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Biomedical subjects

M A Moore

Publications and source records attributed to M A Moore.

At least 163 records · Page 9Linked to original sources
PubMed1995

Dose escalation of paclitaxel with high-dose cyclophosphamide, with analysis of progenitor-cell mobilization and hematologic support of advanced ovarian cancer patients receiving rapidly sequenced high-dose carboplatin/cyclophosphamide courses.

PURPOSE: We commenced a phase I study of escalating dose Taxol (paclitaxel; Bristol-Myers Squibb Co, Wallingford, CT) in addition to cyclophosphamide, to assess its impact on both antitumor efficacy and mobilization of peripheral-blood progenitor cells (PBP). PATIENTS AND METHODS: Induction therapy consisted of two cycles of cyclophosphamide 3.0 g/m2 plus escalating-dose Taxol (dose levels I to IV, 150, 200, 250, and 300 mg/m2, respectively) in cohorts of three, plus filgrastim granulocyte colony-stimulating factor [G-CSF]) and leukaphereses to harvest PBP, followed by four courses of rapidly cycled carboplatin and cyclophosphamide (1,000 and 1,500 mg/m2 per course, respectively), for which hematopoietic rescue was achieved with PBP. RESULTS: Sixteen patients completed all planned cycles of Taxol/cyclophosphamide. Fifty-four cycles of carboplatin/cyclophosphamide were given and rescued with PBP. The median interval between treatments for Taxol/cyclophosphamide courses was 14 days (range, 13 to 21). Twelve patients completed all planned cycles of carboplatin/cyclophosphamide. The median inter-treatment interval for carboplatin/cyclophosphamide courses when rescue was achieved with Taxol/cyclophosphamide-primed PBP was 17 days (range, 14 to 25). The median number of days to recovery of an absolute neutrophil count (ANC) greater than 0.5 was 8 (range, 5 to 12), and of self-sustaining platelet count greater than 20 x 10(9)/L, 11 (range, 8 to 15). There was one episode of fatal sepsis. Of 13 patients assessable for response, there were five patients with pathologic complete responses (38.5%), six patients with microscopic residual disease (46%), and two patients with pathologic partial responses, for an overall response rate of 100%. CONCLUSION: The addition of escalating-dose Taxol to high-dose cyclophosphamide does not compromise PBP mobilization. The use of PBP mobilized in this fashion provides reliable engraftment after sequential administration of high-dose carboplatin/cyclophosphamide. Toxicities produced with this approach are manageable. The response rates demonstrated are promising and warrant further evaluation.

Adenocarcinoma↗
PubMed1995

Hypertension management in renal insufficiency.

Renal failure is on the rise in the elderly, in those with diabetes and hypertension, and in some minority groups. Recognizing mild renal impairment, correcting reversible causes, and controlling blood pressure can serve as deterrents.

Humans↗
PubMed1995

Increased resistance to methotrexate in human hematopoietic cells after gene transfer of the Ser31 DHFR mutant.

Retroviral gene transfer into hematopoietic cells has many experimental as well as clinical applications. Although transduction efficiency of retroviral vectors is higher than with conventional methods, selection of successfully transduced cells may become mandatory for efficient in vivo transfer. We have been evaluating a retroviral construct that meets the criteria for a clinically acceptable selection system. The Ser31 dihydrofolate reductase (DHFR) mutant confers resistance to methotrexate (MTX) due to decreased binding of the drug. while its enzymatic activity remains adequate for normal folate metabolism. Transduction of this vector into murine hematopoietic cells has been recently described and increase in MTX resistance could be observed. We investigated transduction of CD34-antigen positive subpopulations of hematopoietic progenitor cells and CD34-positive/CD38-negative subpopulations enriched for stem cells. We focused on two sources of primary hematopoietic cells, umbilical cord blood (UCB) and peripheral blood (PB) harvested from patients after mobilization with chemotherapy and/or cytokines. Both contain a large number of lineage restricted and pluripotent progenitor cells and can be expanded extensively ex vivo. Potential clinical applications of gene therapy in such cell populations include correction of inborn enzymatic diseases and support of high-dose chemotherapy by transplanting ex vivo transduced progenitor cells rendered more resistant to cytotoxic drugs. The feasibility and efficiency of retroviral transduction into UCB and PB has been reported recently.

Antigens, CD34↗
PubMed1994

Optimization of conditions for ex vivo expansion of CD34+ cells from patients with stage IV breast cancer.

Multiple cycles of high-dose chemotherapy can be hematologically supported by repeated administration of peripheral blood progenitors obtained after mobilization using cytokine alone or in combination with chemotherapy. We have explored the quality of such cells and their potential to undergo ex vivo expansion. Twenty-five leukapheresis samples from 19 patients who had received extensive prior chemotherapy for stage IV breast cancer were subjected to CD34+ cell selection using immunoaffinity columns of immunomagnetic bead separation. Cells were cultured in suspension in the presence of c-kit ligand, interleukin-3, interleukin-6, erythropoietin, and granulocyte colony-stimulating factor. Ten experiments were performed using weekly exchange of media and cytokines (Delta assay). Median myeloid and erythroid progenitors expanded 15-fold at 7 days (range, 7 to 43), 40-fold at 14 days (range, 18 to 470), 46-fold at 21 days (range, 0 to 118), and 21-fold at 28 days (range, 0 to 61). In a system using gas-permeable bags without exchange of media or cytokine, median progenitors expanded 13-fold at 7 days (range, 7 to 36), 14-fold at 10 days (range, 4 to 61), 14-fold at 12 days (range, 3 to 46), and 10-fold at 14 days (range, 1 to 35). Progenitor expansion less than 10-fold occurred in 8% of experiments at day 7, in 17% at day 10, in 43% at day 12, and in 50% at day 14. When autologous plasma, autologous plasma processed (removal of cryoprecipitate, centrifugation, then filtration), or human serum were substituted for 20% fetal calf serum, the ratio of progenitor expansion at 7 days relative to 20% fetal calf serum for 10% human serum, 20% human serum, and 1% autologous plasma processed was 1.01 (range, 0.62 to 1.33), 0.88 (range, 0.61 to 1.20), and 0.96 (range, 0.55 to 1.64), respectively. These findings support the feasibility of ex vivo expansion in a system free of nonhuman proteins of CD34(+)-derived progenitors obtained from the peripheral blood of patients who have received prior chemotherapy.

Animals↗
PubMed1994

Isolation and characterization of human bone marrow microvascular endothelial cells: hematopoietic progenitor cell adhesion.

To examine potential mechanisms by which hematopoiesis may be regulated by endothelial cells within the bone marrow (BM) microenvironment, we have devised a technique for the in vitro study of the interaction of human BM microvascular endothelial cells (BMEC) with hematopoietic cells. Microvessels isolated by collagenase digestion of spicules obtained from filtered BM aspirate were plated on gelatin-coated plastic dishes, and colonies of endothelial cells grown from microvessel explants were further purified by Ulex europaeus lectin affinity separation. BMEC monolayers isolated by this technique grew in typical cobblestone fashion, stained positively with antibody to factor VIII/von Willebrand factor, and incorporated acetylated LDL. Immunohistochemical studies showed that BM microvessels and BMEC monolayers express CD34, PECAM, and thrombospondin. Incubation of resting BMEC with BM mononuclear hematopoietic cells resulted in the selective adhesion of relatively large numbers of CD34+ progenitor cells and megakaryocytes. The binding of purified BM-derived CD34+ progenitor cells to BMEC was dependent on divalent cations and was partially blocked by antibodies to CD34. IL-1 beta treatment of BMEC monolayers resulted in an increase of CD34+ progenitor cell adhesion by mechanisms independent of CD34 or divalent cations. BMEC exhibit specific affinity for CD34+ progenitor cells and megakaryocytes, suggesting that the BM microvasculature may play a role in regulating the trafficking, proliferation, and differentiation of lineage specific hematopoietic elements, and possibly of pluripotent stem cells within the CD34+ population.

Antigens, CD↗
PubMed1994

Characterization of the chicken osteopontin-encoding gene.

A genomic clone of the chicken osteopontin-encoding gene (opn) was isolated and found to be organized as follows: an untranslated 5' exon; a signal peptide; a recognition sequence for phosphorylation by casein kinase II; a domain containing a possible O-linkage site for glycosylation; a second casein kinase II phosphorylation site; an exon containing three functional regions, the poly-Asp sequence of seven consecutive Asp residues, the RGD integrin recognition site and a potential N-linkage site for glycosylation; and a large C-terminal exon which also contains a potential N-linkage site for glycosylation. Primer extension analysis demonstrated only one strong transcriptional start point (tsp) in mRNAs prepared from embryonic bone and cultured osteoblasts. Analysis of the 5' flanking region identified a TATA sequence at -31, an inverted CAAT motif at -57, an AP1-recognition sequence at -84 and a putative vitamin-D-response element (VDRE) sequence at -474. Three plasmid constructs containing 963, 561 and 368 bp of 5' flanking sequence of the avian promoter were used to drive expression of bacterial cat. Comparison of the relative promoter activities of these constructs was carried out in MC3T3/E1 cells, a murine osteoblast cell line. All of the constructs showed approximately 20-fold the levels of expression over background activity of the cat gene without a promoter. Each construct also demonstrated a strong induction with phorbol-12-myristyl-13-acetate (PMA). In contrast, dihydroxycholecalciferol [1,25(OH)2D3] had neither a positive nor a negative effect on the 368- and 936-bp constructs, but was stimulatory for the 561-bp construct.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1994

The effects of drugs on the incorporation of a conformationally-sensitive, hydrophobic probe into the ion channel of the nicotinic acetylcholine receptor.

The pattern of incorporation of the hydrophobic photolabel 3-(trifluoromethyl)-3-(m-[125I]iodophenyl)diazirine([125I]TID) into the nicotinic acetylcholine receptor (AChR) is a sensitive measure of AChR conformation (resting state or desensitized). We determined the ability of tetracaine, dibucaine, procaine, lidocaine, chlorpromazine or phencyclidine to inhibit [125I]TID photolabeling of the AChR as a function of drug concentration, both as a measure of the ability of these drugs to desensitize the AChR, and to characterize the [125I]TID binding site. To localize the site(s) of drug action, experiments were performed in the absence and presence of saturating concentrations of alpha-bungarotoxin (BgTx), to block drug binding to the agonist binding site. On the basis of the concentration dependence of their effects, which was not altered by the presence of BgTx, tetracaine and dibucaine appeared to block [125I]TID incorporation competitively, suggesting that the high-affinity [125I]TID binding site is the non-competitive blocker binding site presumed to exist in the interior of the AChR ion channel. Procaine, chlorpromazine, lidocaine and phencyclidine blocked [125I]TID incorporation at lower concentrations in the absence of BgTx than in its presence, suggesting that these drugs block incorporation by inducing desensitization when bound to their high-affinity non-competitive blocker binding sites and that BgTx countered the drug effect by allosterically stabilizing the resting state.

Anesthetics, Local↗
PubMed1994

Bacterial endotoxin regulation of cytokine receptors on murine bone marrow cells: in vivo and in vitro study.

Bacterial endotoxin (LPS) modulation of CSF-1, granulocyte-macrophage (GM)-CSF, G-CSF, IL-1, TNF, and Kit Ligand receptors on murine bone marrow cells (BMC) in vivo and in vitro was investigated. In vivo LPS reduced the binding of hrIL-1 (> 90%), mrTNF (> 62%), mrGM-CSF (> 42%) and hrG-CSF (> 91%) to BMC within 2 h, but elevated IL-1 binding (> 8.4-fold) between 8 to 48 h. In vitro, LPS decreased G-CSF and IL-1 binding after 8 h yet increased TNF binding in a dose-dependent manner, suggesting that in vivo, the LPS up-regulation of IL-1 binding to BMC was indirect. Because in vivo LPS elevated the levels of TNF, IL-6, GM-CSF, and glucocorticoids, we further examined GM-CSF and TNF modulation of cytokine receptors on BMC in vivo. In vivo, TNF decreased the binding of TNF (> 88%), G-CSF (> 89%), and IL-1 (> 73%) within 30 min, but increased IL-1 binding (> 4.8-fold) after 10 h. In contrast, in vitro TNF decreased IL-1 binding after 8 h, implying that in vivo TNF up-regulation of Il-1 binding to BMC was also due to an indirect mechanism. However, GM-CSF increased IL-1 binding to BMC both in vivo and in vitro after 8 h. Further studies showed that in vitro GM-CSF and dexamethasone synergistically increased IL-1 binding to BMC in a time- and dose-dependent manner. This synergistic modulation depended on synthesis of protein and mRNA, and was due to an increase in receptor number rather than an increase in receptor affinity. Because in vivo, LPS and LPS-induced cytokines (IL-1 and TNF) elicited the secretion of glucocorticoid and CSF activities, our results revealed a mechanism for LPS up-modulation of IL-1R on BMC in vivo.

Animals↗
PubMed1994

Selected factors that influence responses to antihypertensives. Choosing therapy for the uncomplicated patient.

Numerous factors may influence an individual patient's response to antihypertensive therapy. The physician should select therapy that is more likely to effectively control the patient's blood pressure. In addition to age and race, specific properties of the drugs plus the method of administration can influence response. Most antihypertensives can be given once or twice daily without the need for sustained-release dosage forms. The appropriate selection of regular-release products can significantly reduce the cost of therapy and improve adherence to the regimen. Because most antihypertensives exist as isomers of two compounds, response to a given agent can be influenced by the type of product (eg, sustained-release) or the method of administration. When these variables are considered for individual patients, it is more likely that a given drug will be effective.

Adrenergic beta-Antagonists↗
PubMed1994

Dyshematopoiesis in combined immune deficiency with congenital neutropenia.

This report describes a patient with combined immune deficiency associated with congenital neutropenia (CID/CN) and reports a partial characterization of his hematopoietic abnormalities. The CID/CN syndrome described is characterized by neutropenia and by deficiencies in B-lymphoid and T-lymphoid cell number and function. Red cell and platelet counts were normal. In vitro assays indicate that the myeloid lineage was developmentally arrested at the level of the committed monocyte/granulocyte progenitor (CFU-GM), while precursors to the CFU-GM progenitor were normal. In vitro studies showed that the defect in myeloid development was not corrected with G-CSF or GM-CSF. However, combinations of cytokines present in conditioned media from the T-cell lines MO or C5MJ, or defined multiple cytokine combinations containing IL-1, IL-3, GM-CSF, kit ligand, IL-6, and IL-9, restored myelopoiesis in-vitro. In contrast, C5MJ-conditioned media did not correct deficiencies in immune function in the patient's lymphocytes and accessory cells. No abnormalities in the production of G-CSF, GM-CSF, M-CSF, or IL-1 from the patient could be identified to account for the defects in myelopoiesis orimmune function.

B-Lymphocytes↗
PubMed1994

Stabilization of pericardial tissue by dye-mediated photooxidation.

Bovine pericardial tissue was stabilized through a dye-mediated photooxidation reaction. Shrink temperature analysis of the stabilized tissue indicated a material with similar properties to untreated pericardial tissue and unlike identical tissue treated with glutaraldehyde. Photooxidized tissue was resistant to extraction when compared with untreated tissue or control tissues treated in the absence of light or dye. Photooxidized tissue was also resistant to enzymatic digestion by pepsin and to chemical digestion by cyanogen bromide (CNBr). In contrast, untreated or control treated tissues were readily digested by these reagents. Reduction of photooxidized tissue with beta-mercaptoethanol prior to CNBr digestion partially restored susceptibility of the tissue to CNBr digestion, indicating the photooxidation of methionine residues. Soluble collagen derived from bovine pericardium was used as a model compound for the photooxidation reaction. Polyacrylamide gel electrophoresis analysis indicated the photooxidative conversion of collagen into higher molecular weight aggregates consistent with intermolecular crosslink formation. Photooxidized tissue was stable to in vivo degradation when compared with control tissue. Results presented here indicate a crosslinked pericardial tissue produced by dye-mediated photooxidation possessing properties of chemical stability, enzymatic stability, in vivo stability, and biomechanical integrity suitable for use as a biomaterial.

Animals↗
PubMed1994

The desflurane (Tec 6) vaporizer: design, design considerations and performance evaluation.

We have described the design and design considerations of the desflurane Tec 6 "vaporizer" and have tested its performance characteristics. The vaporizer differs from previous vaporizers designed for anaesthesia in that electromechanical rather than mechanical controls accommodate the different physical characteristics of desflurane. This design, while offering perhaps an increased risk of failure (owing to sophisticated electronic components and circuitry), on the other hand offers the decreased likelihood of accidental delivery of very large concentrations of liquid anaesthetic resulting from tilting or overfilling and alarms and warnings not previously incorporated into the design of anaesthetic vaporizers. The output characteristics of the vaporizer are as expected, based on the design: desflurane concentration output in oxygen has accuracy (+/- 15%) which is similar to that of the mechanical vaporizers; output decreases when nitrous oxide is added owing to the lower viscosity, but remains within 20% of the dial setting or 0.5% absolute.

Anesthesia, Inhalation↗
PubMed1994

Humans anesthetized with sevoflurane or isoflurane have similar arrhythmic response to epinephrine.

BACKGROUND: Anesthetics can alter the dose of exogenously administered epinephrine that causes cardiac arrhythmias. The purpose of this study was to test the hypothesis that in humans anesthetized with sevoflurane, the arrhythmic response to epinephrine is not different from the response in humans anesthetized with isoflurane. METHODS: We determined the arrhythmogenicity of submucosally administered epinephrine in 40 ASA physical status 1 or 2 patients who were to undergo transsphenoidal surgery. Patients were assigned randomly to be given 1.0-1.3 minimum alveolar concentration sevoflurane or isoflurane. A surgeon, blinded to the anesthetic and the concentration of epinephrine, injected into the nasal submucosa epinephrine 10, 13.3, or 20 micrograms/ml in saline of volume sufficient for surgical need. We defined a "positive" response as three or more premature ventricular contractions within 5 min after initiation of injection. Responses between anesthetic groups within each dose range of epinephrine were compared by chi-squared analysis. RESULTS: No patient given either anesthetic developed premature ventricular contractions with doses of epinephrine less than 5 micrograms/kg. At larger doses of epinephrine (5-9.9 and 10-14.9 micrograms/kg), the frequency of arrhythmias did not differ between patients given sevoflurane and patients given isoflurane. Patients anesthetized with 1.2 minimum alveolar concentration sevoflurane had blood pressure similar to and heart rate less than those of patients anesthetized with similar concentrations of isoflurane. Blood pressure and heart rate were increased similarly in both groups after laryngoscopy and tracheal intubation and after epinephrine injection. CONCLUSIONS: Sevoflurane and isoflurane do not differ in their sensitization of the human myocardium to the arrhythmogenic effect of exogenously administered epinephrine.

Adult↗
PubMed1994

Rapid increase in desflurane concentration is associated with greater transient cardiovascular stimulation than with rapid increase in isoflurane concentration in humans.

BACKGROUND: Increases in desflurane and isoflurane concentrations can transiently increase arterial blood pressure or heart rate or both during induction of anesthesia. The current study tested the hypothesis that a rapid increase of desflurane concentration in humans increases sympathetic activity and hormonal variables and heart rate and arterial blood pressure more than does an equivalent increase in isoflurane concentration. METHODS: Twelve healthy male volunteers were assigned randomly to receive desflurane and on a separate occasion isoflurane. After induction of anesthesia with propofol 2 mg/kg, anesthesia was maintained at 0.55 MAC (desflurane, 4.0%; isoflurane 0.71% end-tidal) for 32 min. Mechanical ventilation maintained normocapnia throughout anesthesia. Mean arterial blood pressure and heart rate were recorded continuously, and arterial blood was sampled for plasma catecholamine and vasopressin (AVP) concentrations, and plasma renin activity. Anesthetic concentration was increased rapidly to 1.66 MAC (desflurane, 12.0%; isoflurane 2.12% end-tidal), and maintained at this concentration for 32 min, and then rapidly decreased to and maintained at 0.55 MAC for an additional 32 min. RESULTS: Neither anesthetic produced sympathetic or cardiovascular stimulation during their initial rapid wash-in to 0.55 MAC. The rapid increase to 1.66 MAC increased mean arterial blood pressure, heart rate, and plasma epinephrine and norepinephrine concentrations, and plasma renin activity with both desflurane and isoflurane, the former usually producing a response of greater magnitude than the latter. Plasma AVP concentration increased with desflurane only. Increased mean arterial blood pressure returned to control in 4 min. Heart rate decreased 50% of the difference between its peak and the value at 32 min at 1.66 MAC in 2 min with desflurane and in 4 min with isoflurane but did not return to the value at 0.55 MAC with either anesthetic. With desflurane, plasma epinephrine and AVP concentrations decreased quickly from their peak values, remaining elevated for 8 min. Decrease of concentrations of desflurane and isoflurane from 1.66 MAC to 0.55 MAC rapidly decreased heart rate and increased mean arterial blood pressure with both anesthetics. Thirty-two minutes after return to 0.55 MAC, with both anesthetics, only heart rate remained increased relative to the values at 32 min of the initial period of 0.55 MAC anesthesia. CONCLUSIONS: In healthy male volunteers, rapid increases of desflurane or isoflurane from 0.55 to 1.66 MAC increase sympathetic and renin-angiotensin system activity, and cause transient increases in arterial blood pressure and heart rate. Desflurane causes significantly greater increases than isoflurane, and also causes a transient increase in plasma AVP concentration. The temporal relationships suggest that the increased sympathetic activity increases mean arterial blood pressure and heart rate, with mean arterial blood pressure also increased by increased plasma AVP concentration, whereas the delayed, increased plasma renin activity is likely a response to the ensuing hypotension, or earlier inhibition by AVP, or both.

Anesthesia, General↗
PubMed1994

Rapid 1% increases of end-tidal desflurane concentration to greater than 5% transiently increase heart rate and blood pressure in humans.

BACKGROUND: Large (0.5-1.0 MAC), rapid increases of desflurane to concentrations greater than 5% can transiently increase heart rate, mean arterial blood pressure (MAP), sympathetic nerve activity, and plasma epinephrine concentration. We tested the hypothesis that small (1% = 0.14 MAC), rapid increases of desflurane concentration to greater than 5% do not increase heart rate, blood pressure, and plasma catecholamine concentrations. METHODS: Anesthesia was induced with intravenous propofol, 2 mg/kg, in 13 healthy male volunteers, 19-33 yr of age, and ventilation was controlled to maintain normocapnia. We gave 4% end-tidal desflurane in oxygen for 32 min and then imposed successive 1% increases in end-tidal desflurane concentration, each new concentration maintained for 4 min, to a final concentration of 12%. We measured heart rate, MAP and plasma catecholamine concentrations in the awake state, after 4 min at each 1% step, and at times of peak increase of MAP (> or = 10% change). RESULTS: Increases in heart rate and blood pressure of more than 10% occurred with 1% step-increases in only 1 volunteer at 5% desflurane but in 7-10 (MAP) and 8-12 (heart rate) of the 13 volunteers at higher desflurane concentrations. The 1% increases in desflurane concentration to greater than 5% also transiently increased plasma epinephrine concentrations but not vasopressin concentration or plasma renin activity in those volunteers in whom MAP increased. CONCLUSIONS: Small (1%) increases in desflurane concentration to and greater than 6% can transiently increase heart rate, mean arterial pressure, and plasma epinephrine concentration. These data and those from a previous study indicate that these increases occur with a lesser frequency and magnitude than those associated with a single, rapid step from 4% to 12% end-tidal desflurane.

Adult↗
PubMed1994

End-stage renal disease: a southern epidemic.

During the past decade, the annual incidence of patients entering long-term dialysis for end-stage renal disease (ESRD) has been increasing, while mortality from stroke and coronary artery heart disease has been decreasing. In the Southeast, hypertension is the most common cause of ESRD, followed closely by diabetes mellitus occurring most frequently in older minority patients, particularly blacks. The causes of the increase in ESRD are not known. Although control of any degree of hypertension with any antihypertensive drug will slow the progression of renal failure from any cause, captopril, an angiotensin-converting enzyme (ACE) inhibitor, has been shown to slow progressive renal failure in patients with insulin-dependent diabetes mellitus to a greater degree than that expected from only its antihypertensive effect. This series of articles, originally presented at the 1993 annual meeting of the Southern Medical Association, reviews the epidemiology and pathophysiology of ESRD and offers a clinical approach to this serious problem.

Diabetic Nephropathies↗