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Biomedical subjects

P Price

Publications and source records attributed to P Price.

At least 19 recordsLinked to original sources
PubMed1996

Direct cytotoxicity of HIV-1 envelope protein gp120 on human NT neurons.

A new in vitro system comprising a pure population of neurons, human NT cells, was used to characterize the direct neurotoxic effect of HIV-1 envelope protein gp120. Cytotoxicity was monitored by a quantitative assay after exposure to recombinant gp120 in the presence or absence of other reagents. Treatment of mature NT neurons with various doses of gp120 for 24 h caused a decrease of up to 27% in the number of viable cells. This neurotoxicity was abolished by co-treatment with either D-2-amino-5-phosphonopentanoic acid (APV), MK801 or nimodipine, or by culturing cells in a Ca(2+)-free environment. Taken together, these data indicate that gp120 exerts a direct neurotoxic effect by acting through NMDA receptors and Ca2+ channels.

2-Amino-5-phosphonovalerate↗
PubMed1996

The inflammatory macrophage response to MCMV in mice with a retroviral immunodeficiency syndrome (MAIDS).

We have shown that normal C57BL/6J mice are moderately resistant to infection with murine cytomegalovirus (MCMV) and that this resistance is impaired by prior infection with LP-BM5 MuLV, which causes a disease (MAIDS) similar to early HIV-induced disease. This study investigates macrophage function in MAIDS+ mice challenged with MCMV. MAIDS reduces the influx of cells into the peritoneal cavity seen in normal C57BL/6J mice 6 days after MCMV infection. The infiltrates contained cells that resembled activated macrophages, as they took up colloidal gold, expressed the macrophage marker Mac-1, had high levels of acid phosphatase activity, and were lymphocytostatic when co-cultured with activated T cells. MAIDS+ mice had a higher percentage of cells able to take up colloidal gold and higher acid phosphatase activity per cell. The cells were also more lymphocytostatic and produced higher levels of interleukin-1 and tumor necrosis factor-alpha on days 4 and 6 after MCMV infection. Hence, MAIDS enhances baseline and induced macrophage activity, but depresses infiltration into the site of inflammation.

Acid Phosphatase↗
PubMed1996

Measurement of liver blood flow using oxygen-15 labelled water and dynamic positron emission tomography: limitations of model description.

To date no satisfactory method has been available for the quantitative in vivo measurement of the complex hepatic blood flow. In this study two modelling approaches are proposed for the analysis of liver blood flow using positron emission tomography (PET). Five experiments were performed on three foxhounds. The anaesthetised dogs were each given an intravenous bolus injection of oxygen-15 labelled water, and their livers were then scanned using PET. Radioactivity in the blood from the aorta and portal vein was measured directly and simultaneously using closed external circuits. Time-activity curves were constructed from sequential PET data. Data analysis was performed by assuming that water behaves as a freely diffusible tracer and adapting the standard one-compartment blood flow model to describe the dual blood supply of the liver. Two particular modelling approaches were investigated: the dual-input model used both directly measured input functions (i.e. using the hepatic artery and the portal vein input, determined from the radioactivity detected in the aorta and portal vein respectively) whereas the single-input model used only the measured arterial curve and predicted the corresponding portal input function. Hepatic arterial flow, portal flow and blood volume were fitted from the PET data in several regions of the liver. The resulting estimates were then compared with reference blood flow measurements, obtained using a standard microsphere technique. The microspheres were injected in a separate experiment on the same dogs immediately prior to PET scanning. Whilst neither the single- nor the dual-input models accurately reproduced the arterial reference flow values, the flow values from the single-input model were closer to the microsphere flow values. The proposed single-input model would be a good approximation for liver blood flow measurements in man. The observed discrepancies between the PET and microsphere flow values may be due to the inherent temporal and spatial heterogeneity of liver blood flow. The results presented suggest that adaptation of the standard one-compartment blood flow model to describe the dual blood supply of the liver is limited and other flow tracers have to be considered for quantitative PET measurements in the liver.

Animals↗
PubMed1996

Adrenalitis and the adrenocortical response of resistant and susceptible mice to acute murine cytomegalovirus infection.

Murine cytomegalovirus (MCMV) induces adrenalitis in BALB/c mice but does not compromise adrenal function, assessed by levels of circulating adrenocorticotropic hormone (ACTH) and by the response to challenge with synthetic ACTH. Levels of corticosterone increased 2 days after infection in mice of this strain, consistent with previously established interactions between mediators of acute inflammation and activation of the hypothalmus-pituitary-adrenal axis. Moreover, an adrenocortical response was critical to survival of BALB/c (but not C57BL/6) mice 3 days after infection, as pharmacologically or surgically adrenalectomized BALB/c mice died when given doses of virus up to fivefold lower, than they could normally tolerate. However, death could not be prevented by the administration of soluble cytokine receptors to inhibit the action of interleukin 1 (IL-1) or tumour necrosis factor alpha (TNF alpha). The corticosteroid response did not mediate.MCMV-induced thymic atrophy. As the above traits were all less evident in C57BL/6 mice, a common genetic basis is discussed.

Acute Disease↗
PubMed1996

Alpha/beta interferons increase host resistance to murine AIDS.

Murine AIDS (MAIDS) is caused by a defective retrovirus present in the LP-BM5 murine leukemia virus mixture. Strains of inbred mice differ in resistance to MAIDS development; some are susceptible (e.g., C57BL/6), while others are resistant (e.g., CBA and B10.BR). As an early block to viral replication in resistant mice has been demonstrated previously by PCR studies, we postulated that alpha/beta interferons (IFN-alpha/beta) may be involved in resistance to MAIDS. Susceptible C57BL/6 mice infected with LP-BM5 were treated with IFN-alpha/beta or Newcastle disease virus. Newcastle disease virus induces high endogenous IFN-alpha/beta production in mice. Both treatments delayed the development of MAIDS, as assessed by splenomegaly and T- and B-cell proliferation. In addition, an IFN-alpha/beta response was detected by reverse transcription-PCR and dot blotting 3, 6, and 9 h after LP-BM5 infection in resistant mice but not in susceptible mice. These results suggest that the ability to produce IFN-alpha/beta in response to LP-BM5 infection may contribute to host resistance to MAIDS.

Animals↗
PubMed1995

Effect of a retroviral immunodeficiency syndrome on resistance to MCMV: a role for natural killer cells.

Mice exhibiting T cell immunodeficiency and lymphadenopathy induced by LP-BM5 MuLV (MAIDS) were assessed for their ability to control murine cytomegalovirus (MCMV) infection. Elevated replication of MCMV was observed in spleens 4-6 days after MCMV infection. Production of interferon alpha/beta in response to MCMV was abrogated by MAIDS and natural killer (NK) cell activity, assessed by lysis of YAC-1 target cells, was correspondingly depressed on Day 1. However, this was elevated at later times. As previous studies attribute early control of MCMV in C57BL mice with splenic NK1.1 cells, we confirmed that YAC-1 lysis declines and MCMV titres are elevated in M- mice given antibodies to NK1.1 or asialo GM1. However, M+ mice were less severely affected by these regimes. Hence M+ mice may acquire cells that do not express NK1.1 or asialo GM1, but are able to lyse YAC-1 target cells and partially control MCMV replication. MCMV was essentially cleared from the spleens and livers of M+ and M- mice by Day 11, but in the salivary gland MCMV replication was enhanced by MAIDS 11-30 days postinfection. The role of CD4 T cells in this phenomenon is being investigated. Since patients with acquired immunodeficiency syndrome exhibit suppressed T and NK cell activity and experience severe cytomegalovirus disease, the model warrants further study.

Animals↗
PubMed1995

Quality of life.

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Humans↗
PubMed1995

Analysis of hematopoietic stem and progenitor cell populations in cytomegalovirus-infected mice.

We have studied the effects of murine cytomegalovirus (MCMV) infection on bone marrow stem and progenitor cell populations to find an explanation for the defects in hematopoiesis that accompany CMV infections in patients. Sublethal MCMV infection of BALB/c mice resulted in a 5- to 10-fold decrease in the numbers of myeloid (colony-forming unit-granulocyte-macrophage [CFU-GM]) and erythroid (burst-forming unit-erythroid [BFU-E]) progenitor cells in the marrow, but not in primitive myeloerythroid progenitor cell (colony-forming unit-spleen [CFU-S]) numbers. In contrast, we observed a 10- to 20-fold reduction in CFU-S as well as CFU-GM and BFU-E in lethally infected mice. Depletion of marrow CFU-GM was less severe in C57BL/10 and C3H/HeJ mice, which are more resistant to the effects of MCMV infection. Treatment of bone marrow cells with MCMV preparations in vitro did not reduce the numbers of CFU-GM, although up to 10% of the cells were productively infected. This finding suggests that CFU-GM were not susceptible to lytic MCMV infection in vitro and are probably not eliminated by lytic infection in vivo. Increases in the frequencies of Sca-1+Lin- marrow cells, a population that includes cells with the characteristics of pluripotential stem cells, were observed in MCMV-infected BALB/c, C57BL/10, and DBA/2J mice. Increases in the frequencies of c-kit+Lin- marrow cells were only seen in DBA/2J mice. MCMV infection did not impair the function of pluripotential stem cells because transplantation of marrow from MCMV-infected donors into irradiated recipient mice resulted in successful reconstitution of the T, B, and myeloid cell lineages.

Animals↗
PubMed1995

Degradation of subcutaneous implants of bone particles from normal and warfarin-treated rats.

Osteoclasts are multinucleated cells specific to bone tissue and of hemopoietic origin. They are formed by fusion of mononucleated cells in a manner related to the formation of macrophage polykarions. Subcutaneous implantation of mineralized bone particles induces multinucleated giant cell recruitment. There is controversy, however, about the nature of these cells. Although subcutaneous implantation of bone particles derived from warfarin-treated animals has been applied as an in vivo model to study the role of osteocalcin in bone resorption, the exact nature of multinucleated cells elicited in this model is still unclear. In this paper, subcutaneous implants of bone particles from normal and warfarin-treated rats were implanted in Sprague-Dawley rats. Resorption was assessed in 12 and 16 day implants by chemical analysis (calcium content) and by histomorphometric measurement of the bone particle area and the number of multinucleated and tartrate-resistant acid phosphatase-positive cells. No significant difference in calcium content and bone area were observed, after 12 or after 16 days of implantation, between implants from normal and warfarin-treated rats. The number of tartrate-resistant acid phosphatase-positive cells elicited by bone particles represented less than 25% of the number of multinucleated cells and did not differ between bone particles from normal and warfarin-treated rats. By electron microscopy, a majority of multinucleated cells did not show a ruffled border in contact with bone particles, and their morphological features were suggestive of a foreign body giant cell reaction. In our experience this model appears to elicit only a few osteoclasts among multinucleated macrophagic cells and may not be the most appropriate one for the study of resorption of normal or osteocalcin-depleted bone.

Animals↗
PubMed1995

Cytotoxic CD8+ T lymphocytes reactive with human immunodeficiency virus-1 produce granulocyte/macrophage colony-stimulating factor and variable amounts of interleukins 2, 3, and 4 following stimulation with the cognate epitope.

Infection with human immunodeficiency virus type 1 (HIV-1) induces vigorous and persistent cytotoxic CD8+ T cell responses. CTL clones were derived from peripheral blood or cerebrospinal fluid of three HIV-1 patients, with depressed CD4+ T cell counts. When stimulated with HLA-compatible target cells (B-LCL) presensitized with cognate HIV-1 peptides, all clones produced GM-CSF, TNF-alpha, and IFN-gamma and most produced low amounts of IL2, IL3, and IL4. After nonspecific stimulation with a phorbol ester and calcium ionophore, the clones secreted cytokines at levels similar to those from CD4+ lines from an HIV-1 infected donor. The ability of supernatants from the stimulated CTL clones to support the formation of granulocyte-macrophage colonies in normal bone marrow suggests that the GM-CSF was biologically active. Release of cytokines by activated CTL may influence the immunopathogenesis of HIV disease.

CD4-Positive T-Lymphocytes↗
PubMed1995

Can positron emission tomography (PET) be used to detect subclinical response to cancer therapy? The EC PET Oncology Concerted Action and the EORTC PET Study Group.

At the EORTC NCI New Drug Development Meeting in Amsterdam in 1994, a workshop, suggested by the EC PET (positron emission tomography) Oncology concerted action, was held to bring together many of those European PET centres investigating the use of [18F]FDG ([18F]2-fluoro-2 deoxyglucose) PET scanning as a measure of response to cancer therapy. Of the current 31 PET centres in Europe invited to contribute, 15 centres already had data and others expressed interest. Many of the groups were collaborating with local oncologists to measure tumour response to chemotherapy (12 groups) and radiotherapy (three groups) with this technique. Despite variations of methodology, and difficulties in data interpretation, assessment of tumour [18F]FDG uptake was thought to be a reasonable method for the functional imaging of tumours, assessing metabolic rate and providing a measure of tumour response. Broadly, pooling experience, it would appear that changes in [18F]FDG tumour uptake following one or two cycles of chemotherapy treatment was related to ultimate clinical responses. Patients showing most reduction in [18F]FDG uptake achieved the best clinical responses. Data were also available on the effect of chemotherapy on normal tissues and some data on the effect of radiotherapy and tumour response. It was concluded that changes in [18F]FDG uptake as measured with PET may provide useful information on clinical as well as subclinical response of tumours to anticancer therapy. This could be useful as a guide to early response to therapy as well as providing functional assessment of residual masses of disease. More specific markers of cellular proliferation e.g. [11C]thymidine, or [11C]- amino acids may provide even more accurate information. A strategy was outlined whereby PET scanning protocols could parallel EORTC early clinical trials so that [18F]FDG response information could supplement phase I and II clinical studies. Following these developments, an EORTC study group was formed under the auspices of the EORTC research branch, and the strategy for future development in Europe outlined.

Clinical Trials, Phase I as Topic↗
PubMed1995

Non-surgical management of early breast cancer in the United Kingdom: the role and practice of radiotherapy. Clinical Audit Sub-committee of the Faculty of Clinical Oncology, Royal College of Radiologists, and the Joint Council for Clinical Oncology.

This paper reports on the delivery of radiotherapy to the primary site and lymphatic pathways in the management of early stage breast cancer. Radiotherapists were clear that their aim of locoregional radiotherapy was to reduce local recurrence. However, variation in policies for delivery were seen: 80% of radiotherapists did not always give radiotherapy routinely following wide local excision as part of breast conserving management; instead they withheld it selectively for a number of reasons. Only 66% routinely used breast boosts. There was a range of indications for giving radiotherapy to the lymphatic pathways; there was also variation in the management of incompletely or marginally excised primary tumours. Most sources of variation in the practice of radiotherapy in the management of women with early stage breast cancer appeared to arise from scientific uncertainty. However, organizational issues influenced many decisions. These scientific uncertainties and organizational issues are best addressed in the context of multidisciplinary breast clinics.

Breast Neoplasms↗
PubMed1995

Non-surgical management of early breast cancer in the United Kingdom: radiotherapy fractionation practices. Clinical Audit Sub-committee of the Faculty of Clinical Oncology, Royal College of Radiologists, and the Joint Council for Clinical Oncology.

A national survey of British radiotherapy schedules used in women with early breast cancer was undertaken to document variation in treatment practices and to consider its clinical significance. Although the variation is considerable, the analysis suggests that the majority of schedules in use are very similar in terms of treatment intensity when allowance is made for fraction size and overall time. Half the respondents used one of three dosage schedules, which probably differ very little in terms of late normal-tissue effects and tumour control from a conventional schedule giving 50 Gy in daily 2 Gy fractions. Eighty-two percent of respondents were using schedules that are equivalent to a dose of between 45 Gy and 50 Gy in 2 Gy fractions. The study suggests that the protocols in use by a minority of respondents may be unduly conservative or aggressive, and it leads to the proposal that oncologists should set up trials comparing commonly used schedules as a matter of urgency.

Breast↗
PubMed1995

Proliferating cell nuclear antigen (PCNA) immunostaining--a prognostic factor in ovarian cancer?

The measurement of tumour cell proliferation is becoming increasingly recognised in defining prognostic groups. Proliferating cell nuclear antigen (PCNA) immunolocalisation can be used as an index of cell proliferation and may define the extent of departure from normal growth control. The monoclonal antibody PC10 stains PCNA in archival paraffin-embedded tissue. This study investigates its potential as a prognostic marker in early and advanced ovarian cancer. A three-stage immunoperoxidase technique was developed to detect the monoclonal antibody PC10. Archival paraffin-embedded tissue from 19 stage I ovarian tumours (13 malignant and six borderline) and 79 advanced (stage IIb-IV) ovarian tumours (patients entered into the Third North-West Thames Ovarian Cancer Trial) was immunostained with PC10. PC10 immunostaining was performed successfully in 91.8% of cases. The PC10 labelling index (PC10 LI) ranged from 1.5% to 88% with a mean value of 47.4%. Stage I borderline tumours had significantly lower PCNA labelling indexes than stage I malignant tumours (P < 0.048). In advanced disease there was an inverse correlation between PC10 and overall survival, and in those patients who underwent good debulking surgery (37 patients with disease < 2 cm diameter) a low PC10 value (< 36.5%) correlated with improved survival (log-rank trend test for survival, chi 2 = 5.75, P = 0.017). PCNA immunostaining defines a good prognostic subgroup in adequately debulked patients with ovarian cancer.

Adult↗