Biomedical subjects

M Bailey

Publications and source records attributed to M Bailey.

At least 19 recordsLinked to original sources

PubMed2007

Kappa immunoglobulin light chain polymorphisms and survival after allogeneic transplantation for B-cell malignancies: a potential graft-vs-leukaemia target.

In the human leucocyte antigen (HLA)-matched haematopoietic stem cell transplantation (HSCT) setting, minor histocompatibility antigen (mHA) disparities between recipient and donor can lead to graft-vs-host disease (GVHD) or graft rejection. Graft-vs-leukaemia (GVL) effect is a beneficial T-cell-mediated immune response that can also occur following HLA-matched HSCT. mHAs with tissue expression restricted to cells of the haematopoietic system are particularly relevant as immunotherapeutic targets for destroying malignant cells without inducing GVHD. Therefore, it is important to identify further haematopoietic-restricted polymorphic mHAs, which may have the potential to be used clinically for adoptive immunotherapy. Polymorphic mismatching of minor antigens, such as the B-cell-specific protein, the kappa immunoglobulin light chain (kappa) may play a role in the incidence of GVL and therefore the survival of transplant recipients following transplantation for B-cell malignancies. Polymorphisms in the constant region of the immunoglobulin kappa polypeptide chain have been defined involving single amino acid changes at positions 153 and 191. In this study, 51 HLA-matched B-cell malignancy transplant pairs were kappa typed by polymerase chain reaction and restriction enzyme digestion to investigate the association between kappa allotype disparity and outcome after transplantation. Kappa allotype disparity between transplant pairs may be associated with an increased survival compared with pairs not mismatched for kappa, as kappa mismatched recipients had a higher percentage of complete remissions and a decreased level of relapse in comparison with the nonmismatched recipients. HLA peptide prediction software was used to determine which HLA types were the best binders for kappa peptides. It was observed that patients with tissue types predicted to bind the kappa Km(1,2) peptides had better survival outcomes and no relapse compared with those with tissue types not predicted to bind the kappa Km(1,2) peptides. This study may contribute to the assessment of the clinical role of kappa with regard to the outcome of allogeneic transplantation for B-cell malignancies.

Graft vs Leukemia Effect↗

PubMed2006

General guidelines for the assessment of internal dose from monitoring data: progress of the IDEAS project.

In recent major international intercomparison exercises on intake and internal dose assessments from monitoring data, the results calculated by different participants varied significantly. Based on this experience the need for harmonisation of the procedures has been formulated within an EU 5th Framework Programme research project. The aim of the project, IDEAS, is to develop general guidelines for standardising assessments of intakes and internal doses. The IDEAS project started in October 2001 and ended in June 2005. The project is closely related to some goals of the work of Committee 2 of the ICRP and since 2003 there has been close cooperation between the two groups. To ensure that the guidelines are applicable to a wide range of practical situations, the first step was to compile a database of well-documented cases of internal contamination. In parallel, an improved version of an existing software package was developed and distributed to the partners for further use. A large number of cases from the database was evaluated independently by the partners and the results reviewed. Based on these evaluations, guidelines were drafted and discussed with dosimetry professionals from around the world by means of a virtual workshop on the Internet early in 2004. The guidelines have been revised and refined on the basis of the experiences and discussions in this virtual workshop. The general philosophy of the Guidelines is presented here, focusing on the principles of harmonisation, optimisation and proportionality. Finally, the proposed Levels of Task to structure the approach of internal dose evaluation are reported.

Algorithms↗

PubMed2006

IDEAS internal contamination database: a compilation of published internal contamination cases. A tool for the internal dosimetry community.

In the scope of the IDEAS project to develop General Guidelines for the Assessment of Internal Dose from Monitoring data, two databases were compiled. The IDEAS Bibliography database contains references dealing with problems related to cases of internal contamination. The IDEAS Internal Contamination Database now contains more than 200 cases of internal contamination. In the near future, the IDEAS Internal Contamination database will be made available to the internal dosimetry community. The database has several potential applications, including: training, testing biokinetic models, testing software for calculating intakes and doses from bioassay data, comparison of data from a new accidental intake with that from previous exposures to similar materials. The database is by no means complete, and this presentation is also an appeal for internal contamination cases to extend and update it.

Biological Assay↗

PubMed2006

Persistently high levels of immunosuppressive cytokines in patients after radical prostatectomy.

A significant proportion of men undergoing 'curative' radical prostatectomy (RP) for organ-confined prostate cancer relapse within 5 years. A number of adverse risk factors have been identified, but to date no adjuvant treatment as improved the outlook for these men. We proposed that these patients, despite small tumour burdens, may be immunosuppressed from their cancer, which may be amenable to immune modulation. We investigated their immune profile using sensitive functional cytokine assays, both pre- and post-surgery. In comparison with controls, RP patients expressed higher levels of both T helper type 1 (Th1) (interleukin (IL)-2 and tumour necrosis factor-alpha) and Th2 cytokines (IL-4, -5 and -10) with little change after removal of tumour. Further analysis based on known poor-prognostic factors indicated a trend to expression of higher levels of Th2 cytokines IL-4 and IL-5 in worse prognosis patients rather than the mixed Th1/2 found across the whole cohort. Persistently high levels of both Th1 and Th2 cytokines were detected in RP compared to control patients, despite the removal of relatively small tumour burdens. Cytokine expression studies may be useful as surrogate marker of potential disease progression, and could be used to identify patients who may benefit from immune modulation post-surgery.

Aged↗

PubMed2006

Bim, Bad and Bmf: intrinsically unstructured BH3-only proteins that undergo a localized conformational change upon binding to prosurvival Bcl-2 targets.

All BH3-only proteins, key initiators of programmed cell death, interact tightly with multiple binding partners and have sequences of low complexity, properties that are the hallmark of intrinsically unstructured proteins (IUPs). We show, using spectroscopic methods, that the BH3-only proteins Bim, Bad and Bmf are unstructured in the absence of binding partners. Detailed sequence analyses are consistent with this observation and suggest that most BH3-only proteins are unstructured. When Bim binds and inactivates prosurvival proteins, most residues remain disordered, only the BH3 element becomes structured, and the short alpha-helical molecular recognition element can be considered to behave as a 'bead on a string'. Coupled folding and binding is typical of many IUPs that have important signaling roles, such as BH3-only proteins, as the inherent structural plasticity favors interaction with multiple targets. This understanding offers promise for the development of BH3 mimetics, as multiple modes of binding are tolerated.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Multiple effects of the lectin-inhibitory sugars D-glucosamine and N-acetyl-glucosamine on tsetse-trypanosome interactions.

We are studying early events in the establishment of Trypanosoma brucei in the tsetse midgut using fluorescent trypanosomes to increase visibility. Feeding flies with the lectin-inhibitory sugars D-glucosamine (GlcN) or N-acetyl-glucosamine (GlcNAc) has previously been shown to enhance fly susceptibility to infection with trypanosomes and, as expected, we found that both sugars increased midgut infection rates of Glossina morsitans morsitans with T. brucei. However, GlcNAc did not show the inhibitory effect on salivary gland infection rate reported previously for GlcN. Both sugars significantly slowed the movement of the bloodmeal along the midgut. GlcN also significantly increased the size of the bloodmeal taken and fly mortality. The most surprising finding was that GlcNAc stimulated trypanosome growth not only in the midgut, but also in vitro in the absence of any factor derived from the fly. Thus our direct comparison of the effects of GlcN and GlcNAc on the trypanosome-tsetse interaction has shown that these sugars impact on trypanosome growth and tsetse physiology in different ways and are not interchangeable as suggested in the literature. The sugars cause multiple effects, not restricted solely to the inhibition of midgut lectins. These findings have implications for current models of tsetse susceptibility to trypanosome infection.

Acetylglucosamine↗

PubMed2006

Analysis of a cross between green and red fluorescent trypanosomes.

Trypanosoma brucei undergoes genetic exchange in its insect vector, but the mechanism is unknown and no one has yet seen the process. By crossing genetically engineered red and green fluorescent trypanosomes, we have been able to pinpoint the location of genetic exchange in the fly and search for intermediate stages. In experimental crosses of red and green parental trypanosomes, yellow hybrid trypanosomes first appeared in the fly salivary glands as early as 13 days after infection and were observed only in flies with a mixture of red and green trypanosomes in one or both salivary glands. Despite high numbers of flies with mixed infections, yellow trypanosomes were not detected in the fly midgut or proventriculus. The hybrid nature of yellow trypanosomes was confirmed by analysis of molecular karyotypes and microsatellite alleles. As well as yellow hybrids, hybrid trypanosomes with red, green or no fluorescence were also recovered from fly salivary glands. Analysis of microsatellite alleles in parental and progeny clones showed Mendelian inheritance. Our findings are consistent with the hypothesis that mating takes place between trypanosomes in the salivary glands of the fly before they attach to the salivary gland epithelium.

Animals↗

PubMed2006

The larynx as an immunological organ: immunological architecture in the pig as a large animal model.

The larynx is a mucosal organ positioned at the divergence of the respiratory and digestive tracts. It is exposed to a wide variety of environmental components, including foreign antigens, tobacco smoke, laryngopharyngeal reflux and pollutants. The mucosal immune system generates either active immune responses or tolerance, depending on the nature of the antigen and we hypothesize that the larynx is important organ for immunological decision-making in the airway. Because the pig is an ideal large animal model in which to explore laryngological research questions, such as those relating to laryngeal transplantation, we investigated the normal mucosal immunology of the porcine larynx. Pig larynges and tracheae were processed and prepared for bright-field microscopy and quantitative, multiple-colour immunofluorescence histology using pig-specific monoclonal antibodies. There was an abundance of immunologically active cells within the mucosa of the larynx and trachea of both the newborn and adult animal. Specifically, major histocompatibility complex class II (MHC class II+) cells, CD4+ and CD8+ cells were identified, although regional differences in numbers were apparent: specifically, the supraglottis contained fewer immunologically relevant cells than other sites sampled. There was a significant correlation between the numbers of MHC class II+ and CD4+ cells indicating co-ordinate regulation and therefore functional local interactions. The presence of such an immunological structure suggests that the larynx may have important functions in respiratory immunology and that it may trigger strong alloresponses after laryngeal transplantation.

Animals↗

PubMed2006

Major histocompatibility complex class I expression in human tonsillar and laryngeal epithelium.

Understanding the immunological structure of the upper aerodigestive tract is important for analysing the interaction between incident challenges, such as human papillomavirus infection, and disease, particularly head and neck cancer. We have shown previously that tonsillar and laryngeal epithelium express major histocompatibility complex (MHC) class II locus products, but that expression of human leucocyte antigen (HLA)-DQ is reduced compared to HLA-DR. This may confer a decreased repertoire of presented T cell epitopes generated by the processing of exogenous peptides in upper airway mucosa. To determine whether the peptide repertoire presented by MHC class I loci varies in stratified squamous epithelium, laryngeal and tonsillar biopsies were taken from 19 otherwise healthy patients (M : F 6 : 13, 16-64 years). Quantitative immunofluorescence microscopy, using antibodies to MHC class I alpha-chain (pan-locus specific, HLA-A, HLA-B + C) and beta(2)-microglobulin, showed lower expression of the alpha-chain in laryngeal and tonsillar epithelium than in either lamina propria (tonsil 73% versus 89%, P < 0.0001; larynx 68% versus 85%, P < 0.005). Within the epithelium itself, the intensity of alpha-chain expression decreased from the basal to apical layers. In paired squamous epithelia from the two sites, alpha-chain expression was significantly higher in the tonsil compared to the larynx (79% versus 62%, P < 0.05). We suggest that these findings reflect functional stratification of these epithelia with the superficial layer, most exposed to incident challenges, less equipped to present antigens to conventional T cells. This may affect immunosurveillance directed at viral and tumour-related epitopes in the upper airway.

Adolescent↗

PubMed2006

Early immunological changes associated with laryngeal transplantation in a major histocompatibility complex-matched pig model.

Laryngeal transplantation is an increasingly viable proposition for patients with irreversible diseases of the larynx. One human transplant has been performed successfully, but many questions remain before routine transplantation can begin. In order to measure the immunological changes in mismatched transplants, it is first necessary to know the immediate combined effects of ischaemia-reperfusion injury (IRI) plus the added insult of major surgery in a fully matched setting. We measured the changes in immunologically active mucosal cells following 3 h of cold ischaemia and 8 h of in situ reperfusion in a major histocompatibility complex (MHC)-matched minipig model (n = 4). Biopsies were prepared for quantitative, multiple-colour immunofluorescence histology. The number of immunologically active cells was significantly altered above (supraglottis) and below (subglottis) the vocal cords following transplantation and reperfusion (P < 0.05, P < 0.001, respectively). However, the direction of the change differed between the two subsites: cell numbers decreased post-transplant in the supraglottis and increased in the subglottis. Despite the statistical evidence for IRI, these changes were less than the large normal inter- and intrapig variation in cell counts. Therefore, the significance of IRI in exacerbating loss of function or rejection of a laryngeal allograft is open to question. Longer-term studies are required.

Animals↗

PubMed2006

The dynamics and associations of airway neutrophilia post lung transplantation.

UNLABELLED: Bronchoalveolar lavage (BAL) neutrophilia has been repeatedly observed in lung transplant recipients with established bronchiolitis obliterans syndrome (BOS). Little is known of the fluctuations in BAL and airway neutrophilic inflammation post-transplant. This prospective longitudinal study aimed to evaluate the dynamic changes of lung allograft neutrophils with time, immunosuppression, infection and BOS. A total of 28, initially healthy, BOS 0, lung transplant recipients underwent 134 bronchoscopic assessments, including BAL and endobronchial biopsies (EBB) (with immunohistochemistry) over 3-year follow up. Subsequently, 21 developed BOS 0p and 16 ultimately BOS. Compared to controls, there was early and persistent BAL neutrophilia (p < 0.05), contrasting with an initially normal EBB that shows a progressive increased airway wall neutrophil infiltrate. BAL neutrophilia (but not airway wall neutrophilia) was most striking when there was concomitant bronchopulmonary infection, particularly in the patients with BOS. Univariate and multivariate analyses suggested that BAL neutrophilia was linked to markers of infection while EBB neutrophilia was linked with coexistent inflammation with macrophages and lymphocytes. IN CONCLUSION: (i) BAL neutrophilia is predominantly associated with infection; (ii) Airway wall neutrophilia (as monitored by EBB) increases with time post-transplant and is not associated with infection; (iii) By itself, BOS is not the major contributor to BAL and EBB neutrophilia.

Adult↗

PubMed2006

Human papillomavirus and head and neck cancer: a systematic review and meta-analysis.

It has been suggested that the link between human papillomavirus (HPV) and head and neck squamous cell carcinoma (HNSCC) is specific to carcinoma of the tonsil. We systematically reviewed studies that tested for HPV16 exposure in anatomically defined sites in the head and neck and a control group. The association between HPV16 and cancer was strongest for tonsil (OR: 15.1, 95% CI: 6.8-33.7), intermediate for oropharynx (OR: 4.3, 95% CI: 2.1-8.9) and weakest for oral (OR: 2.0, 95% CI: 1.2-3.4) and larynx (OR: 2.0, 95% CI: 1.0-4.2). To investigate heterogeneity, further stratification by method of HPV16 detection, suggested that variation in the magnitude of the HPV-cancer association with cancer site was restricted to studies using ELISA: among studies using PCR, the magnitude of the summary odds ratios was similar across the four sites. The association between HPV16 infection and HNSCC in specific sites suggests the strongest and most consistent association is with tonsil cancer, and the magnitude of this association is consistent with an infectious aetiology. However, the method of viral detection may be an important source of heterogeneity. Resolution of this issue will require further studies using both methods, examining associations separately in different sites.

Carcinoma, Squamous Cell↗

PubMed2006

Swine and circovirus.

In the 1990s Post-weaning, multi-systemic wasting syndrome (PMWS) emerged in N. America and Europe as a major disease problem with significant welfare and economic consequences for pig producers. The disease, characterised by wasting, respiratory, enteric and lymphoid system problems in pigs of 4-16 weeks of age, has since spread so that today it has a global distribution. PCV-2 is consistently associated with PMWS, is more abundant in association with PMWS and is considered by many to be the causative agent of the syndrome. However, several lines of evidence indicate that PCV-2 is necessary but not sufficient to cause the full range of clinical signs associated with PMWS, suggesting the involvement of an as yet unidentified factor or factors. The process of identifying unknown agents and their respective roles in the pathogenesis of complex syndromes now has an ever broadening spectrum of analytical techniques available. Immune phenotyping, cytokine responses, micro-array profiling, and proteomics are just some of the techniques available. This paper describes the philosophy and the application of these and classical techniques in an integrated, holistic manner to the problem of PMWS and circoviruses, by examination of samples collected from a prospective, clinical case-control study, and discusses some of the preliminary findings in relation to the efforts to understand the aetiopathogenesis of PMWS.

Animals↗

PubMed2005

Encasement of bedding does not improve asthma in atopic adult asthmatics.

AIM: We evaluated the impact of impermeable bed covers on asthma in asthmatics with clinically relevant house dust mite (HDM) sensitization. METHODS: The study included 32 HDM-sensitized asthmatics in whom HDM allergy was considered as a significant factor in their asthma. They were randomized into either an intervention group whose bedding was encased with impermeable covers, or a control group who received cotton covers. Before and 3 and 6 months after encasement, dust samples were collected from the bedding and assayed for Der p 1. Clinical outcomes included quality of life, lung function, bronchial reactivity to methacholine, symptoms, medications and peak flow rates. RESULTS: Baseline Der p 1 levels in both the active and the placebo groups were comparable and high (19.2 vs 18.9 microg/g of dust). There was a significant reduction in Der p 1 levels in the active group after 6 months, but not in the placebo group (7.3 vs 21.9 microg/g of dust). Quality of life improved significantly in both the intervention and control groups, but there was no significant difference in the improvements between the groups. There was no significant change in lung function, symptoms, and requirements for medications. CONCLUSIONS: Encasement of bedding significantly reduced the Der p 1 levels. However, this was not sufficient to produce worthwhile clinical improvement in those in whom dust mite avoidance might well have been recommended as part of their clinical management.

Adult↗

PubMed2005

The influence of environment on development of the mucosal immune system.

The mucosal immune system expresses active responses against pathogens and also tolerance against harmless food and commensal bacterial antigens. The mechanisms that determine which of these outcomes occur after recognition of antigens by T-cells are not clear. One possibility is that it is determined by the initial interaction between a dendritic and a naïve T-cell in organised lymphoid tissue. However, such organised structures are, evolutionarily, quite recent and the original immune system must have made appropriate responses in more diffuse immunological architecture; a second possibility is that the critical interaction is between primed T-cells and their environment, in the lamina propria of the intestine. The mucosal immune system of neonates is poorly developed and inefficient at expressing appropriate immune responses. Development is influenced by a range of environmental factors including maternally derived antigen or antibody and commensal flora and pathogens. The intestine is a complex immunological structure in which the immune system and the macro- and microenvironment interact.

Animals↗

PubMed2005

Validation of computer-assisted, pixel-based analysis of multiple-colour immunofluorescence histology.

Developments in immunohistology allow the routine simultaneous use on tissue sections of three monoclonal antibodies, tagged with different fluorochromes. Such staining can identify seven different cell populations and the limiting factor is rapid, reliable and reproducible analysis. Future reliance on computer-assisted analysis of digitised images depends on validation against manual counting, often viewed as the 'gold standard'. In this study images were digitised from sections of normal porcine skin, inflamed skin and tonsil, simultaneously stained with three monoclonal antibodies. Combinations of staining were quantified by four manual counts and by pixel-based area measurement. On individual images, the correlation between automated and manual measurements was poor. Despite this, the concordance between manual and automated measurements in the means and variances of tissues was good, and both techniques identified the same changes in inflamed versus normal tissues. In addition, pixel-based counting permitted statistical analysis of co-localisation of cell types in tissue sections. We conclude that automated counting is acceptable for the assessment of tissues, is faster and provides less opportunity for observer variation than manual counting. We also demonstrate that the technique is applicable where more than three fluorochromes are used such that manual counting becomes essentially impossible.

Animals↗

PubMed2005

The development of the mucosal immune system pre- and post-weaning: balancing regulatory and effector function.

The mucosal immune system fulfils the primary function of defence against potential pathogens that may enter across vulnerable surface epithelia. However, a secondary function of the intestinal immune system is to discriminate between pathogen-associated and 'harmless' antigens, expressing active responses against the former and tolerance to the latter. Control of immune responses appears to be an active process, involving local generation of IgA and of regulatory and/or regulated T lymphocytes. Two important periods of maximum exposure to novel antigens occur in the young animal, immediately after birth and at weaning. In both cases the antigenic composition of the intestinal contents can shift suddenly, as a result of a novel diet and of colonisation by novel strains and species of bacteria. Changes in lifestyles of man, and husbandry of animals, have resulted in weaning becoming much more abrupt than previously in evolution, increasing the number of antigens that must be simultaneously evaluated by neonates. Thus, birth and weaning are likely to represent hazard and critical control points in the development of appropriate responses to pathogens and harmless dietary and commensal antigens. Neonates are born with relatively undeveloped mucosal immune systems. At birth this factor may prevent both expression of active immune responses and development of tolerance. However, colonisation by intestinal flora expands the mucosal immune system in antigen-specific and non-specific ways. At weaning antibody to fed proteins can be detected, indicating active immune responses to fed proteins. It is proposed that under normal conditions the ability of the mucosal immune system to mount active responses to foreign antigens develops simultaneously with the ability to control and regulate such responses. Problems arise when one or other arm of the immune system develops inappropriately, resulting in inappropriate effector responses to harmless food proteins (allergy) or inadequate responses to pathogens (disease susceptibility).

Animals↗

PubMed2005

Physical activity alone and with others as predictors of sense of belonging and mental health in retirees.

A high sense of belonging to the community and physical activity are associated with improved mental health in older people. The present study tested a model incorporating physical activities performed alone and with others as predictors of sense of belonging, depression and suicide ideation. One hundred and ninety four retired adults (87 males, 107 females, mean age 68 years) completed the Yale Physical Activity Survey, the Sense of Belonging Instrument, the Suicide Subscale of the General Health Questionnaire and the Zung Depression Inventory. Within the context of the model, neither participating in physical activities alone, nor with at least one other person, predicted sense of belonging, depression or suicide ideation. Having the abilities and motivation to belong was a predictor of participating in physical activities with others and actual feelings of belonging and contributed to predicting mental health in retirees. It was concluded that simply performing activities with others was not associated with a sense of belonging or mental health. Rather, sense of belonging may need to be facilitated in order for mental health to be enhanced.

Activities of Daily Living↗