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Biomedical subjects

S Cooper

Publications and source records attributed to S Cooper.

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

Myeloid progenitor cell regulatory effects of vascular endothelial cell growth factor.

Vascular endothelial cell growth factor (VEGF) is a ligand for the tyrosine kinase receptor Flk-1/KDR and Flt1 and is considered to be an endothelial cell specific mitogen that plays an important role in angiogenesis. Since Flk-1 mRNA has been detected in primitive and more mature hematopoietic cells, recombinant human VEGF was evaluated for its influence on hematopoiesis, which was assayed as in vitro colony formation by myeloid progenitor cells from human bone marrow. VEGF enhanced colony formation by mature subsets of granulocyte-macrophage and erythroid progenitor cells that had been stimulated with a colony stimulating factor. In contrast, VEGF inhibited colony formation by more immature subsets of granulocyte-macrophage, erythroid and multipotential progenitor cells synergistically stimulated to proliferate with a colony stimulating factor and either steel factor or the ligand for the Flt-3 receptor tyrosine kinase. VEGF produced effects similar to those given above on purified CD34 progenitor cells from bone marrow and VEGF effects were neutralized by VEGF antibodies. However, when assessed for effects on single sorted CD34 cells, VEGF only enhanced or suppressed colony formation by granulocyte-macrophage progenitor cells and the amplitude of the response was less than that observed when populations of these cells were tested. In the single cell assays, VEGF had no effect on colony formation by erythroid or multipotential progenitors. These results suggest that the effects of VEGF, which were not species specific, are mediated by both direct and indirect actions on the progenitors and thereby identify new activities for this important factor.

Animals↗
PubMed1995

Treatment of cutaneous angiosarcomas of the head and neck.

A total of six patients with cutaneous angiosarcomas involving the head and neck were treated during the period 1985-1994. The distribution of sites between the scalp and the rest of the head and neck was equal. Initial local treatment involved surgery for four patients and radiotherapy for two patients. In the surgical group, following seemingly adequate macroscopic surgical excision, all four patients had inadequate surgical margins on histology. Five of six patients had disease recurrence within the head and neck and of these a further three went on to have a second episode of recurrence. Median time to recurrence was 8 months. All cases were misdiagnosed clinically at initial presentation and three of six had initial inconclusive histology. Cutaneous angiosarcomas of the head and neck is an aggressive multicentric cancer. Radiotherapy offers the only real chance of obtaining adequate local control even if surgical excision is carried out. Radiotherapy must encompass wide fields and whole scalp irradiation is mandatory for scalp lesions. A combination of laterally opposed photon and electron fields provides a simple, quick and effective means to deliver a tumoricidal dose of 50 Gy to the whole scalp with minimal irradiation of the underlying brain.

Aged↗
PubMed1995

Pyloric duplications: review and case study.

Gastric duplications are unusual congenital anomalies that often require surgical treatment. Pyloric duplications are particularly rare; few are reported in the English literature. This article reviews the literature on pyloric duplications and describes a pyloric duplication associated with hypertrophic pyloric stenosis in a 5-week-old child and a duplication that recurred 7 years later.

Humans↗
PubMed1995

Flt3 ligand stimulates/costimulates the growth of myeloid stem/progenitor cells.

The present studies evaluated effects of recombinant human (rhu) and murine (rmu) flt3 ligand (flt3-L) on colony formation by subsets of myeloid stem and progenitor cells present in low-density (LD) and cell-sorted CD34 hu cord blood (CB) and bone marrow (BM) cells and unseparated mu BM cells. By itself, flt3-L had weak colony-stimulating activity. It stimulated small dispersed CFU-GM-type colonies, but not BFU-E, CFU-GEMM, or HPP-CFC colonies, from LD and CD34 huCB and BM. However, flt3-L had additive to greater-than-additive effects on colony number and size by CFU-GM stimulated with GM-CSF or IL-3, with or without Steel factor (SLF); by CFU-G stimulated by G-CSF with or without SLF; by CFU-M stimulated by CSF-1; and by BFU-E, CFU-GEMM, and HPP-CFC stimulated by Epo with or without IL-3 or SLF. Flt3-L enhanced the effects of SLF, alone and in combination with other CSFs. Similar effects were apparent on LD and sorted CD34 cells and also at the level of single sorted and isolated CD34 cells/well. Flt3-L enhanced expansion of immature subsets of huCD34(+)-column separated CB CFU-GM stimulated by the potent combination of SLF and PIXY321 (a GM-CSF/IL-3 fusion protein). While flt3-L did not enhance the replating capacity of CFU-GEMM plated in the presence of Epo and SLF, it enhanced numbers of these CFU-GEMM colonies with the capacity to be replated. Flt3-L effects were not species-specific; rhu and rmu forms were active on huCB/BM and muBM. These results demonstrate the potent direct-acting stimulating/costimulating activities of flt3-L in vitro on myeloid stem/progenitor cells.

Adult↗
PubMed1995

Adeno-associated virus 2-mediated gene transfer and functional expression of the human granulocyte-macrophage colony-stimulating factor.

It is becoming increasingly clear that the adeno-associated virus 2 (AAV)-based vector system may prove to be useful for high-efficiency gene transfer in human cells as well as for potential gene therapy in humans. A recombinant AAV vector containing the gene for a human hematopoietic growth factor, granulocyte-macrophage colony-stimulating factor (GM-CSF), was constructed and used to infect COS-1 cells, a monkey kidney cell line. COS-1 cells infected with the recombinant virus, but not mock-infected cells, expressed high levels of the human GM-CSF gene transcripts. Furthermore, in co-cultivation experiments with the recombinant virus-infected cells, but not in those with mock-infected cells, active proliferation of a GM-CSF-dependent human megakaryocytic leukemia cell line, M07e, could be obtained in the absence of exogenously added GM-CSF. The recombinant GM-CSF protein released into the supernatant was biologically active in progenitor cell assays carried out with primary human hematopoietic cells, and this activity was specifically abrogated by treatment of the supernatant with anti-GM-CSF antibodies. This recombinant virus may be potentially useful in the management and gene therapy of a variety of malignant disorders in the human hematopoietic system.

Animals↗
PubMed1995

Estrogen loss upregulates hematopoiesis in the mouse: a mediating role of IL-6.

We have previously demonstrated that ovariectomy causes an increase in the number of colony-forming unit granulocyte/macrophage (CFU-GM) and an upregulation of osteoclastogenesis in mice, both of which are mediated by interleukin-6 (IL-6). IL-6 is involved in the development of several hematopoietic progenitors, including the burst-forming unit-erythroid (BFU-E) and multipotent CFUs (CFU-GEMM). Therefore, we performed studies to examine if other hematopoietic progenitors, besides CFU-GM and their progeny, are affected by estrogen loss. We found that ovariectomy caused an increase in the number of CFU-GEMM and BFU-E, as well as an increase of CFU-GM in marrow cells of the femur. Administration of 17 beta-estradiol or a neutralizing antibody against IL-6 prevented the ovariectomy-induced increase in the number of these progenitors in the marrow. Ovariectomy also caused an increase in the number of circulating lymphocytes, neutrophils, and monocytes, which were suppressed by administration of 17 beta-estradiol or the neutralizing antibody against IL-6; however, the number of circulating platelets was unaffected by loss of ovarian function. These data establish that, in addition to upregulation of osteoclastogenesis, loss of estrogens in the mouse causes widespread effects on hematopoiesis, which are apparently mediated by IL-6.

Animals↗
PubMed1995

Effects of in vivo treatment with PIXY321 (GM-CSF/IL-3 fusion protein) on proliferation kinetics of bone marrow and blood myeloid progenitor cells in patients with sarcoma.

PIXY321, a stimulator of multipotent colony-forming units (CFU-GEMM), burst-forming unit-erythroid (BFU-E), and colony-forming units granulocyte/macrophage (CFU-GM) progenitor cell proliferation in vitro, is currently being assessed in phase-I/-II clinical trials. We evaluated kinetics of CFU-GEMM, BFU-E, and CFU-GM proliferation in bone marrow (BM), blood, and granulocyte (CFU-G) and macrophage (CFU-M) progenitors in BM of chemotherapy-naive patients with sarcoma-administered PIXY321 (25 to 1000 micrograms/m2/day subcutaneously for 14 days). BM and/or blood cells from three to four patients at each dosage were assessed before, during, 1 to 2 days, and 7 days following treatment with PIXY321. Cells were pulse-treated in vitro with or without high-specific activity tritiated thymidine (3H-dThr) (to assess the percentage of progenitors in S-phase of cell cycle) and cultured for immature and more mature subsets of CFU-GEMM, BFU-E, CFU-GM, and for CFU-G and CFU-M. Despite heterogeneity in baseline cycling status of progenitors in BM, administration of 125 to 500 micrograms PIXY321 to patients at least doubled (p < 0.001) cycling rates of all BM progenitors. The cycling rates of blood progenitors increased from a slow or non-cycling state to > 38% cells in cycle. Within 1 to 2 days after cessation of PIXY321 infusion, all progenitors were in a slow or noncycling phase below that of many of the pre-BM samples (immature and mature CFU-GM and mature BFU-E) or were back to background levels (CFU-G, CFU-M, CFU-GEMM, and immature BFU-E). These cycling effects were similar to those previously noted for BM CFU-GM and BFU-E in patients on clinical trial with GM-CSF. In contrast, higher dosages of PIXY321, especially 1000 micrograms, increased cycling of BM and blood progenitor cells early during treatment, but cycling rates decreased while patients were still being administered PIXY321; decreased cycling was maintained after cessation of PIXY321. PIXY321 is thus highly active in vivo as a stimulator of multipotential and more lineage-restricted progenitors. The kinetics of progenitor cell proliferation noted in this study highlight differences seen with GM-CSF and G-CSF. The effects described here could be of relevance in design of future clinical trials using PIXY321 as an adjunct treatment in patients undergoing cytoreductive therapy.

Blood Cells↗
PubMed1994

Adeno-associated virus 2-mediated high efficiency gene transfer into immature and mature subsets of hematopoietic progenitor cells in human umbilical cord blood.

Recombinant adeno-associated virus 2 (AAV) virions were constructed containing a gene for resistance to neomycin (neoR), under the control of either the herpesvirus thymidine kinase (TK) gene promoter (vTK-Neo), or the human parvovirus B19 p6 promoter (vB19-Neo), as well as those containing an upstream erythroid cell-specific enhancer (HS-2) from the locus control region of the human beta-globin gene cluster (vHS2-TK-Neo; vHS2-B19-Neo). These recombinant virions were used to infect either low density or highly enriched populations of CD34+ cells isolated from human umbilical cord blood. In clonogenic assays initiated with cells infected with the different recombinant AAV-Neo virions, equivalent high frequency transduction of the neoR gene into slow-cycling multipotential, erythroid, and granulocyte/macrophage (GM) progenitor cells, including those with high proliferative potential, was obtained without prestimulation with growth factors, indicating that these immature and mature hematopoietic progenitor cells were susceptible to infection by the recombinant AAV virions. Successful transduction did not require and was not enhanced by prestimulation of these cell populations with cytokines. The functional activity of the transduced neo gene was evident by the development of resistance to the drug G418, a neomycin analogue. Individual high and low proliferative colony-forming unit (CFU)-GM, burst-forming unit-erythroid, and CFU-granulocyte erythroid macrophage megakaryocyte colonies from mock-infected, or the recombinant virus-infected cultures were subjected to polymerase chain reaction analysis using a neo-specific synthetic oligonucleotide primer pair. A 276-bp DNA fragment that hybridized with a neo-specific DNA probe on Southern blots was only detected in those colonies cloned from the recombinant virus-infected cells, indicating stable integration of the transduced neo gene. These studies suggest that parvovirus-based vectors may prove to be a useful alternative to the more commonly used retroviral vectors for high efficiency gene transfer into slow or noncycling primitive hematopoietic progenitor cells, without the need for growth factor stimulation, which could potentially lead to differentiation of these cells before transplantation.

Antigens, CD↗
PubMed1994

Age-dependent decline of nigrostriatal dopaminergic function: a positron emission tomographic study of grandparents and their grandchildren.

Despite postmortem evidence for an age-related decline in nigrostriatal dopaminergic function, position emission tomography (PET) studies have produced inconsistent results. This may be due to differences in methods or of subject selection. To investigate further the effect of age on dopaminergic function, we performed PET with 6-L-[18F]fluorodopa (FD) on 12 pairs of grandchildren and their grandparents. The FD uptake rate constant (Ki) was calculated using a graphical method for the whole striatum to avoid confounding of the results by striatal atrophy. The mean Ki was significantly lower in grandparents (p = 0.020). These PET observations represent in vivo confirmation of postmortem evidence that nigrostriatal dopaminergic function declines with aging.

Adult↗
PubMed1994

O6-methylguanine-DNA adducts in rat lymphocytes after in vivo exposure to N-nitrosodimethylamine (NDMA).

A non-invasive approach in immunopathological risk assessment was applied for analysis of the in vivo formation of DNA adducts. DNA methylation was studied in peripheral blood lymphocytes (PBLs) collected from Sprague-Dawley rats exposed to a single dose (75 mg/kg b.w.) of N-nitrosodimethylamine (NDMA). Three different techniques were applied for characterization and quantification of DNA adducts: (i) colloidal gold ultraimmunocytochemical localization of O6-methylguanosine (O6-meG)-DNA adducts, using affinity-purified, polyclonal antibody directed against O6-meG, (ii) quantitative assay using enzyme-linked immunosorbent assay (ELISA), amplified by the avidin-biotin (AB) system, and (iii) high-performance liquid chromatography (HPLC). The O6-meG-immunoreactive sites in PBLs seem to be concentrated in the nucleus. However, significant immunolabelling was also noted in the cytoplasm of the in vivo NDMA-exposed PBLs. Control preparations showed no specific gold immunolabelling. The O6-meG-DNA adduct formation in PBLs and hepatocytes, at 2-24 h following the exposure to NDMA, was analogous for both types of cells. The data showed high correlation for the ELISA and HPLC analytical methods. The data suggest an efficient O6-metG-DNA repair mechanism in lymphocytes, possibly analogous to the enzymatic repair of DNA adducts in liver cells.

Animals↗
PubMed1994

Synthesis of DnaK protein during the division cycle of Escherichia coli.

DnaK protein is involved in the initiation of DNA synthesis from the Escherichia coli chromosome as well as from the replication origins of phage lambda and P1. The synthesis of dnaK mRNA and protein has been reported to vary during the cell cycle of Caulobacter crescentus (Gomes et al., 1990). We have measured the expression of DnaK protein during the E. coli division cycle using the membrane-elution method. Cells labelled with a radioactive amino acid at different times during the division cycle were analysed for radiolabelled DnaK protein by quantitative immunoprecipitation, gel electrophoresis and autoradiography. In contrast to reports of cell-cycle-specific synthesis of DnaK protein in C. crescentus, we find the synthesis of DnaK protein to be invariant during the E. coli division cycle. Its synthesis occurs exponentially, as does the synthesis of total cell protein.

Autoradiography↗
PubMed1994

Analgesic effect of intraarticular morphine, bupivacaine, and morphine/bupivacaine after arthroscopic knee surgery.

In a double-blind randomized fashion, 38 patients were divided into four groups according to the intraarticular injection received after arthroscopic surgery. Patients in group I (n = 7) received saline, group II (n = 10) morphine, group III bupivacaine, and group IV (n = 11) morphine and bupivacaine. Before surgery and at 0.5, 1, 1.5, 2, 6, and 24 h postoperatively, pain levels were recorded. In addition, postoperative supplemental i.v. morphine requested by the patient was tabulated. Results showed that the mean consumption of supplemental analgesia was lowest in the morphine/bupivacaine group. Although there was a statistically significant difference in pain scores between the saline group and the other three groups during the early postoperative period, there was no significant difference in pain scores between the morphine, bupivacaine, and morphine/bupivacaine groups. We conclude that postoperative, intraarticular injection of analgesics is beneficial in reducing pain levels. The combination of morphine/bupivacaine appears to be the most beneficial analgesic due to its low supplemental analgesic requirements postoperatively.

Adult↗
PubMed1994

Effect of 443c81, an inhaled mu-opioid receptor agonist in asthma.

Stimulation of exposed C-fibre afferent nerve endings by inflammatory mediators may contribute to airway inflammation and bronchoconstriction in asthma through the release of neuropeptides from collateral nerve endings. The polar opioid peptide 443c81 is a mu-opioid receptor agonist which inhibits C-fibre activation and non-cholinergic neurally mediated bronchoconstriction in animal models. We have compared the effect of 443c81 (5 ml of a 4 mg/ml solution nebulized) four times daily for 7 days with placebo on asthma control in a double-blind parallel group study of 40 subjects with mild asthma. Twenty subjects (12 male, mean FEV1 83% predicted) received placebo and 20 (15 male, mean FEV1 91% predicted) 443c81 after a 1 week run-in. Efficacy was assessed by comparing changes from baseline values in FEV1, provocative dose of histamine causing a 20% fall in FEV1 (PD20), symptom scores, bronchodilator use and home peak flow readings. 443c81 had no acute effect on FEV1 and the mean changes in FEV1 after 1 week of treatment were not significantly different (placebo -0.9%; 443c81-3.8%). One hour after the first dose of 443c81 PD20 increased from a geometric mean of 0.88 to 1.48 mumol (mean change 0.76 doubling doses; 95% CI 0.23, 1.29) but this did not differ significantly from the change with placebo (mean difference between 443c81 and placebo 0.63 doubling doses; 95% CI -0.2, 1.5; P = 0.095). After 1 week's treatment, PD20 was similar to baseline values with 443c81 (0.78 mumol) and placebo (baseline 0.71, post-treatment 0.93 mumol).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1994

Relation of pulmonary lymphangio-leiomyomatosis to use of the oral contraceptive pill and fertility in the UK: a national case control study.

BACKGROUND: Pulmonary lymphangioleiomyomatosis is a rare progressive disease of unknown aetiology affecting premenopausal women. Since the oral contraceptive pill has been implicated in its pathogenesis, a case control study was carried out to determine whether women with the disease were more likely to have taken the oral contraceptive pill, and whether the disease was associated with other conditions related to sex hormones including pregnancy, parity, and fibroids. METHODS: All chest physicians in the UK were asked for details of all live patients with pulmonary lymphangioleiomyomatosis; the patient's family doctor was then asked for four age and sex matched control subjects from their patient register. Details of lifetime use of the oral contraceptive pill, pregnancy, parity, history of fibroids, and smoking were obtained from cases and controls. Relative odds of exposure to potential risk factors were estimated by conditional logistic regression. RESULTS: Medical details were obtained from all 23 cases of lymphangioleiomyomatosis identified; questionnaires were completed by 21 cases (one by proxy) and by 46 matched controls of mean (SD) age 43 (10) and 44 (11) years, respectively. The patients had a mean age of 34 (9) years at onset of symptoms and a median (range) time of 2 (0-29) years from onset of symptoms to diagnosis. Compared with control subjects, cases did not differ in the use of the oral contraceptive pill (odds ratio (OR) 0.39, 95% CI 0.09 to 1.68), diagnosis of fibroids (OR 3.12; 95% CI 0.52 to 18.7), age of menarche, menstrual history, or lifetime smoking. They were, however, less likely to have been pregnant (OR 0.14, 95% CI 0.03 to 0.71) or to have had children (OR 0.13, 95% CI 0.03 to 0.67). More pregnancies had ended in spontaneous abortion (28% v 8%) but the proportion of women undergoing spontaneous abortion was similar in cases and controls (OR 2.13, 95% CI 0.47 to 9.3). CONCLUSIONS: This study does not support the hypothesis that use of the oral contraceptive pill is causally associated with the development of pulmonary lymphangioleiomyomatosis. Sex hormones may be involved, however, since patients were less likely to have been pregnant or to have had children, and tended to have had more spontaneous abortions and an increased incidence of fibroids.

Abortion, Spontaneous↗
PubMed1994

Performance and metabolic effects of benzodiazepine during submaximal exercise.

The present study examined whether benzodiazepine (BZ) intake alters performance and selected hormonal and metabolic variables during submaximal exercise. Seven triathletes completed two cycling trials at 85% maximum O2 uptake starting 3 h after an ingestion of either a placebo (PLA) of gelatin or BZ (1.5 mg lorazepam) and continuing until exhaustion, according to a double-blind randomized protocol. Blood samples were collected at rest; 5, 10, and 15 min; and exhaustion for dopamine (DA), norepinephrine (NE), epinephrine (Epi), adrenocorticotropic hormone (ACTH), cortisol (CORT), insulin (INS), free fatty acid, blood glucose, and lactate (La) determinations. Time of cycling was not significantly changed after BZ or PLA administration (22.9 +/- 2.5 vs. 23.5 +/- 3.8 min, respectively). A decrease in CORT and an increase in INS (P < 0.05) were observed with BZ before cycling. In comparison with rest, exercise resulted in a decrease in INS and an increase in all the other variables investigated (P < 0.001), but DA, NE, Epi, ACTH, CORT, La, and free fatty acid were significantly less elevated under BZ (P < 0.05). No change was found in glucose and INS levels between the two treatments at the end of the test. There was a strong correlation under both PLA and BZ conditions between DA, NE, Epi, and ACTH and also between Epi and La levels. From these data, BZ intake did appear to alter metabolism but did not influence performance during intense submaximal exercise.

Adrenocorticotropic Hormone↗
PubMed1994

Findings of magnetic resonance and colour-flow Doppler imaging of orbital embryonal rhabdomyosarcoma.

The authors describe a case of embryonal rhabdomyosarcoma of the orbit evaluated with magnetic resonance imaging (MRI) and colour-flow Doppler imaging. MRI demonstrated a markedly enhancing tumour with no discrete vessels. Colour-flow Doppler ultrasonography showed evidence of perfusion; however, discrete vascular channels were difficult to visualize, and no evidence of large vessels within the tumour was found at surgery. The differential diagnosis of this condition is discussed, as well as the potential role of colour-flow Doppler imaging in the assessment of orbital tumours, a role in which this method has not yet been widely applied.

Child, Preschool↗
PubMed1994

Reproducibility of fluorine-18-6-fluorodopa positron emission tomography in normal human subjects.

UNLABELLED: Fluorine-18-6-fluorodopa (FD) positron emission tomography (PET) is established for measuring nigrostriatal dopaminergic function. This is despite the absence of data on the reproducibility of results. METHODS: With an ECAT 953B/31 tomograph, we performed two or three repeated FD PET scans in 10 normal subjects to measure the scan-to-scan variation in the total striatal uptake rate constant (Ki). RESULTS: We found a scan-to-scan standard deviation (s.d.) of 8.7% of the mean. The between-subject s.d. was 26% of the mean, resulting in a reliability coefficient of 90%. Analysis of the variation in the components contributing to Ki showed a reliability varying from 77% to 86% (depending on the different time points analyzed) for emission data measured by the PET camera. The reliability of the blood radioactivity time course, as reflected by the stretch time, varied from 43% to 81%. The overall reliability for the correction of the blood time course for metabolites of FD was 71%. Variation in the blood radioactivity contributed to the variability of Ki by 50% more than the metabolite correction and by 200% more than the emission data. CONCLUSION: The striatal Ki is a reliable measurement; it has a 95% chance of lying within +/- 18% of its value for an individual normal subject.

Adult↗