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Biomedical subjects

P Price

Publications and source records attributed to P Price.

At least 109 records · Page 6Linked to original sources
PubMed1999

The role of IL-12 in the control of MCMV is fundamentally different in mice with a retroviral immunodeficiency syndrome (MAIDS).

The present study investigates the susceptibility of C57BL mice exhibiting T cell immunodeficiency and lymphadenopathy induced by LP-BM5 murine leukaemia virus (MAIDS) to murine cytomegalovirus (MCMV). Treatment of normal (M-) mice with anti-IL-12 increased the contribution of IgG1 to the hypergammaglobulinaemia induced by MCMV, consistent with a shift towards a Th2 phenotype. This impaired control of early MCMV replication in the liver, with little effect in the spleen. Control of hepatic infection correlated with a vigorous splenic NK cytotoxic response in a subgroup of IL-12-depleted M- mice that remained healthy, while others became moribund. Mortality in IL-12-depleted MAIDS (M+) mice given MCMV was ultimately greater than in M- controls, but was delayed despite high levels of MCMV in the liver. IL-12 was required for optimal control of MCMV replication in M+ mice. This may involve cytotoxic activity because similar levels of infection were seen in bg/bg M+ mice, where the beige mutation impairs the formation of cytotoxic granules. Hence the ability of M+ mice to tolerate high titres of MCMV during acute infection may enable innate cytotoxic responses to clear MCMV. Interleukin-12 depletion of M- mice also increased salivary gland MCMV titres and depressed delayed-type hypersensitivity responses to MCMV antigen, normally mediated by CD4+ T cells. These changes were not observed in IL-12-depleted M+ mice.

Animals↗
PubMed1999

The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases.

An individual's major histocompatibility complex (MHC) ancestral haplotype (AH) is the clearest single determinant of susceptibility to MHC associated immunopathological disease, as it defines the alleles carried at all loci in the MHC. However, the direct effects of any of the 150-200 genes that constitute the MHC are difficult to determine since recombination only occurs at defined hotspots. This review concerns the 8.1 AH (HLA-A1, C7, B8, C4AQ0, C4B1, DR3, DQ2), which is carried by most Caucasians with HLA-B8. It is associated with accelerated human immunodeficiency virus (HIV) disease, and susceptibility to insulin-dependent diabetes mellitus (IDDM), systemic lupus erythematosus, dermatitis herpetiformis, common variable immunodeficiency and IgA deficiency, myasthenia gravis and several other conditions. We have mapped susceptibility genes for HIV, IDDM and myasthenia gravis to the central MHC between HLA-B and the tumour necrosis factor or complement genes. Here we consider which of the remaining 8.1-associated diseases are more closely associated with HLA-DR3 and/or DQ2. Several candidate genes in the central MHC have the potential to modulate immune or inflammatory responses in an antigen-independent manner, as is seen in studies of cultured cells from healthy carriers of the 8.1 AH. Hence these genes may act as a common co-factor in the diverse immunopathological conditions associated with the 8.1 AH.

Animals↗
PubMed1999

Characterisation of the human central MHC gene, BAT1: genomic structure and expression.

The BAT1 gene (D6S81E) encodes a member of the DEAD-box family of RNA-binding proteins, and lies in the central MHC. This region contains genes which affect susceptibility to immunopathological diseases. A 14-kb section of the human MHC containing the BAT1 gene and a further 5-kb telomeric of BAT1 was sequenced using DNA from individuals homozygous for HLA-A1, B8, DR3 and HLA- A1, B57, DR7. Analysis of our sequences and the previously reported human cDNA sequence showed that the expressed sequence of the 8.1 and 57.1 haplotypes is identical with only minor substitutions in the introns. Phylogenetic analysis suggests BAT1 may be a translation initiation factor. Screening of cells and tissues for BAT1 mRNA suggests an abundant member of a family of proteins expressed in multiple cell types, notably macrophages and hepatocytes. Expression was independent of MHC haplotype, consistent with the lack of sequence polymorphism.

Blotting, Northern↗
PubMed1999

Clinical evaluation of a new pressure-relieving mattress.

In introducing a new mattress into practice it is important to evaluate its performance from both the patient's and nurse's perspective. A total of 20 patients admitted to the integrated medical unit were recruited and nursed on a new pressure-relieving mattress offering two modes of pressure relief (Duo). All patients had been recently admitted to hospital and were considered to be 'at very high risk' of developing a pressure ulcer, with an initial Waterlow score > 20. Data were collected on admission, mid-point (three to four days) and study exit (seven days). The primary objective was to investigate the condition of patients' skin and the mode of choice for pressure relief. The secondary objective was to investigate reasons for nurses' and patients' choices. Structured interviews were conducted with the patient, ward nurse and research nurse whenever possible. Nineteen patients maintained or improved their skin condition during the evaluation.

Aged↗
PubMed1999

Challenging the pressure sore paradigm.

This study determines the effectiveness of a new low-unit-cost support system in patients at very high risk of developing pressure sores. In a prospective randomised controlled trial, a low-pressure inflatable mattress and cushion system (Repose) was compared to a dynamic support mattress (Nimbus II) used in conjunction with an alternating-pressure cushion (Alpha TranCell) in 80 patients with fractured neck of femur and high scores on a pressure sore risk assessment scale. All patients received best standard care, including turning at regular intervals. Skin condition was assessed in 17 locations on admission, preoperatively, and seven and 14 days postoperatively. No difference was found between the groups in skin condition or the occurrence and severity of pressure sores at any time point.

Aged↗
PubMed1999

Structure and polymorphism of two stress-activated protein kinase genes centromeric of the MHC: SAPK2a and SAPK4.

As MHC genes are potent determinants of susceptibility to immunopathological diseases, the mapping of SAPK2a (CSBP) and SAPK4 to chromosome 6p 21.2-21.3 suggested that these genes may mediate the effects of the MHC on disease. Here we describe the genomic structure and localisation of both genes approximately 2.3Mb centromeric of HLA-DP. Examination of the complete coding region and selected intronic regions of SAPK2a and SAPK4 from 22 human EBV-transformed B-cell lines of different MHC haplotypes and racial background revealed complete sequence conservation. There were no notable differences in levels of expression of SAPK2a and SAPK4 mRNA in cell lines of different MHC haplotypes or racial origin. Examination of the SAPK2a and SAPK4 sequences from two chimpanzees revealed 3 nucleotide differences between human and chimpanzee in each gene resulting in only one amino acid change in SAPK4, and 6 nucleotide substitutions plus 2 deletions in 600bp of intronic sequence from SAPK4. This highlights the selective pressure placed on these genes to maintain their protein sequence, but does not favour a role in genetic regulation of disease or provide evidence of linkage disequilibrium with the MHC.

Amino Acid Sequence↗
PubMed1998

Pharmacokinetic assessment of novel anti-cancer drugs using spectral analysis and positron emission tomography: a feasibility study.

PURPOSE: The aim of this study was to investigate the feasibility of evaluating the pharmacokinetics of radiolabeled anti-cancer drugs using spectral analysis, a non-compartmental tracer kinetic modeling technique, and positron emission tomography (PET). METHODS: Dynamic PET studies were performed on patients receiving tracer doses of 5-fluorouracil (5-[18F]-FU) and two developmental drugs [11C]-temozolomide and [11C]-acridine carboxamide. Spectral analysis was then used to (a) determine individual and group average pharmacokinetics, (b) predict tumour handling in response to different drug administration regimens, and (c) produce functional parametric images describing regional pharmacokinetics. RESULTS: Spectral analysis could distinguish tumour kinetics from normal tissue kinetics in an individual [11C]-temozolomide study and demonstrated a markedly greater volume of distribution (VD) in glioma than in normal brain, although there was no appreciable difference in mean residence time. Analysis of pooled acridine carboxamide data (n = 22) revealed a relatively large VD (and prolonged retention) in the liver and spleen and a markedly lower VD (and initial uptake) in the brain. Continuous infusion of 5-[18F]-FU was predicted to achieve a concentration in colorectal metastases in liver approximately 10 times that achieved in plasma at 10 h after commencement of the infusion. CONCLUSIONS: We conclude that spectral analysis provides important pharmacokinetic information about radiolabeled anti-cancer drugs with relatively few model assumptions.

Acridines↗
PubMed1998

F2-isoprostane generation in isolated ferret lungs after oxidant injury or ventilated ischemia.

Pulmonary edema develops when pulmonary blood flow is interrupted, then restored. Because the lung is not always hypoxic when ischemic, mechanisms of pulmonary ischemia-reperfusion injury are likely to differ from systemic organs, where reactive oxygen species generated during reperfusion mediate organ dysfunction. We previously showed that pulmonary vascular permeability of isolated ferret lungs increased prior to reperfusion, if ventilation was maintained while blood flow was impaired. To determine whether reactive oxygen metabolites generated during ischemia mediated ischemic injury, we measured tissue levels of F2-isoprostanes as an index of lipid peroxidation, 30 min after administration of glucose (5 mM)-glucose oxidase (GOX, 0.1 U/ml), or after short (45 min) or long (180 min) ventilated ischemia, in isolated ferret lungs. Osmotic reflection coefficient for albumin (sigma alb), an estimate of vascular protein permeability, was measured in the same lungs. Tissue F2-isoprostanes increased 375% after exposure to glucose-GOX in association with a 42% decrease in sigma alb, and administration of catalase (CAT, 100,000 U) and superoxide dismutase (SOD, 25,000 U) completely attenuated this lipid peroxidation. In contrast, tissue F2-isoprostanes increased only 60% following 45 min of ischemia, then did not increase additionally. sigma alb was not altered by 45 min of ischemia, but decreased 72% following 180 min of ischemia. CAT+SOD did not alter F2-isoprostane formation during ischemia, but partially attenuated vascular injury. These results suggest that tissue levels of F2-isoprostanes reflect lung lipid peroxidation, but that F2-isoprostane generation does not directly increase vascular permeability following ventilated pulmonary ischemia.

Animals↗
PubMed1998

What is the role of radiation-chemotherapy in the radical non-surgical management of carcinoma of the oesophagus? Upper GI Cancer Working Party of the UK Medical Research Council.

The optimal radical non-surgical management of carcinoma of the oesophagus has yet to be determined. The combination of high-dose radiotherapy with chemotherapy is being explored, particularly in North America. The MRC Upper GI Working Party has debated the areas where there is scientific uncertainty and which clinical trials may be appropriate to undertake in the UK.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Radiobiological prediction of normal tissue toxicities and tumour response in the radiotherapy of advanced non-small-cell lung cancer.

A number of randomized studies have been carried out in the UK and USA to determine the optimal radiotherapy dose schedule for advanced non-small-cell lung cancer (NSCLC). We have examined eight radiotherapy regimens from data taken from four randomized phase III studies carried out in the UK (1264 patients): 10 Gy single fraction; 17 Gy in two fractions over 8 days; 30 Gy in ten fractions over 14 days; 22.5 Gy in five fractions in 5 days; 27 Gy in six fractions over 11 days; 30 Gy in six fractions over 11 days; 36 Gy in 12 fractions over 16 days; and 39 Gy in 13 fractions over 17 days. We compared the clinical results in palliation, toxicity and survival with four regimens taken from one randomized study from the USA (365 patients): 40 Gy in 20 fractions over 4 weeks; 40 Gy 'split course' in ten fractions in 4 weeks; 50 Gy in 25 fractions over 5 weeks; and 60 Gy in 30 fractions over 6 weeks. Using the linear-quadratic (LQ) radiobiological model, we have calculated the radiobiological equivalent dose (BED) for acute-reacting tissues (BED10), late-reacting tissues (BED1.7) and tumour (BED25), and related the predicted response to the observed response in each tissue. There was a good correlation between the predicted response and the reported response in the case of late-reacting tissue toxicity and tumour response. The model confirmed that, in good performance status patients, a higher value for BED25 correlated with a higher degree of local control and survival and that radiotherapy regimens with a higher value for BED1.7 were associated with five cases of cord myelopathy, if the spinal cord was not shielded. In poor performance status patients the model suggested that the optimal regimen was a single fraction of 10 Gy because this resulted in an equivalent degree of symptom control as other regimens, needed only one hospital visit and was less likely to result in cord damage, thus, allowing for the possibility of retreatment at a later date.

Carcinoma, Non-Small-Cell Lung↗
PubMed1998

Factors influencing the effects of murine cytomegalovirus on the pancreas.

BACKGROUND: As human cytomegalovirus (HCMV) infections are implicated in insulin-dependent diabetes mellitus (IDDM), the effects of murine (M)CMV infection of inbred mice on the pancreas are of interest. RESULTS: Inflammation and periacinar oedema peaked on day 3 and were replaced by a focal inflammation, but infected cells were rare. The islets were spared in C57BL mice. Insulitis normally seen in non-obese diabetic (NOD) mice was accelerated, but infected NOD mice did not become glycosuric. Isotypes of total and autoreactive antibodies suggested a shift to a Th 1 response (IgG2a) in all MCMV-infected mice. MCMV-induced pancreatitis was not affected by MHC genes but was similar or less severe in BALB/c mice. As these lack the Cmv1 gene, which provides a protective natural killer (NK) cell response in C57BL congenic mice, the C57BL background may carry a pancreatitis susceptibility gene able to counter NK-mediated restriction of viral replication. Consistently, congenic mice expressing Cmvl on a BALB/c background did not display pancreatitis, unless depleted of NK cells. In vivo treatment with soluble cytokine receptors suggested that interleukin 1 (IL-1) and/or tumour necrosis factor alpha contribute to acinar necrosis in C57BL mice.

Animals↗
PubMed1998

The association between murine cytomegalovirus induced hepatitis and the accumulation of oval cells.

The accumulation of oval cells is an early event in the development of hepatocellular carcinoma induced by certain experimental regimes involving hepatocarcinogens. Oval cells have also been observed during chronic hepatitis induced by alcohol and iron overload. In this study, livers of murine cytomegalovirus (MCMV) infected mice were examined to determine whether hepatitis induced by this virus could initiate oval cell proliferation. BALB/c and C57BL/6 mice were infected with MCMV and studied 4, 8, 10 and 12 months later, alongside control (uninfected) mice. The livers were examined histochemically, immunocytochemically and by in situ hybridization to identify oval cells, inflammatory cells and proliferating cells. Oval cells were seen in the periportal regions of livers from MCMV infected BALB/c mice. These increased in number from 4 to 12 months after infection in parallel with increases in the numbers of inflammatory cells, even though cells expressing MCMV antigens were no longer evident in these samples. Proliferating oval cells and hepatocytes were identified by PCNA staining, indicating an increased level of liver regeneration in the infected livers. C57BL/6 mice are less susceptible to persistent MCMV hepatitis and had fewer oval cells than BALB/c mice. Thus the study demonstrates an association between MCMV induced hepatitis, inflammation, and presence of oval cells.

Animals↗
PubMed1998

Parametric image reconstruction using spectral analysis of PET projection data.

Spectral analysis is a general modelling approach that enables calculation of parametric images from reconstructed tracer kinetic data independent of an assumed compartmental structure. We investigated the validity of applying spectral analysis directly to projection data motivated by the advantages that: (i) the number of reconstructions is reduced by an order of magnitude and (ii) iterative reconstruction becomes practical which may improve signal-to-noise ratio (SNR). A dynamic software phantom with typical 2-[11C]thymidine kinetics was used to compare projection-based and image-based methods and to assess bias-variance trade-offs using iterative expectation maximization (EM) reconstruction. We found that the two approaches are not exactly equivalent due to properties of the non-negative least-squares algorithm. However, the differences are small (< 5%) and mainly affect parameters related to early and late time points on the impulse response function (K1 and, to a lesser extent, VD). The optimal number of EM iteration was 15-30 with up to a two-fold improvement in SNR over filtered back projection. We conclude that projection-based spectral analysis with EM reconstruction yields accurate parametric images with high SNR and has potential application to a wide range of positron emission tomography ligands.

Algorithms↗
PubMed1998

Contrasting phenotypes of liver-infiltrating leucocytes isolated from MCMV-infected BALB/c and C57BL/6 mice.

We characterized liver-infiltrating leucocytes (LIL) from BALB/c and C57BL/6 mice 0-56 days after murine cytomegalovirus (MCMV) infection. Inflammation clears from C57BL/6 mice 4-5 weeks post infection (pi), but persists for several months in BALB/c mice. The LIL obtained were 60-80% Thy 1.2+ by flow cytometry. The percentage of CD8+ cells rose sharply in all mice 7 days pi, with little decrease in BALB/c mice by day 56. CD4-CD8-Thy 1.2+/TCR alpha beta + cells were more prevalent in LIL than lymph node cells (LNC) irrespective of MCMV infection, whilst infection increased the proportion of CD8+ L-selectin- LIL (but not LNC). LIL from both mouse strains demonstrated cytotoxic activity against YAC-1 cells, but only LIL from BALB/c mice proliferated spontaneously ex vivo 21 days pi, as measured by tritiated thymidine incorporation. BALB/c LIL produced IFN gamma and IgG2a 7-21 days pi, whilst IL-10 secretion was similar in both strains. Thus, persistent hepatitis in BALB/c mice is associated with activation and proliferation of intrahepatic leucocytes with some bias towards a Th1 response.

Animals↗