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Biomedical subjects

P Price

Publications and source records attributed to P Price.

At least 91 records · Page 5Linked to original sources

A novel locus affecting serum levels of IgG2a maps to the murine H2 region.

The effects of genes in the murine H2 region on basal immunoglobulin levels were investigated and ratios of IgG1/IgG2a were calculated, as low ratios indicate a Th1 cytokine mileu. H2b mice with B10 or BALB genetic backgrounds had higher levels of IgG2a than H2k and H2d congenic strains, and hence had low IgG1/IgG2a ratios. B10 (H2b) mice generally had high levels of IgG2b, IgG3, IgA and IgM, but this outcome was more variable. The high IgG2a phenotype was denoted Igis1 (Immunoglobulin isotype-1) and mapped telomeric of IEbeta using B10.A(4R) mice (high IgG2a) and B10.A(3R) and B10.A(5R) mice (low IgG2a). Further mapping in B10.A(2R), B10.A(1R) and B10.A(18R) mice placed Igis1 in the 27kb region between G7c and G7e.

Animals↗

Lymphocytes from H2 mice produce lower levels of several cytokines than congenic H2 or H2 mice.

Inbred mice of congenic strains that differ only in their H2 haplotype were used to examine the effects of MHC genes on production of cytokines. Spleen and lymph node cells were stimulated with mitogens in vitro, and cytokine protein was assessed by ELISA and/or bioassays. Cells from H2b mice synthesized less IL-3, IL-4, IL-5, TNF and IL-10 (less clearly) than the equivalent cells from H2k or H2d mice. Production of IL-6 by H2b spleen and lymph node cells was lower than that by cells from H2d mice. In addition, lower lymphoproliferative responses were observed in lymph node cultures from H2b mice. These effects were evident in congenic B10 and BALB strains. B10 H2b mice stimulated in vivo with anti-CD3 had lower levels of IFN-gamma and IL-5 protein in their serum compared with equivalent H2k and H2d mice. Because class I- or II-mediated antigen presentation was not required in our model, an immunoregulatory gene in the central MHC is implicated. Preliminary studies of MHC recombinant mice suggested that the gene or genes responsible lie telomeric of IEbeta. Evidence that the H2b haplotype carries an immunoregulatory allele with a small but consistent effect on cytokine production warrants further investigation.

Animals↗

Immune restoration disease after the treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy.

BACKGROUND: To determine if infectious disease events in HIV-infected patients treated with highly active antiretroviral therapy (HAART) are a consequence of the restoration of pathogen-specific immune responses, a single-centre retrospective study of all HIV-infected patients commencing HAART prior to 1 July 1997 was undertaken to determine the incidence, characteristics and time of onset of disease episodes in HAART responders (decrease in plasma HIV RNA of > 1 log10 copies/mL). METHODS: Baseline and post-therapy changes in CD4 T-cell counts and HIV RNA were compared in patients with and without disease and delayed-type hypersensitivity responses to mycobacterial antigens were measured in selected patients. RESULTS: Thirty-three of 132 HAART responders (25%) exhibited one or more disease episodes after HAART, related to a pre-existent or subclinical infection by an opportunistic pathogen. Disease episodes were most often related to infections by mycobacteria or herpesviruses but hepatitis C virus (HCV), molluscum contagiosum virus and human papilloma virus were also implicated. They were most common in patients with a baseline CD4 T-cell count of < 50/uL and occurred most often during the first 2 months of therapy and when CD4 T-cell counts were increasing. Mycobacteria- and HCV-related diseases were associated with restoration of pathogen-specific immune responses. CONCLUSIONS: We conclude that improved immune function in immunodeficient patients treated with HAART may restore pathogen-specific immune responses and cause inflammation in tissues infected by those pathogens.

AIDS-Related Opportunistic Infections↗

Suicide risk assessment: a review of procedures.

Suicide risk assessment is an important part of the nurse's role. Suicide screening is an integral component of the assessment process. It should be systematic and follow a prescribed procedure: client self assessment, holistic assessment and diagnosis. The Gatehouse Assessment Centre in Warrington, UK, a predominantly nurse led centre, was opened in 1995, operates 365 days, 9 am till 9 pm, with open referral. The Centre offers psychiatric assessment, short-term treatments or referral on without hospital beds. In line with local and national policy, the Gatehouse team have introduced suicide rating scales as part of their risk screening process. However, the team have encountered problems using their designated scale, adapted from the Suicide Intent Scale, Pierce (1981). The major problem with the use of a rating scale was that, as a one off scoring system, it did not reflect the dynamic nature of suicidal behaviour. Furthermore, it is questionable whether a tool developed for research purposes would be used in the same way in practice. From a clinical perspective, the tool was capable of measurement only and failed to assist a dynamic holistic assessment required by practitioners. It was, therefore, necessary to review and evaluate the risk assessment procedure. In order to address these problems an assessment procedure which is more than a once only 'score' was piloted. The procedure incorporated risk screeners. Rather than rely on a value weighting system, or a positive or negative conclusion, it took account of the continuum of risk which is contingent on a broad range of factors. It took account of the accumulation of risk factors which may be increased or reduced in the light of unfolding events. Details of the new procedure, how it has been incorporated into the assessment process and subsequent management plan, and methodological considerations for further study are detailed.

Adult↗

Oxidative stress and NF-kappaB activation: correlation in patients following allogeneic bone marrow transplantation.

Although in vitro data has linked reactive oxygen species (ROS) to activation of nuclear factor kappaB (NF-kappaB), little data exist regarding this relationship in human disease. We hypothesized that bone marrow transplantation (BMT) would impart a degree of oxidative stress that might lead to in vivo activation of the redox-sensitive transcription factor NF-kappaB. Because NF-kappaB regulates transcription of many proinflammatory mediators, we reasoned that activation of NF-kappaB might contribute to the development of transplant-related complications. To evaluate NF-kappaB activation in humans, we measured NF-kappaB binding activity in nuclear extracts of bronchoalveolar lavage (BAL) cells obtained before and after allogeneic bone marrow transplantation (BMT) in 7 patients. Changes in BAL cell NF-kappaB binding activity were compared with changes in urinary F2-isoprostane concentration, an indicator of in vivo free radical-catalyzed lipid peroxidation. Although the extent of in vivo lipid peroxidation has substantial interindividual variability over time, we found a strong correlation between the pre/post-BMT ratio of urinary isoprostane concentrations and pre/post-BMT ratio of NF-kappaB binding activity in BAL cells, R = 0.96, p = 0.0005). This correlation is selective, because no relationship was found between the transcription factor CREB and urinary F2-isoprostane excretion. Although limited by the small number of patients studied, our data link oxidant stress to NF-kappaB activation in human alveolar macrophages following BMT. It is possible that such interactions may contribute to the clinical course after BMT by affecting transcription of proinflammatory genes.

Adult↗

The impact of foot complications on health-related quality of life in patients with diabetes.

BACKGROUND: The concept of health-related quality of life (HRQoL) has been the focus of much debate in recent years. However, within diabetes the focus has centred on the behavioural adaptation to a chronic disease state. The impact of foot complications is witnessed regularly in the clinical setting; amputation in this group is usually preceded by ulceration and a worsening cycle of foot problems. OBJECTIVE: This review sets out to investigate the literature on foot complications in those with diabetes, to assess the cost to the individual in terms of impact on everyday living. CONCLUSION: The literature on the specific impact of foot complications is limited, but indicates a situation in which those with diabetic foot ulceration may have an even poorer HRQoL than those who have experienced an amputation related to diabetes. In order to assess the full impact of new treatments or therapeutic interventions, it is vital that further research is conducted in this area.

Amputation, Surgical↗

The cost-effectiveness of wound management protocols of care.

A European cost-effectiveness study has been conducted using published clinical trial data from multinational studies on chronic venous leg ulcers and pressure sores. Data relevant to UK chronic wound management practice have been extracted and are presented here. A total of 15 pressure sore studies involving 519 wounds, and 12 leg ulcer studies involving 843 ulcers were used in a pooled analysis. The study objectives included the calculation of comparative costs in pound sterling for three different treatment protocols for each wound type. The protocols have been adapted for UK clinical practice in both hospital and community settings and are based on primary dressings and nurse time costs, wound cleansing and debridement, the use of fillers, and compression as appropriate. The focus of the study has been the cost-effectiveness comparison (as measured by cost per healed wound) of two modern dressings - Granuflex(R) hydrocolloid dressing and Apligraf(R) skin replacement - and traditional gauze dressings in the treatment of venous leg ulcers and, in the case of pressure sores, comparison of Granuflex(R) Comfeel(R) hydrocolloid dressings and traditional saline gauze dressings. The choice of dressings studied was dictated by the available published literature. The construction of treatment protocols and assumptions on treatments otherwise missing from published papers has been achieved through the use of an expert panel. Results show Granuflex(R) to be 50% more cost-effective, at 422 pounds per healed wound, than Comfeel(R) (643 pounds) and 500% more so than saline gauze (2548 pounds) in the treatment of pressure sores. Granuflex(R) at 342 pounds was also more cost-effective than gauze (541 pounds) or Apligraf(R) (6741 pounds) in the treatment of venous leg ulcers. These data will provide a valuable adjunct to published clinical evidence, offering further information upon which carers can base their choice of wound dressing.

Bandages↗

The effect of a radiant heat dressing on pressure ulcers.

The use of heat in wound healing has been demonstrated to aid oxygen flow and hence healing in acute wounds. However, the situation in chronic wounds is less clear. This study was designed to investigate the benefits of using a radiant heat therapy system in the treatment of Stage 3 and 4 pressure ulcers. Despite randomisation, patients receiving radiant heat therapy were more infirm than those receiving standard treatment. This prospective, single-centre, randomised trial resulted in an accelerated rate of healing for those receiving heat therapy compared to a standard treatment: time difference to 75% of original area = 6.4 days (p = 0.057), to 50% of original area = 9.6 days (p = 0.039), time to 25% = 7.2 days (p = 0.01). This new development warrants further investigation to fully assess the role of a thermoregulation system in chronic wound healing.

Aged↗

A general method to correct PET data for tissue metabolites using a dual-scan approach.

UNLABELLED: This article presents and analyses a general method of correcting for the presence of radiolabeled metabolites from a parent radiotracer in tissue during PET scanning. The method is based on a dual-scan approach, i.e., parent scan together with an independent supplementary scan in which the radiolabeled metabolite of interest itself is administered. The method corrects for the presence of systemically derived radiolabeled metabolite delivered to the tissues of interest through the blood. METHODS: Data from the supplementary scan are analyzed to obtain the tissue impulse response function for the metabolite. The time course of the radiolabeled metabolite in plasma in the parent scan is convolved with its tissue impulse response function to derive a correction term. This is not a simple subtraction technique but 1 that takes account of the different time-activity curves of the radiolabeled metabolite in the 2 scans. RESULTS: The method, its implications, and its limitations are discussed with respect to [11C]thymidine and its principal metabolite 11CO2. CONCLUSION: The general method, based on a dual-scan approach, can be used to correct for radiolabeled metabolites in tissues of interest during PET scanning. The correction accounts for radiolabeled metabolites that are derived systemically and delivered to the tissues of interest through the blood.

Carbon Dioxide↗

The H2(b) haplotype modifies the production of pro-inflammatory cytokines: implications for immunopathology.

Congenic strains of mice which differ only in their H2 haplotype were used to examine the effects of MHC genes on production of pro-inflammatory cytokines, as we have shown previously that H2(b) mice produce low levels of T cell cytokines compared to congenic H2(k) and H2(d) mice. RNase protection assays were used to assess cytokine mRNA and cytokine protein was assessed by ELISA or bioassay. Concanavalin A or phorbol myristate acetate/calcium ionophore/anti-CD3 stimulation of spleen cells from H2(b) congenic mice induced less IL-1, IL-2, IFN-gamma and MIF mRNA and/or protein than the equivalent cells from H2(d) mice. However, following stimulation with lipopolysaccharide or phorbol myristate acetate/calcium ionophore, peritoneal cells from H2(b) mice synthesised significantly more IL-1 beta, TNF-alpha, TNFR and IFN-gamma protein and IFN-gamma mRNA than cells from congenic H2(k) or H2(d) mice. These differences were evident in congenic C57BL/10 and/or BALB/c strains. We suggest that the low IL-1 production in H2(b) spleen cultures is secondary to lower T cell activation. Evidence that the H2(b) haplotype carries an immunoregulatory allele which affects cytokine production warrants further investigation.

Animals↗

Abuse during and before pregnancy: prevalence and cultural correlates.

This study examined the prevalence of abuse during pregnancy and the influence of cultural norms and acculturation on abuse in 1,004 Mexican American, Puerto Rican, Cuban American, Central American, African American and Anglo American women. Women were recruited from consecutive delivery logs in general community hospitals in Florida and Massachusetts. The Index of Spouse Abuse and the Abuse Assessment Screen ascertained history of adult physical, sexual, and emotional abuse, abuse during pregnancy, and childhood sexual abuse. An Interview Protocol assessed cultural attitudes, acculturation, and demographic information. Hispanic American women, as a whole, did not differ significantly from Anglo American women in their prevalence of abuse during pregnancy, after controlling for sociodemographic variables. However, Cuban American and Central American partners were significantly less likely to abuse their pregnant partners than were other groups even after adjustment. Women who spoke only Spanish (less acculturated) were less likely to report physical abuse from their partners both before and during pregnancy. Cultural norms, such as a partner's belief in wife/mother role supremacy and cultural group acceptability of men hitting women, were significantly positively related to both physical and emotional abuse. Other risk factors for abuse were the abuser not being the biological father of the baby, low income and little education, and being unmarried.

Acculturation↗

The central MHC gene IKBL carries a structural polymorphism that is associated with HLA-A3,B7,DR15.

Susceptibility to several disorders, including insulin-dependent diabetes mellitus and multiple sclerosis, has been associated with alleles of HLA class II genes and loci in the TNF cluster in the central major histocompatibility complex (MHC) region. As recombination within this region is rare, it is difficult to determine which genes are important. This will be facilitated by the identification of functional polymorphisms. Hence we are sequencing reverse transcription-polymerase chain reaction products derived from central MHC genes in well characterized and conserved ancestral haplotypes. Here we address the IKBL gene, which lies near the TNF cluster at the telomeric end of the central MHC. Although the IKBL cDNA sequence was conserved between most ancestral haplotypes, a synonymous nucleotide substitution, a 3' untranslated region substitution, and a single nonsynonymous substitution were identified. The latter (IKBL+738) was present in multiple examples of the 7.1 haplotype [HLA-A3, B7, DR2 (DR15)] and resulted in a cysteine to arginine substitution in a predicted protein kinase C phosphorylation site. This polymorphism did not occur in 18 other common haplotypes from the 10th International Histocompatibility Workshop and thus appears haplospecific. A role for IKBL+738 in the association between HLA-A3,B7,DR2(DR15) and susceptibility to multiple sclerosis is discussed.

Adaptor Proteins, Signal Transducing↗

Susceptibility to multiple sclerosis mediated by HLA-DRB1 is influenced by a second gene telomeric of the TNF cluster.

Susceptibility to multiple sclerosis (MS) is clearly associated with human leukocyte antigen (HLA)-DRB1*1501, but some studies show associations with HLA-B7 and -B18. These are often co-expressed with DRB1*1501 in the ancestral haplotypes (AH) denoted 7.1 (HLA-A3, B7, tumor necrosis factor [TNF]a11b4, DRB1*1501) and 18.1 (HLA-A25, B18, TNFa10b4, DRB 1*1501). Here we present a systematic study of 218 patients and 274 controls typed at all standard class II and TNF microsatellite loci, and a novel non-synonymous polymorphism in the central major histocompatibility complex gene, inhibitor of kappa B-like protein (IKBL). The C allele at IKBL+738 is only found on the 7.1 haplotype. HLA-DRB1*1501 was associated with disease, as expected. When subjects expressing DRB 1*501 were analyzed separately, TNFa11b4 and IKBL+738C were less common in the patients and, hence, mark an allele that mediates resistance which lies telomeric of IKBL. TNFa10b4 and TNFa1b5 were more common in DRB1*1501 patients than in controls. These alleles have been associated with the 18.1 and 18.2 AH, respectively. Since no component of these haplotypes was an independent risk factor in this study, it appears likely that a gene linked to TNFa10b4 and TNFa1b5 modifies the effect of the susceptibility locus marked by HLA-DRB1*1501. Potential candidate genes telomeric of the TNF cluster are discussed.

Adaptor Proteins, Signal Transducing↗

Raltitrexed (Tomudex) concomitant with radiotherapy as adjuvant treatment for patients with rectal cancer: preliminary results of phase I studies.

Radiotherapy, either alone or in combination with chemotherapy, may reduce local recurrence of rectal cancer following surgery and improve survival of patients with operable and advanced/recurrent/inoperable disease. Chemotherapy with 5-fluorouracil in combination with radiotherapy has been used both before and after surgery; however, the optimum schedule is unclear. In addition, alternative chemotherapy with raltitrexed (Tomudex) may be more convenient and better tolerated. The preliminary results of three phase I dose-finding studies are described, combining escalating doses of raltitrexed with radiotherapy as pre- or postoperative treatment for operable rectal cancer or as treatment for advanced/inoperable/recurrent rectal cancer. The recommended dose of raltitrexed when combined with adjuvant radiotherapy is likely to be 2.6 mg/m2. This is a small dose reduction compared with the dose of raltitrexed for the treatment of advanced colorectal cancer (3.0 mg/m2); however, toxicity appears to be lower using the pre-operative approach. Neo-adjuvant therapy with raltitrexed plus radiotherapy also demonstrated clinical activity in the pre-operative study, which showed that 22% of patients achieved a complete response and 56% a partial response. Once the recommended dose has been defined in each setting, large-scale studies will be undertaken as appropriate.

Aged↗

Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group.

[18F]-fluorodeoxyglucose ([18F]-FDG) uptake is enhanced in most malignant tumours which in turn can be measured using positron emission tomography (PET). A number of small clinical trials have indicated that quantification of the change in tumour [18F]-FDG uptake may provide an early, sensitive, pharmacodynamic marker of the tumoricidal effect of anticancer drugs. This may allow for the introduction of subclinical response for anticancer drug evaluation in early clinical trials and improvements in patient management. For comparison of results from smaller clinical trials and larger-scale multicentre trials a consensus is desirable for: (i) common measurement criteria; and (ii) reporting of alterations in [18F]-FDG uptake with treatment. This paper summarises the current status of the technique and recommendations on the measurement of [18F]-FDG uptake for tumour response monitoring from a consensus meeting of the European Organization for Research and Treatment of Cancer (EORTC) PET study group held in Brussels in February 1998 and confirmed at a subsequent meeting in March 1999.

Antineoplastic Agents↗

Periodontal attachment loss in HIV-infected patients is associated with the major histocompatibility complex 8.1 haplotype (HLA-A1,B8,DR3).

Periodontal attachment loss is mediated by overproduction of tumour necrosis factor (TNF) and interleukin (IL)-1, and appears to have a genetic component. The 8.1 major histocompatibility complex (MHC) ancestral haplotype (HLA-A1,B8,TNFA-308(2),DR3) is associated with elevated TNF production and predisposes carriers to several autoimmune/immunopathological disorders, including rapid progression of HIV disease, but not early onset periodontal disease in healthy individuals. Rather a high proportion of subjects with severe periodontal disease carry allele 2 at IL-1A-889 and IL-1B+3953. We predicted that genetic associations may be different or clearer in HIV patients, as they often show elevated production of TNF and IL-1 and periodontal attachment loss. Hence periodontal parameters and IL-1 polymorphisms were assessed in HIV-positive subjects expressing HLA-B8 with or without other markers of the 8.1 haplotype. Of 16 HLA-B8 subjects, 13 demonstrated elevated probing pocket depth and clinical attachment loss. The difference was statistically significant and did not correlate with smoking, age, CD4 T-cell counts, HIV viral load or levels of dental plaque. As TNFA-308 (allele 2) was present in four non-B8 subjects who had minimal attachment loss, it may not mediate the effect of the 8.1 haplotype. Moreover, polymorphisms at IL-1A-889 and IL-1B+3953 did not significantly affect periodontal parameters. Thus a central MHC gene characteristic of the 8.1 haplotype was the clearest determinant of periodontal attachment loss in HIV-infected individuals.

Adult↗