DOX conjugates resulted in the delivery of more biologically active DOX to tumors with a concomitant increase in potency and efficacy over that which could be achieved with either unconjugated DOX or BR64-SS-DOX conjugates. Delivery of DOX by BR64-SS-DOX conjugates resulted in complete regressions and cures of both DOX-sensitive lung xenografts and DOX-intensitive colon tumor xenografts. These results demonstrate the importance of linker stability when delivering drugs such as DOX to carcinomas via internalizing antibodies and are likely to have direct relevance to the clinical utility of MAb-directed delivery.

Animals↗

PubMed1997

Compact tunable Cr:LiSAF laser for infrared matrix-assisted laser desorption/ionization.

A tunable Cr:LiSAF laser-pumped optical parametric oscillator was used for mid-infrared matrix-assisted laser desorption/ionization (MALDI) mass spectrometry experiments. The mass spectra of substance P, bovine insulin and pd(T)10 in the 2.88-2.96 microns range showed excellent single shot signal quality (signal-to-noise-ratio, resolution) but poor shot-to-shot reproducibility. The reproducibility is expected to improve with more stable laser design. No correlation was found between the absorption spectrum of the matrix and the MALDI response.

Animals↗

PubMed1997

Disposition of conjugate-bound and free doxorubicin in tumor-bearing mice following administration of a BR96-doxorubicin immunoconjugate (BMS 182248).

PURPOSE: The chimeric BR96-doxorubicin (DOX) immunoconjugate, BMS 182248, has induced remissions and cures of human lung adenocarcinoma (L2987) implanted in athymic mice. The purpose of this study was to evaluate the biodistribution of DOX after BMS 182248 administration to tumor-bearing mice and to evaluate the ability of BMS 182248 to target DOX to tumors. METHODS: For this evaluation, L2987-implanted mice were given BMS 182248 (5 mg DOX/kg; three doses 4 days apart) and the levels of both conjugate-bound and free DOX in plasma, tumor, liver and heart were determined. RESULTS: Conjugate-bound DOX comprised the majority of plasma DOX, with relatively low levels of free DOX present. From plasma, conjugate-bound DOX distributed to the tissues examined with the order of concentration (per gram of tissue) being tumor > liver > heart. Free DOX was also detected in liver and heart, but at concentrations lower than those present after an equivalent DOX dose (5 mg/kg; three doses 4 days apart). The total exposure of heart to free DOX after BMS 182248 administration was about one-quarter of that found after the administration of DOX alone. The elimination kinetics of both conjugate-bound and free DOX from heart and liver after BMS 182248 administration paralleled those observed from plasma, indicating that equilibrium had been attained between these nontumor tissues and plasma. The elimination kinetics of both entities from tumors, however, were different from those from plasma, liver and heart. BMS 182248 produced sustained levels of both conjugate-bound and free DOX which were present throughout the experiment. This suggested that, in contrast to normal tissues, tumor tissue retention of BMS 182248 by antigen-promoted binding had occurred and that kinetics of free DOX in the tumors were controlled by the rate of release of DOX from tumor-associated BMS 182248. As a result of this retention, the tumor concentrations of free DOX after BMS 182248 administration exceeded those produced by i.v. administration of DOX at the same dose, a finding consistent with the greater antitumor activity of BMS 182248 relative to DOX. BMS 182248 also liberated DOX upon incubation with rat liver lysosomes and was accumulated by L2987 cells in culture, with the subsequent intracellular release of DOX. CONCLUSIONS: BMS 182248 effectively delivered DOX to L2987 xenografts implanted in athymic mice and produced higher and more prolonged tumor concentrations of free DOX than the administration of DOX alone. Following BMS 182248 administration, normal tissues (liver and heart) were exposed to lower overall concentrations of free DOX than were produced by administration of an equivalent DOX dose.

Adenocarcinoma↗

PubMed1996

C/EBP activators are required for HIV-1 replication and proviral induction in monocytic cell lines.

Previous work has shown that C/EBP sites and C/EBP transcriptional activators are necessary for HIV-1 LTR activity in monocytes/macrophages. We have investigated the role that C/EBP proteins play in induction and replication of HIV-1. Ectopic expression of the dominant negative C/EBP protein LIP inhibited HIV-1 mRNA and virus production in activated U1 cells, demonstrating that C/EBP proteins are required for provirus induction. U1 lines overexpressing C/EBP activator NF-IL-6 produced more viral mRNA and virus particles following cellular activation than control lines, demonstrating that C/EBP proteins are limiting for virus transcription. HIV-1 harboring mutations within two C/EBP sites were crippled in their ability to replicate in U937 promonocytic cells, indicating that these sites are required for replication. These data identify C/EBP proteins as regulators of HIV-1 expression in monocytes/macrophages.

Antiviral Agents↗

PubMed1995

The effect of inhaled adrenaline on lung function of recurrently wheezy infants less than 18 months old.

Inhaled bronchodilators have been shown not to improve lung function in infants with wheeze. This observation has led to the suggestion that airway wall edema may be more important than bronchoconstriction in infants with airway narrowing. Inhaled adrenaline is used to relieve upper airway edema in children with croup and has been demonstrated to improve clinical scores and lower pulmonary resistance in some infants with wheeze associated with bronchiolitis. The aim of the present study was to examine the effect of inhaled adrenaline on lung function in a group of infants with recurrent wheeze. Eleven infants aged 10 to 18 months with a history of recurrent wheeze were studied during an asymptomatic interval. Respiratory function was assessed (1) by measuring maximal expiratory flow at functional residual capacity (VmaxFRC) during a forced partial expiratory maneuver and (2) by measuring conductance of the respiratory system (Grs) using a single expiratory occlusion technique. Following baseline measurements, the infants received 0.5 mg/kg adrenaline by nebulizer and serial lung function tests were repeated at 5 min intervals. Ten infants had abnormal baseline lung function (median VmaxFRC 44.2% predicted; median Grs 34% predicted). Using a random effects model, VmaxFRC and Grs declined significantly at 10 and 5 min after adrenaline, respectively. No significant improvements from baseline were observed in either measurement for up to 30 min following adrenaline delivery. It is concluded that inhaled adrenaline did not relieve airways obstruction in this group of asymptomatic infants with recurrent wheeze.

Administration, Inhalation↗

PubMed1995

C/EBP proteins activate transcription from the human immunodeficiency virus type 1 long terminal repeat in macrophages/monocytes.

Three binding sites for C/EBP proteins are found in the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) (V. M. Tesmer, A. Rajadhyaksha, J. Babin, and M. Bina, Proc. Natl. Acad. Sci. USA 90:7298-7302, 1993). We have determined the functional role of C/EBP proteins and C/EBP sites in regulating transcription from the HIV-1 LTR in monocytes/macrophages. Inhibition of endogenous C/EBP proteins, using either an excess of C/EBP binding sites or a trans-dominant negative inhibitor, demonstrated that C/EBP proteins are required for basal and activated levels of HIV-1 LTR transcription in the promonocytic cell line U937. Northern (RNA) blots and binding assays showed that NF-IL6 is the only known C/EBP family member which is increased when U937 cells are activated. Mutational analyses of the HIV-1 LTR showed that one C/EBP site is required for normal LTR transcription both before and after cellular activation and that the two 3' C/EBP sites are functionally equivalent. However, transcription from crippled HIV-1 LTRs lacking C/EBP sites can still be induced following activation of U937 cells. Several models are suggested for how elevated NF-IL6 may participate in an autostimulatory loop involving HIV infection, macrophage activation, cytokine expression, and HIV replication.

Base Sequence↗

PubMed1995

Lessons in transcriptional regulation learned from studies on immunoglobulin genes.

In this article, we consider basic principles of eukaryotic gene transcriptional regulation which have emerged from studies on immunoglobulin heavy chain and kappa chain genes. Four areas are considered: (1) regulation by distant enhancer elements, (2) multiple regulators in a given element including particular families of regulators which were discovered by studying Ig genes, (3) achieving tissue specificity of transcription by multiple mechanisms and (4) the importance of chromatin structure for transcriptional regulation.

Animals↗

PubMed1994

GATA elements are necessary for the activity and tissue specificity of the T-cell receptor beta-chain transcriptional enhancer.

Three high-affinity binding sites for the GATA family of transcriptional regulators have been identified within the T-cell receptor beta-chain (TCR beta) transcriptional enhancer, and their functional significance has been determined in an effort to understand the T-cell specificity of the enhancer more fully. One site, TE4, is important for activity of the enhancer in T cells. Neither site TE1 nor site TE2 can functionally replace a mutated TE4 site in T cells; however, the same protein, probably GATA-3, binds all three sites, as judged by electrophoretic mobility shift, oligonucleotide competition, and proteolytic clipping assays. These data suggest that additional proteins are critical for the ability of GATA-3 to activate the TCR beta enhancer. In fibroblasts, the GATA sequence at site TE1 appears to bind a negative regulator. Since this is not true in B cells, B cells and fibroblasts appear to have different mechanisms for negative regulation of the TCR beta enhancer.

Animals↗

PubMed1994

Bronchoalveolar lavage.

Bronchoalveolar lavage has a well established role in the diagnosis of pulmonary infections, particularly those due to opportunistic organisms in an immunocompromised host. Recent studies of infants and adults with inflammatory lung disease have helped our understanding of the mechanisms underlying these disorders and their responses to treatment. With increasing recognition that pulmonary events in utero and in early infancy are important in the pathogenesis of lung diseases such as asthma, studies of the lung's responses to various environmental insults in this population might guide us to developing effective preventative and therapeutic strategies. Bronchoalveolar lavage is one method for assessing a number of pulmonary components and may be useful in this regard, particularly if combined with new methods for examining inflammatory responses, such as those utilising the polymerase chain reaction to assess cellular expression for inflammatory cytokines and growth factors.

Bronchoalveolar Lavage Fluid↗

PubMed1993

Cure of xenografted human carcinomas by BR96-doxorubicin immunoconjugates.

Immunoconjugates (BR96-DOX) were prepared between chimeric monoclonal antibody BR96 and the anticancer drug doxorubicin. The monoclonal antibody binds an antigen related to Lewis Y that is abundantly expressed at the surface of cells from many human carcinomas; it has a high degree of tumor selectivity and is internalized after binding. BR96-DOX induced complete regressions and cures of xenografted human lung, breast, and colon carcinomas growing subcutaneously in athymic mice and cured 70 percent of mice bearing extensive metastases of a human lung carcinoma. Also, BR96-DOX cured 94 percent of athymic rats with subcutaneous human lung carcinoma, even though the rats, like humans and in contrast to mice, expressed the BR96 target antigen in normal tissues.

Animals↗

PubMed1993

Effect of salbutamol on histamine induced bronchoconstriction in healthy infants.

BACKGROUND: The effect of inhaled beta 2 adrenergic drugs on infants with wheezing disorders remains controversial. Salbutamol inhibits the bronchial responsiveness of infants to histamine and nebulised water but whether or not it acts as a bronchodilator in this age group is unclear. The aim of the present study was to determine whether salbutamol can hasten the reversal of histamine induced bronchoconstriction in infants. METHODS: Bronchial challenge with histamine was performed in 40 infants aged 12 months or less with no previous history of respiratory symptoms. Response to histamine was assessed by forced partial expiratory flow/volume curves to measure maximal flow at functional residual capacity (VmaxFRC). After a fall of 40% or more from baseline VmaxFRC, each infant was randomly assigned to receive either salbutamol 0.5% or saline 0.9% solution by nebuliser. The rate of recovery of VmaxFRC and the time to reach baseline VmaxFRC were derived by linear regression. RESULTS: Infants who received salbutamol had a significantly faster rate of recovery (geometric mean 8.5 ml/s/min) than those who received saline (4.1 ml/s/min). Considerable interindividual variation was observed in the time from maximum bronchoconstriction to recovery of baseline VmaxFRC in both groups of subjects. CONCLUSIONS: Salbutamol significantly speeds the reversal of histamine induced bronchoconstriction in infants during the first 12 months of life. This observation provides further evidence to support the presence of functional beta adrenergic receptors in the airways of infants.

Administration, Inhalation↗

PubMed1992

Antigen-specific activity of carcinoma-reactive BR64-doxorubicin conjugates evaluated in vitro and in human tumor xenograft models.

The anticarcinoma antibody BR64 was conjugated to a doxorubicin derivative, doxorubicin 13-[3-(2-pyridyldithio)propionyl]hydrazone, and the resulting conjugates (BR64-DOX) were evaluated for activity and immunological specificity in vitro and in human tumor xenograft models. The BR64-DOX immunoconjugates retained immunoreactivity and cytotoxicity and demonstrated antigen-specific cytotoxicity in vitro. The potency of BR64-DOX immunoconjugates in vitro was related to the drug:monoclonal antibody mole ratio of the conjugates. The antitumor activity of BR64-DOX conjugates was consistently superior to the maximal activity obtained with the parent drug, doxorubicin (DOX), in established human lung and human breast carcinoma xenograft models. The superior antitumor activity of BR64-DOX conjugates was reflected both in tumor growth inhibition and in regressions and cures of established tumors following the administration of tolerated doses of BR64-DOX. The antitumor activity of BR64-DOX conjugates was not the result of synergism between monoclonal antibody BR64 and DOX, because mixtures consisting of monoclonal antibody and optimized DOX were not more active than an equivalent dose of DOX administered alone. The antitumor activity of BR64-DOX conjugates was antigen specific; equivalent doses of nonbinding isotype-matched conjugates were not active against established tumor xenografts.

Adenocarcinoma↗

PubMed1992

Status of kappa L chain gene rearrangements and c-kit and IL-7 receptor expression in stromal cell-dependent pre-B cells.

Studies from several laboratories have provided evidence that distinct stromal cell-derived signals are involved in the maturation of pre-B cells into surface Ig expressing B lymphocytes. In order to define the stage of development at which these stimuli act, various polymerase chain reaction strategies were used to characterize the status of kappa L chain gene rearrangements in nontransformed, stromal cell dependent pre-B cells. These cells were obtained from lymphoid colonies whose growth was potentiated by factors from a stromal cell line. kappa L chain genes in cells from many of these colonies were rearranged, and analysis of the Jk genes used indicated a bias toward the most 3' loci. However, the use of a reverse transcriptase PCR strategy failed to detect mature kappa transcripts, indicating that stromal cell mediators exist that allow pre-B cells to progress to the stage at which L chain genes are rearranged but not expressed. Reverse transcriptase PCR further revealed that no transcripts for c-kit (the receptor for kit-ligand) and the IL-7R could be detected in these cells. This suggests that these receptors are no longer expressed by the time cells have undergone kappa rearrangements and minimize a role for stromal cell-derived kit-ligand and IL-7 in mediating the pre-B to B cell transition.

Animals↗

PubMed1990

Functional characterization of two stromal cell lines that support B lymphopoiesis.

Bone marrow stromal cells have well documented effects on the production of B lymphocytes, but whether or not stromal cell signals are involved in the pre-B to B cell transition is unclear. The potential of two stromal cell lines, S10 and S17, in this process was examined. Initial experiments, using a short term liquid culture, indicated that S10 and S17 stroma efficiently supported the generation of clonable B cells (B lymphocyte CFU) from their immediate precursors in fresh bone marrow. The contribution of macrophages and other accessory cells in those experiments was minimized through use of a colony assay system that permits the direct effects of stromal cell signals on single B cell progenitors to be evaluated. The results indicated that soluble mediators from the S10 and S17 lines could support colony formation from fresh or cultured surface Ig- bone marrow cells. Colonies supported by S17 stroma appeared on day 15 and contained cells that expressed the B220 Ag; surface IgM expression was never observed. S10 supported colonies appeared on day 7 and routinely included surface IgM+ cells. Individual colonies were capable of undergoing additional growth when picked and replated directly onto the different stroma. Those colonies replated onto S10 stroma generated surface IgM expressing cells in up to 60% of experiments, but colonies transferred onto the S17 cell line included B cells only 10% of the time. These data demonstrate that stromal cells alone can provide the signals necessary for generating a surface IgM+ B cell from precursors but that not all stromal cell lines are equally efficient at doing so.

Animals↗