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Biomedical subjects

G Cox

Publications and source records attributed to G Cox.

At least 73 records · Page 4Linked to original sources
PubMed1998

Liposomal vincristine for the treatment of human acute lymphoblastic leukaemia in severe combined immunodeficient (SCID) mice.

Non-obese diabetic NOD/SCID mice have been used to grow human leukaemia as a systemic disease. The animals were inoculated with leukaemic cells obtained from a 36-year-old male with early B-cell precursor acute lymphoblastic leukaemia and on day 15 were given the first of three weekly injections of 1 mg/kg vincristine or equimolar liposomal vincristine. The development of leukaemia in the mice was monitored by taking weekly blood samples and measuring the cell content by flow cytometry. The median time to 50% human cells in the peripheral blood of mice treated with free vincristine was 41 d from the start of treatment compared with 49 d for mice treated with liposomal vincristine (P < 0.01). The median day of death for mice treated with free vincristine was 47 d from the start of treatment and 57 d for mice receiving liposomal vincristine (P<0.01), thus providing a 21% increase in lifespan for animals treated with the liposomal preparation. There was slightly greater weight loss in mice treated with free vincristine than those given liposomal vincristine. Measurement of in vitro colony forming bone marrow progenitor cells in similarly treated, tumour-free mice, showed no difference in progenitor cell survival between mice that received either type of vincristine. We conclude that encapsulating vincristine in liposomes improves the therapeutic index of this drug measured in mice bearing human leukaemia. This may lead to use of the drug in conventional combination chemotherapy with greater safety or, in this setting, at higher dosage.

Adult↗
PubMed1998

Induced sputum, bronchoalveolar lavage and blood from mild asthmatics: inflammatory cells, lymphocyte subsets and soluble markers compared.

Airway inflammation in asthma can be measured directly by invasive bronchoalveolar lavage (BAL), directly and relatively noninvasively by induced sputum and indirectly from peripheral blood. We compared cellular and fluid phase indices of inflammation in induced sputum, BAL and blood from 11 adults with mild stable asthma. On one day, induced sputum selected from saliva was collected and on the next, blood and BAL. Median results of sputum compared with BAL showed a higher number of nonsquamous cells (53 versus 0.8 x 10(6) cells x mL(-1), p=0.003), more neutrophils (34.3 versus 1.0%, p<0.001), CD4+ and CD19+ T-cells (76.5 versus 54.7%, p=0.01 and 5.2 versus 1.1%, p=0.03, respectively), fewer macrophages (603 versus 95.0%, p=0.002) and markedly higher levels of eosinophil cationic protein (ECP) (264 versus 2.0 microg x L(-1), p<0.001), tryptase (17.6 versus 2.2 UI x L(-1), p<0.001) and fibrinogen (1,400 versus 150 microg x L(-1), p=0.001). Sputum and BAL neutrophils and CD4+ T-cells were strongly correlated. Sputum and BAL differed from blood by having higher proportions of T-cells (94.9 and 98.9% versus 87.7%, p=0.002) and lower proportions of CD19+ T-lymphocytes (p=0.04 and 0.006). Sputum also differed from blood by having higher proportions of CD4+ T-cells (76.5 versus 51.4%, p=0.001), lower proportions of CD8+ cells (24.0 versus 403%, p=0.04) and a higher CD4+/CD8+ ratio (3.3 versus 1.4, p=0.01). We conclude that in mild asthmatics, sputum, bronchoalveolar lavage and blood measure different compartments of inflammation. Induced selected sputum has the advantage over bronchoalveolar lavage of higher density of cell recovery and stronger signal for fluid-phase markers.

Adult↗
PubMed1998

Otitis media with effusion and size at birth.

To investigate whether recurrent or persistent otitis media with effusion (OME) was associated with particular patterns of fetal growth, we conducted a case control study of 129 children admitted for insertion of grommets and 150 controls. The risk of OME was not statistically significantly related to gestational age or individual measures of size at birth, but the ratio of head circumference to total length and the ponderal index at birth were statistically significantly lower in children with OME, both before and after adjustment for the potentially confounding effects of sex, age at current operation, and maternal gravidity. Mothers of cases were 2.2 times more likely than those of controls to have had one or more previous pregnancies that had not ended in a live birth (95% CI 1.3-3.8). We conclude that fetal growth, reflected by proportions at birth, may affect later risk of recurrent and persistent OME.

Anthropometry↗
PubMed1997

Dexamethasone-induced suppression of apoptosis in human neutrophils requires continuous stimulation of new protein synthesis.

We examined the mechanisms of corticosteroid inhibition of cell death by apoptosis in human neutrophils. Suppression of apoptosis by dexamethasone was abolished by co-treatment with the protein synthesis inhibitor cycloheximide. At doses of 1 microg/mL cycloheximide did not reduce basal survival of neutrophils but effectively inhibited dexamethasone-induced increases in 24-h survival (24.4 +/- 8.7 vs. 49.6 +/- 10%, P < 0.01). Similar results were obtained with actinomycin D, an inhibitor of mRNA synthesis. The factor(s) responsible for mediating increased survival following dexamethasone treatment is not active extracellularly because dexamethasone-treated neutrophil-conditioned medium (CM) had no effect on the survival of naive neutrophils when the direct effects of dexamethasone were neutralized with the steroid antagonist RU-486. In contrast, LPS-treated neutrophil CM significantly increased neutrophil survival even after addition of polymyxin b. The survival effect of dexamethasone required the continuous presence of the agonist because addition of RU-486 caused prompt development of apoptosis in dexamethasone-treated cells. When naive and dexamethasone-treated cells were examined by mRNA differential display, a limited number of cDNA bands were consistently and reproducibly detected that were increased in intensity, indicating up-regulation by dexamethasone. Thus, corticosteroid regulation of neutrophil apoptosis is a specific effect that depends on continuous stimulation of synthesis of a (protein) survival factor.

Apoptosis↗
PubMed1997

Secretory leukocyte proteinase inhibitor is a major leukocyte elastase inhibitor in human neutrophils.

Secretory leukocyte proteinase inhibitor (SLPI) is the main neutrophil elastase (HLE) inhibitor found in the upper airways during pulmonary inflammation. It has been shown to be synthesized and secreted in vitro by epithelial cells and has been localized in tracheal glands and bronchiolar epithelial cells by immunocytochemistry. In this study, using immunodetection and immunopurification techniques with specific anti-SLPI immunoglobulin G (IgG), we show that SLPI is present as a native 14-kDa molecule in neutrophil cytosol. In addition, we demonstrate that SLPI is the major inhibitor of HLE present in neutrophil cytosol because pre-incubation with specific anti-SLPI IgG was able to inhibit completely the anti-HLE activity of the cytosol. SLPI can be secreted (probably in an inactive form) by neutrophils and its secretion is enhanced when the cells are stimulated with phorbol myristate acetate (PMA). Elafin, an elastase-specific inhibitor, is also present in minute amounts in neutrophil cytosol and its secretion can be up-regulated. The presence of SLPI in the cytosol of neutrophils may serve as a protective screen against proteinases spilling from azurophilic granules. An alternative or supplementary role may be the maintenance of a differentiated phenotype.

Cell Differentiation↗
PubMed1996

Assessment of nerve ultrastructure by fibre-optic confocal microscopy.

Fibre-optic technology combined with confocality produces a microscope capable of optical thin sectioning. In this original study, tibial nerves have been stained in a rat model with a vital dye, 4-(4-diethylaminostyryl)-N-methylpyridinium iodide, and analysed by fibre-optic confocal microscopy to produce detailed images of nerve ultrastructure. Schwann cells, nodes of Ranvier and longitudinal myelinated sheaths enclosing axons were clearly visible. Single axons appeared as brightly staining longitudinal structures. This allowed easy tracing of multiple signal axons within the nerve tissue. An accurate measurement of internodal lengths was easily accomplished. This technique is comparable to current histological techniques, but does not require biopsy, thin sectioning or tissue fixing. This study offers a standard for further in vivo microscopy, including the possibility of monitoring the progression of nerve regeneration following microsurgical neurorraphy.

Animals↗
PubMed1996

IL-10 enhances resolution of pulmonary inflammation in vivo by promoting apoptosis of neutrophils.

Interleukin-10 (IL-10) has been shown to be protective in models of sepsis. This protection is mediated in part by inhibition of monokine-dependent processes. Because IL-10 can act on other cells to regulate inflammatory events, and because we have previously shown that clearance of inflammation is an active process, we examined whether IL-10 could regulate processes of resolution during pulmonary inflammation induced by lipopolysaccharide (LPS) challenge. Administration of 1 microgram of IL-10 with 6 micrograms LPS intratracheally to rats did not alter the time of onset or the magnitude of the initial response, as assessed by bronchoalveolar lavage (BAL) neutrophilia. However, the extent of the neutrophilia was markedly reduced at 18 h, and longer, after challenge. During ex vivo culture of cells obtained by BAL, neutrophils died by apoptosis and were engulfed by macrophages. Clearance of neutrophils was more rapid in the cultured BAL of rats treated with IL-10. In separate experiments, IL-10 did not reduce survival rates of untreated human neutrophils, but did inhibit LPS-induced increases in survival in a dose-dependent fashion. Thus IL-10 did not modulate the onset of, or peak of, neutrophil accumulation in response to LPS but did promote the clearance of recruited neutrophils in vivo. The mechanism of this anti-inflammatory action may be through the prevention of stimulated increases in neutrophil survival.

Animals↗
PubMed1996

MTT assay overestimates human airway smooth muscle cell number in culture.

In this study, we evaluated the accuracy of the MTT (a tetrazolium salt) assay for cell counting by comparing it to haemocytometer. When airway smooth muscle cells were cultured in RPMI with fetal calf serum < or = 5%, no significant differences were observed in cell number counted by the two methods. For cells cultured in 10% serum, however, the result was 20% higher when counted by MTT assay. Rhodamine 123 uptake was similar in ASMCs cultured in the presence of serum at 5 and 10% indicating no difference in total mitochondrial activity per cell. Serum at > 5% may modulate the activity of enzymes responsible for reduction of MTT. Our results indicate that the MTT assay may not be accurate under certain conditions, especially when the treatment of cells can affect the enzymes that account for MTT reduction in addition to stimulating cell growth.

Bronchi↗
PubMed1995

Glucocorticoid treatment inhibits apoptosis in human neutrophils. Separation of survival and activation outcomes.

We examined the direct effects of glucocorticoid treatment on neutrophil survival and function in vitro. Four different glucocorticoids caused a dose-dependent inhibition of apoptosis leading to increased survival of neutrophils. Maximal effects were found with dexamethasone at 10(-6) M, 16.6 +/- 6.2 vs 54.6 +/- 6.9, at 24 h (p < 0.05). Nonglucocorticoid steroids did not modulate apoptosis in neutrophils. Furthermore, the effect was inhibited in a dose-dependent manner by the glucocorticoid antagonist RU 486. Glucocorticoid-treated neutrophils produced significantly more superoxide in response to FMLP than untreated controls (p < 0.05). However, both basal and stimulated superoxide production were less than that found with freshly isolated cells. Such lack of priming or activation by glucocorticoids is in contrast to previous experience when increased survival was accompanied by cell activation. When compared with other stimuli, the effect of glucocorticoids at 24 h was similar to that of LPS but less than that of granulocyte-macrophage colony-stimulating factor (GM-CSF), 52 +/- 4, 57 +/- 6, and 70 +/- 4, respectively (p < 0.05). When added in combination, dexamethasone did not increase survival with LPS, but did augment the effect of GM-CSF, suggesting diversity in the mechanisms by which these stimuli regulate apoptosis. These data indicate that glucocorticoids can augment the effector potential of neutrophils by prolonging their survival and functional responsiveness, and such treatment might be detrimental in vivo because of delay in neutrophil apoptosis and in ultimate clearance of them from tissues.

Apoptosis↗
PubMed1995

Initial experience with asynchronous transfer mode for use in a medical imaging network.

Picture archiving and communication Systems (PACS) for medical imaging have always suffered from band-width limitations, throughput, and proprietary protocols. Commercially available local area networks have been hard pressed to meet the requirements of image transfer in a time consistent with patient-care needs. Recent technologic advances provide potential solutions to these constraints. Asynchronous transfer mode (ATM) provides the aggregate bandwidth and throughput that may be sufficient to satisfy the medical imaging community. Networks using prototype ATM technology have been available and commercial hardware is now becoming available. This report presents initial performance results of an ATM network and its suitability for use in a digital imaging network. Throughput of 10 Mbytes/sec was attained with Transmission Control Protocol/Internet Protocol using commercially available hardware.

Computer Communication Networks↗
PubMed1995

De virginibus puerisque: the function of the human foreskin considered from an evolutionary perspective.

The functional significance of the human male foreskin is considered in evolutionary terms. It is postulated that there is a lifetime's reproductive advantage in delaying the age of first coitus, and hence of first childbirth, for some years after puberty, until the parents are better established as providers. Phimosis and preputial adhesions are common in human males because they have selective advantage, tending to impede and therefore delay the onset of sexual activity. The physical signs of female virginity have an analogous function, and have been selected for in the same way. This hypothesis also provides a consistent explanation for the worldwide tradition of circumcision and for the common practice of masturbation by human males.

Adolescent↗
PubMed1995

Macrophage engulfment of apoptotic neutrophils contributes to the resolution of acute pulmonary inflammation in vivo.

For resolution of inflammation to occur, it is necessary both to limit leukocyte influx and to clear now redundant cells from the tissues. Recent evidence from in vitro studies suggests that clearance may be an active process, accomplished in part by macrophage engulfment of intact cells that have undergone programmed cell death or apoptosis. However, the kinetics of these events and their association with the resolution of acute inflammatory responses in vivo remain to be elucidated. To investigate these events, we examined an animal model of acute, limited, neutrophilic pulmonary inflammation. Cells were obtained by bronchoalveolar lavage (BAL) of rats at various time points after intratracheal administration of lipopolysaccharide (LPS). Apoptotic neutrophils were rarely seen in BAL from control animals but were detected after neutrophil influx had occurred in response to LPS challenge. Macrophage engulfment of these cells was identified at light microscopy and confirmed at electron microscopy. The proportion of macrophages that had engulfed apoptotic neutrophils was maximal 24 h after LPS challenge and declined thereafter as total neutrophil numbers fell. During the resolution phase, the alveolar macrophages became positive for peroxidase, indicating the presence of neutrophil granule contents in their cytoplasm. These observations demonstrate that apoptosis of leukocytes indeed occurs during the course of an acute inflammatory response in vivo and that the emergence of apoptotic neutrophils and macrophage engulfment of these cells are temporally correlated with the resolution of acute inflammation.

Animals↗
PubMed1994

A novel transcriptional suppressor located within a downstream intron of the BCR gene.

A reciprocal translocation between chromosomes 9 and 22 creates the Philadelphia (Ph1) chromosome in chronic myelogenous leukemia. This translocation results in the fusion of the ABL and the BCR genes to form a BCR/ABL fusion gene, the product of which has a greatly increased protein tyrosine kinase activity in comparison with the normal ABL protein. The chromosome 22 translocation breakpoints are concentrated within a 5.8-kilobase region named the major break-point cluster region (Mbcr). Gel mobility shift and DNase I footprinting assays have defined binding sites for three proteins, BIF 1-3 (BCR intron factors 1-3), lying within a 427-base pair fragment of the Mbcr. This 427-base pair fragment functions as a transcriptional silencer with both the BCR as well as a heterologous promoter. The silencing is position- and orientation-independent. The transcriptional effects are greatest in chronic myelogenous leukemia cells, decreased in HeLa and B-cells, and absent in T-lymphocytes. Gel mobility shift assays show a corresponding difference in pattern when the T-lymphocyte nuclear extract is compared with other cell lines. The Mbcr appears to contain a novel group of transcriptional silencers that share a common binding motif with a recently described suppressor in the mouse Adh-1 gene.

Base Composition↗
PubMed1994

Synovial sarcoma of the larynx in a child: case report and histological appearances.

Synovial sarcoma of the larynx is extremely rare having been reported only six times previously in the literature. We add another case report, which to our knowledge is the first recorded case in a child. We discuss the alternative approach of combination chemotherapy and radiotherapy which in this case led to a remission lasting about 3 years. The immunohistological and ultrastructural characteristics of the tumour are also presented.

Adolescent↗
PubMed1994

The physiological and ventilatory responses to repeated 60 s sprints following sodium citrate ingestion.

This study examined the influence of sodium citrate on changes in selected blood, ventilatory and performance variables in response to intermittent sprint exercise. Eight moderately active male students completed three tests over a 6 day experimental period. The first test involved incremental exercise to determine VO2 max, while the second and third tests were identical in nature and involved five 60 s sprints cycling against 0.075 kg kg-1 body mass (BM); each of the five sprints was separated by 5 min passive seated recovery. Three days separated the VO2 max test and first interval test, while a further 3 days elapsed between the first and second interval tests. Ninety minutes prior to each interval test, the subjects consumed either a solution of sodium citrate (0.5 g kg-1 BM) or a placebo solution (1 g of calcium carbonate and 4 mg of sodium chloride). These were randomly administered in a double-blind crossover procedure so that every subject consumed each solution prior to the interval test over the 6 day period. Measures of work, VE, VO2, VCO2, post-exercise plasma lactate, and changes in both venous blood pH and venous blood bicarbonate (HCO3-) were measured during each interval test. Although analysis of variance failed to identify differences in performance between the two solutions, both exercise VCO2 and changes in venous blood HCO3- were higher in the citrate condition (P < 0.05). In addition, both peak post-exercise plasma lactate concentrations and post-exercise venous blood pH were significantly higher following citrate ingestion. Although these data are consistent with greater clearance of lactate and H+ from the active muscle cells following citrate ingestion, performance between the two trials was the same.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗