Search PubMed⌕ Search

Biomedical subjects

D Bowman

Publications and source records attributed to D Bowman.

At least 19 recordsLinked to original sources
PubMed1999

Allogeneic bronchoalveolar lavage cells induce the histology and immunology of lung allograft rejection in recipient murine lungs: role of intercellular adhesion molecule-1 on donor cells.

BACKGROUND: Intercellular adhesion molecule (ICAM)-1 expressed on accessory cells has a key role in antigen presentation. The histology and immunology of lung allograft rejection is postulated to result from donor lung accessory cells presenting alloantigens to recipient lymphocytes, and, therefore, ICAM-1 may have a crucial role in the rejection process. We have previously reported that the instillation of allogeneic (C57BL/6, I-a(b)) bronchoalveolar lavage (BAL) cells (96% macrophages, 2% dendritic cells) into the lungs of recipient BALB/c mice (I-a(d)) induced the histology and immunology of acute lung allograft rejection. Using this model, the purpose of the current study was to determine the role of ICAM-1 on donor lung cells in lung allograft rejection. METHODS: BALB/c mice received allogeneic BAL cells from wild-type or ICAM-1 mutant (lacking ICAM-1 expression) C57BL/6 mice by nasal insufflation weekly for 4 weeks. Recipient mice underwent BAL and serum collection for the determination of T helper 1/T helper 2 cytokines and IgG subtypes. Lung histology was graded using standard criteria for allograft rejection. RESULTS: Although wild-type cells induced a lymphocytic vasculitis and bronchitis, ICAM-1 mutant allogeneic BAL cells only induced a lymphocytic vasculitis in recipient lungs. Both wild-type and ICAM-1 mutant cells induced up-regulated local interferon-gamma and IgG2a production, and deposition of IgG2a in recipient lungs. CONCLUSIONS: These data show that ICAM-1 on donor lung accessory cells mediates differential effects on the histology and immunology of acute lung allograft rejection.

Animals↗
PubMed1998

Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: To determine the relative efficacy of an intensive cyclophosphamide, epirubicin, and fluorouracil (CEF) adjuvant chemotherapy regimen compared with cyclophosphamide, methotrexate, and fluorouracil (CMF) in node-positive breast cancer. PATIENTS AND METHODS: Premenopausal women with node-positive breast cancer were randomly allocated to receive either cyclophosphamide 100 mg/m2 orally days 1 through 14; methotrexate 40 mg/m2 intravenously (i.v.) days 1 and 8; and fluorouracil 600 mg/m2 i.v. days 1 and 8 or cyclophosphomide 75 mg/m2 orally days 1 through 14; epirubicin 60 mg/m2 i.v. days 1 and 8; and fluorouracil 500 mg/m2 i.v. days 1 and 8. Each cycle was administered monthly for 6 months. Patients administered CEF received antibiotic prophylaxis with cotrimoxazole two tablets twice a day for the duration of chemotherapy. RESULTS: The median follow-up was 59 months. One hundred sixty-nine of the 359 CMF patients developed recurrence compared with 132 of the 351 CEF patients. The corresponding 5-year relapse-free survival rates were 53% and 63%, respectively (P = .009). One hundred seven CMF patients died compared with 85 CEF patients. The corresponding 5-year actuarial survival rates were 70% and 77%, respectively (P = .03). The rate of hospitalization for febrile neutropenia was 1.1% in the CMF group compared with 8.5% in the CEF group. There was one case of congestive heart failure in a patient who received CMF compared with none in the CEF group. Acute leukemia occurred in five patients in the CEF group. CONCLUSION: The results of this trial show the superiority of CEF over CMF in terms of both disease-free and overall survival in premenopausal women with axillary node-positive breast cancer.

Adult↗
PubMed1997

Information needs and decisional preferences in women with breast cancer.

OBJECTIVE: To determine the degree of involvement women with breast cancer wanted in medical decision making, extent to which they believed they had achieved their preferred level of involvement, and types of information they judged to be most important. DESIGN AND SETTING: Cross-sectional survey at 2 tertiary oncology referral clinics and 2 community hospital oncology clinics in Winnipeg, Manitoba. PATIENTS: Consecutive sample of 1012 women with a confirmed diagnosis of breast cancer who were scheduled for a visit at 1 of 4 hospital oncology clinics. MAIN OUTCOME MEASURES: The following measures were used: (1) Preferences about various levels of participation in treatment decision making; (2) the extent to which subjects believed they had achieved their preferred levels of involvement in decision making; and (3) priority needs for information and how these needs differed by selected sociodemographic, disease, and treatment variables. RESULTS: A total of 22% of women wanted to select their own cancer treatment, 44% wanted to select their treatment collaboratively with their physicians, and 34% wanted to delegate this responsibility to their physicians. Only 42% of women believed they had achieved their preferred level of control in decision making. The 2 most highly ranked types of information were related to knowing about chances of cure and spread of disease. Women younger than 50 years rated information about physical and sexual attractiveness as more important than did older women (P<.001); women older than 70 years rated information about self-care as more important than did younger women (P=.002); and women who had a positive family history of breast cancer rated information about family risk as more important than did other women (P=.03). CONCLUSIONS: The substantial discrepancy between women's preferred and attained levels of involvement in treatment decision making suggests that systematic approaches to assess and respond to women's desired level of participation in treatment decision making need to be evaluated. Priorities for information identified in this study provide an empirical basis to guide communication with women seeking care for breast cancer.

Adult↗
PubMed1997

The development of Ca2+ channel responses and their coupling to exocytosis in cultured cerebellar granule cells.

Using single-cell imaging, we investigated developmental changes in the modulation of KCl-evoked Ca2+ entry by various voltage-dependent Ca2+ channels and the coupling of these channels to exocytosis in cultured cerebellar granule neurons. A component of the KCl-evoked Ca2+ elevation sensitive to nifedipine and localized at cell somata, decreases with culture age. A component blocked by 200 nM omega-Agatoxin-IVA increases with age and whilst localized primarily at the cell somata, also becomes evident at the neurites. The change in activity between nifedipine-sensitive Ca2+ channels and omega-Agatoxin-IVA-sensitive Ca2+ channels occurs at 13 days in vitro at cell somata. A component of Ca2+ entry insensitive to nifedipine and 200 nM omega-Agatoxin-IVA is localized primarily at the neurites and is apparent at all ages. Single-cell imaging of exocytosis using FM1-43 destaining indicates that the residual, but not the nifedipine- or omega-Agatoxin-IVA-sensitive components of Ca2+ entry, modulates exocytosis. However cells cultured for 20-26 days develop a component of Ca2+ entry at the neurites which is sensitive to 200 nM omega-Agatoxin-IVA and omega-Conotoxin-MVIIC and which partially controls release. Immunolocalization studies reveal that binding sites for omega-Conotoxin-GVIA are present throughout development, even though this toxin does not inhibit KCl-evoked [Ca2+]c elevations or exocytosis. 300 nM omega-Agatoxin-IVA labels both somata and, at later developmental stages, neurites, consistent with the functional studies.

Animals↗
PubMed1997

Randomized trial of cyclophosphamide, methotrexate, and fluorouracil chemotherapy added to tamoxifen as adjuvant therapy in postmenopausal women with node-positive estrogen and/or progesterone receptor-positive breast cancer: a report of the National Cancer Institute of Canada Clinical Trials Group. Breast Cancer Site Group.

PURPOSE AND METHODS: By the mid 1980s, tamoxifen alone was considered standard adjuvant therapy for postmenopausal women with node-positive, estrogen receptor (ER)- or progesterone receptor (PgR)-positive breast cancer. From 1984 through 1990, 705 eligible postmenopausal women with node-positive, ER- or PgR-positive breast cancer were randomized to a National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) study that compared tamoxifen 30 mg by mouth daily for 2 years (TAM) versus TAM plus chemotherapy with all-intravenous cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and fluorouracil 600 mg/m2 given every 21 days for eight cycles (CMF). RESULTS: There were no significant differences in overall survival, recurrence-free survival, locoregional recurrence-free survival, or distant recurrence-free survival between the two treatment arms. However, there was significantly greater severe toxicity, which included leukopenia (P < .0001), nausea and vomiting (P < .0001), and thromboembolic events (P < .0001), as well as significantly more mild or greater toxicity, which included thrombocytopenia (P = .04), anemia (P = .02), infection (P = .0004), mucositis (P = .0001), diarrhea (P = .0001), and neurologic toxicity (P = .006), in women who received TAM plus CMF. CONCLUSION: The addition of CMF to TAM adds no benefit and considerable toxicity in this group of women.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Disease management interventions to improve outcomes in congestive heart failure.

This study is part of a planned 24-month, multicenter, longitudinal comparison of a comprehensive congestive heart failure (CHF) disease management program and was designed to determine effectiveness after 12 months of implementation. The impact of interventions such as telemonitoring of patients, post-hospitalization follow-up, and provider education on selected primary outcomes (hospital admission and readmission rates, length of stay, total hospital days, and emergency room utilization) in a managed care setting was evaluated. Subjects in the study included all participants in the managed care plan, as well as 149 selected program participants. The effects of the program were analyzed for pure CHF and CHF-related diagnoses, with outcomes for the third quarter of 1996 (postintervention follow-up) being compared with those for the third quarter of 1995 (preintervention baseline). Overall, the data demonstrated significantly reduced admission and readmission rates for patients with the pure CHF diagnosis. Among the entire CHF patient population, the third quarter admission rate declined 63% (P = 0.00002), and the 30-day and 90-day readmission rates declined 75% (P = 0.02) and 74% (P = 0.004), respectively. Among program participants with pure CHF diagnoses, the 30-day readmission rate was reduced to 0, and an 83% reduction occurred for both the third quarter admission (P = 0.008) and 90-day readmission (P = 0.06) rates. In addition, the average length of stay for patients with CHF-related diagnoses was significantly reduced among both plan participants (P = 0.03) and program participants (P = 0.001). Reductions were also seen in total hospital days and emergency room utilization. These data thus indicate that a comprehensive disease management program can reduce healthcare utilization not only among CHF patients in the program but also among the entire managed care plan population.

Disease Management↗
PubMed1996

Inhibition of acetylcholine release from presynaptic terminals of skate electric organ by calcium channel antagonists: a detailed pharmacological study.

Release of acetylcholine (ACh) from the presynaptic terminals in skate electric organ was tested for its sensitivity to calcium channel antagonists. A pharmacological profile was established by measuring inhibition of K(+)-stimulated release of [3H]ACh from prelabelled tissue slices. Peptide antagonists of N-type (omega-conotoxins GVIA and MVIIA) and P-type (omega-agatoxin-IVA) channels had no effect, whereas both omega-conotoxins MVIIC and SVIB produced concentration-dependent inhibition and could completely block ACh release. omega-Conotoxin GVIA and omega-agatoxin IVA did not attenuate the block by omega-conotoxin MVIIC. The inorganic ions, Cd2+ and Ni2+, also produced a full inhibition of release (Cd2+ > > Ni2+) and Gd3+ a partial one. Drugs targeting L-type channels (diltiazem, nifedipine and verapamil) at low microM concentrations and a synthetic analogue of the polyamine toxin from funnel web spider venom (sFTX) at 1 mM were all non-inhibitory. Inhibition by omega-conotoxins MVIIC (IC50 25 nM) and SVIB (IC50 500 nM) was reversible and modulated by external concentrations of Ca2+. Inhibitory potency was increased by lowering and decreased by elevating external Ca2+. This "antagonistic" effect of Ca2+ was also seen with Cd2+ inhibition. The inhibitory potency of omega-conotoxin MVIIC was unaffected by predepolarisation. End plate potentials generated by release of endogenous ACh in electrically-stimulated slices were also reversibly blocked by Cd2+ and omega-conotoxins MVIIC and SVIB but were unaffected by omega-conotoxin GVIA and omega-agatoxin IVA. It is concluded that ACh release in skate electric organ depends on presynaptic calcium channels which have different pharmacological properties from established sub-types.

Acetylcholine↗
PubMed1995

Affinity purification of rat cortical and chicken forebrain synaptosomes using a biotinylated derivative of omega-CgTx GVIA.

We describe a magnetophoretic method for the affinity purification of synaptosomes expressing omega-CgTx GVIA-sensitive, N-type voltage-sensitive calcium channels (VSCCs). The method utilizes a biotinylated derivative of omega-CgTx GVIA which retains its ability to displace [125I] omega-CgTx GVIA from its binding sites on rat synaptic membranes. When coupled to streptavidin coated magnetizable beads, the hexanoyl spacer between omega-CgTx GVIA and the biotin:streptavidin bead complex is sufficiently long to allow flexibility of the toxin to bind to its receptor on synaptosomes. We have used this ligand successfully to isolate deaggregated synaptosomes from the parent fractions of chicken forebrain and rat cortex. In the chicken synaptosome parent fraction, omega-CgTx GVIA (1 nM-1 microM) produced a concentration-dependent block of the KCl-induced intracellular free Ca2+, [Ca2+]i, elevation with an IC50 of 28 nM. After affinity magnetophoresis no increase in [Ca2+]i elevation was observed in either the bound or unbound fractions. In the rat synaptosome parent fraction, the KCl-induced increase in free intracellular Ca2+ ([Ca2+]i) elevation was partially blocked by omega-CgTx GVIA (17 +/- 2% / 1 microM) and to a greater extent by omega-Aga IVA (55 +/- / 1 microM): a combination of the two toxins was additive (72 +/- 4% / 1 microM). The block obtained by omega-CgTx GVIA (1 microM) in the unbound fraction was reduced to 3 +/- 2%, whereas that by omega-Aga IVA (1 microM) increased to 82 +/- 3%. The block obtained by a combination of both toxins (83 +/- 2%) was the same as that with omega-Aga IVA alone (82 +/- 3%). No increase in free [Ca2+]i elevation was observed in the bound fraction although single synaptosome-like structures, displaying synaptophysin immunoreactivity, were detected on the beads. We conclude that omega-CgTx GVIA-sensitive N-type calcium channels are present on all chicken forebrain synaptosomes but only a subset of rat cortical synaptosomes.

Animals↗
PubMed1995

Characteristics of a human N-type calcium channel expressed in HEK293 cells.

The human alpha 1B-1 alpha 2b beta 1-2 Ca2+ channel was stably expressed in HEK293 cells producing a human brain N-type voltage-dependent calcium channel (VDCC). Whole cell voltage-clamp electrophysiology and fura-2 based microfluorimetry have been used to study its characteristics. Calcium currents (ICa) recorded in transfected HEK293 cells were activated at potentials more depolarized than -20 mV with peak currents occurring at approx + 10 mV in 5 mM extracellular CaCl2. ICa and associated rises in intracellular free calcium concentrations ([Ca2+]i) were sensitive to changes in both the [Ca2+]o and holding potential. Steady-state inactivation was half maximal at a holding potential of -60 mV. Ba2+ was a more effective charge carrier than Ca2+ through the alpha 1B-1 alpha 2b beta 1-2 Ca2+ channel and combinations of both Ba2+ and Ca2+ as charge carriers resulted in the anomalous mole fraction effect. Ca2+ influx into transfected HEK293 cells was irreversibly inhibited by omega-conotoxin-GVIA (omega-CgTx-GVIA; 10 nM-1 microM) and omega-conotoxin-MVIIA; 100 nM-1 microM) whereas 1 microM) whereas no reductions were seen with agents which block P or L-type Ca2+ channels. The inorganic ions, gadolinium (Gd3+), cadmium (Cd2+) and nickel (Ni2+) reduced the ICa under voltage-clamp conditions in a concentration-dependent manner. The order of potency of the three ions was Gd3+ > Cd2+ > Ni2+. These experiments suggest that the cloned and expressed alpha 1B-1 alpha 2b beta 1-2 Ca2+ channel subunits form channels in HEK293 cells that exhibit properties consistent with the activity of the native-N-type VDCC previously described in neurons.

Cadmium↗
PubMed1995

3-D reconstruction of Ir-192 implant dosimetry for irradiating gingival carcinoma on the mandibular alveolar ridge.

A recurrent cancer in the gingiva has been treated by specially fabricating a dental acrylic appliance. This replica of the floor of the mouth, gums, and teeth was constructed with the use of a vinyl polysiloxine impression material. The tumor boundaries were marked in the fabricated appliance with four metal wires to localize the surface and periphery of the tumor. The appliance was molded to hold Ir-192 wires in near contact with the target surface and to allow afterloading. A specially designed lead shield was imbedded onto the dorsal surface of the appliance so as to reduce dose to the tongue and maxillary structures of the mouth. Simulation films and 3-D treatment planning were used to generate isodose distributions and to allow preplanning. The dose calculation algorithm was modified to account for the attenuation in the lead shield represented in three dimensions. The Ir-192 mold was successfully applied for 38 hours in two sessions 1 week apart.

Aged↗
PubMed1995

Novel pharmacological sensitivity of the presynaptic calcium channels controlling acetylcholine release in skate electric organ.

The presynaptic terminals of skate (Raja montagui) electric organ were tested for their sensitivity to calcium channel antagonists. Acetylcholine (ACh) release and the elevation of intraterminal Ca2+ concentrations triggered by K+ depolarisation were studied. ACh release was measured as 3H efflux from slices of organ prelabelled with [3H]choline. Depolarisation caused a marked, Ca(2+)-dependent increase in 3H efflux that was completely blocked by 100 microM Cd2+ and by 300 nM omega-conotoxin-MVIIC (MVIIC). Inhibition by MVIIC was concentration dependent (IC50 of approximately 20 nM) and reversible. No inhibition was seen with nifedipine (5 microM) or the two other peptide antagonists studied: omega-conotoxin-GVIA (GVIA) at 5 microM and omega-agatoxin-IVA (Aga-IVA) at 1 microM. In a "nerve plate" preparation (a presynaptic plexus of nerve fibres, Schwann cells, and nerve terminals) changes in intraterminal Ca2+ concentrations were measured by microfluorimetry using fluo-3. An increase in fluorescence, indicating a rise in the free [Ca2+], rapidly followed K+ depolarisation, and this change was restricted to the nerve terminals. This response was insensitive to nifedipine (5 microM), GVIA (5 microM), and Aga-IVA (300 nM) but almost completely abolished by MVIIC (1 microM). MVIIC inhibition was concentration dependent and partially reversible. These results show that the nerve terminals in skate electric organ have calcium channels with a pharmacological sensitivity that is markedly different from the established L, N, and P types in other systems but shares some, but not all, of the features of the recently described Q type.

Acetylcholine↗
PubMed1995

A full likelihood procedure for analysing exchangeable binary data.

A full-likelihood procedure is proposed for analyzing correlated binary data under the assumption of exchangeability. The binomial and beta-binomial models are shown to occur as special cases correspondingly, respectively, to the choice of degenerate and beta-mixing distributions. For a finite exchangeable binary sequence of random variables, expressions for the joint distribution, moments, and correlations of all orders are derived. Maximum likelihood estimates of the moments of all orders are computed and used to estimate correlations and the distribution of the number of responses in a cluster. In an application to developmental toxicology data analysis, the procedure introduced is compared with a beta-binomial and a generalized estimating equation procedure in which mean response and intralitter correlation are linked to dose.

2,4,5-Trichlorophenoxyacetic Acid↗
PubMed1995

Estimating variance functions in developmental toxicity studies.

The presence of intralitter correlation is a well known issue for analysis of the developmental toxicology data. The intralitter correlation coefficients observed in developmental toxicology data are generally different across dose groups. In this paper we use a generalized estimating equation procedure to model jointly the mean parameters and the intralitter correlation coefficients as functions of dose levels. Our procedure is similar to that used by Prentice and Zhao (1991, Biometrics 47, 825-839) for estimating the mean and variance parameters.

2,4,5-Trichlorophenoxyacetic Acid↗
PubMed1994

Omega-conotoxin MVIIC reversibly inhibits a human N-type calcium channel and calcium influx into chick synaptosomes.

We have investigated the effects of omega-CmTX MVIIC on the recombinant alpha 1B-mediated calcium channel expressed in HEK 293 cells and on the predominantly N-type calcium channel in chick synaptosomes. omega-CmTX MVIIC potently and reversibly inhibited the calcium current through alpha 1B-mediated calcium channels and inhibited KCl-evoked increases in [Ca2+]i in chick synaptosomes in a concentration-dependent manner.

Action Potentials↗
PubMed1994

Growth of tumor derived activated T-cells for the treatment of cancer.

This report describes the production of Tumor Derived Activated Cell cultures (TDAC, also called tumor infiltrating lymphocytes) from patient tumor biopsies and our preliminary experience growing these cells to therapeutic levels using artificial capillary bioreactor cultures. TDAC were successfully grown in medium containing Interleukin 2 from 80% of the 113 tumor biopsies tested. There was no significant difference in success (growth to 1 x 10(9) cells) comparing primary and metastatic tumors. Many of the tumors were shipped to the laboratory from distant sites. Success rate did decrease with the length of time for tumor transport. Interleukin 4 was beneficial in the development of 1 of 4 TDAC cultures which did not grow with IL-2 only. Seventy-seven bioreactor cultures were initiated for 31 patients. On the average, 1.9 x 10(9) TDAC were inoculated per bioreactor; 3.3 x 10(10) were harvested in 22 days. Twelve liters of medium were required per 1 x 10(10) TDAC produced. TDAC cultures contained T cells with variable ratios of CD4 to CD8 cells. Secreted granulocyte monocyte colony stimulating factor, interferon gamma and tumor necrosis factor were measured in the bioreactor cartridge conditioned medium. Twenty three patients were evaluated. Partial responses were observed in 4 patients including a dramatic remission of scalp nodules in a patient with renal cancer. Results showed that therapeutic amounts of TDAC cells may be produced in a reasonable and cost effective manner using artificial capillary bioreactor cultures.

Biopsy↗
PubMed1993

A three-dimensional view of precursor messenger RNA metabolism within the mammalian nucleus.

A quantitative three-dimensional analysis of nuclear components involved in precursor messenger RNA metabolism was performed with a combination of fluorescence hybridization, immunofluorescence, and digital imaging microscopy. Polyadenylate [poly(A)] RNA-rich transcript domains were discrete, internal nuclear regions that formed a ventrally positioned horizontal array in monolayer cells. A dimmer, sometimes strand-like, poly(A) RNA signal was dispersed throughout the nucleoplasm. Spliceosome assembly factor SC-35 localized within the center of individual domains. These data support a nuclear model in which there is a specific topological arrangement of noncontiguous centers involved in precursor messenger RNA metabolism, from which RNA transport toward the nuclear envelope radiates.

Cell Nucleus↗