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Biomedical subjects

P McCullagh

Publications and source records attributed to P McCullagh.

At least 19 recordsLinked to original sources
PubMed2002

An application of linear output error modelling for studying lymphocyte migration in peripheral lymphoid tissues.

Lymphocyte recirculation between lymphatic and blood vessels and migration through tissues are essential mechanisms underlying immunological surveillance. However, the kinetics of lymphocyte migration through lymphoid tissues remains poorly understood. The present study of lymphocyte migration, based on a sheep model and entailing the long term cannulation of blood vessels and lymphatic vessels efferent from lymph nodes, represents the first attempt to apply control engineering based models to overcome some of the experimental impediments to understanding the complex phenomena involved in lymphocyte migration. An output error model order (1,2,nk) was systematically selected under given criteria from four classes of Linear Time-Invariant Single-Input Single-Output, (LTI-SISO) systems to represent the peripheral lymph node system. The unit impulse responses were simulated under noise free conditions and their features were extracted to describe the dynamics of the system. The findings from this study revealed novel information about several aspects of the dynamics of lymphocyte migration.

Animals↗
PubMed2001

Segregation of B lymphocytes into stationary apoptotic and migratory proliferating subpopulations in agglomerate cultures with ileal epithelium.

The B lymphocyte-epithelial cell interactions that define the microenvironment of the ileal Peyer's patch, the primary B lymphocyte organ of the fetal lamb, have been replicated in tissue culture. Mixed suspensions of ileal epithelial cells, lymphocytes and fibroblasts from fetuses of 63-103 days of gestation organized into macroscopically visible agglomerates within 72 h. These agglomerates contained translucent spherical cavities and were enclosed within a marginal cell layer and surrounded by an expanding corona of emigrating cells. The lining of the cavities and the marginal layer consisted of well-differentiated, polarized columnar ileal epithelial cells. One population of B lymphocytes in the initial mixed suspension differentiated into two discrete populations reproducing the characteristics of intact fetal ileal Peyer's patches. B cells apposed to follicle-associated epithelium (FAE) within agglomerates underwent apoptosis. The other population of emigrant B cells proliferated and expressed the BAQ44A differentiation marker. Differentiation of ileal epithelial cells into FAE, typical of Peyer's patches, was markedly accelerated. The mutually inductive influences of intestinal epithelial cells and B lymphocytes in these agglomerates replicate normal mid-gestational fetal development of the mucosal immune system and afford new opportunities for its further investigation.

Animals↗
PubMed2001

Effect of early fetal splenectomy on prenatal B-cell development in sheep.

The contribution of early splenic B-cell populations to the colonization of the ileal Peyer's patch was investigated following the surgical removal of the spleen in a series of 56-day-old fetal sheep. The fetuses were killed at 140 days of gestation and the ileal Peyer's patch, the distal jejunal lymph node which drains the Peyer's patch, and a peripheral lymph node, the superficial cervical lymph node, were examined. Enzyme and immunohistochemical evaluation concluded that the distribution of B cells, T cells and stromal cells in the ileal Peyer's patch was similar in splenectomized and normal fetal sheep. Thus, the presence of the fetal spleen was not essential for the colonization of the ileal Peyer's patch and other early sites of B-cell accumulation would appear capable of generating the necessary precursor populations. Investigation of B-cell populations in lymph nodes used a combination of terminal deoxynucleotidyl-transferase-mediated deoxyuridine-triphosphate nick-end-labelling (TUNEL) histochemistry and immunofluorescence to determine the average number of apoptotic B cells in the primary follicles of the outer cortex of splenectomized and normal lambs. A significantly increased number of apoptotic B cells was present in the distal jejunal lymph node but not in the superficial cervical lymph node of splenectomized lambs. This finding suggests that splenectomy affected prenatal B-cell development in fetal sheep and raises questions as to the regulation of B-cell lymphopoiesis in a species using a post-rearrangement organ of diversification.

Animals↗
PubMed2001

Splenectomy of the fetal lamb early in development as a model for congenital asplenia.

BACKGROUND: The liability to overwhelming infection of children lacking a spleen either as a result of its congenital absence or because of splenectomy, has been frequently documented. Although there have been numerous studies of the consequences of experimental splenectomy in postnatal animals, this is the first study of the effects of this operation in early fetal life. METHODS: A technique is described for microsurgical removal of the spleen from fetal lambs approximately one-third of the way through gestation, when the fetus is approximately the size of a mouse. Lambs that had been splenectomized in utero were submitted to haematological examination in postnatal life and were challenged with pneumococcal polysaccharide to test their immunological competence. RESULTS: Lambs in which splenectomy had been performed close to the gestational age of initiation of the splenic contribution to differentiation of immune and haemopoietic systems, exhibited insignificant deviations from normality in postnatal life. CONCLUSION: Provided the spleen is removed from the fetal lamb sufficiently early in gestation, it is possible for other lymphoid tissues to compensate for most of the deficiencies that would be anticipated in animals lacking a spleen. In this experiment, splenectomy was performed at approximately the developmental stage equivalent to that at which the spontaneous interruption of development that leads to human congenital asplenia occurs. The absence of major postnatal abnormalities observed in these lambs reinforces the significance of the associated abnormalities in the development of the clinical deficits observed in children with spontaneous asplenia.

Animals↗
PubMed2001

Student-centered distance learning in health and medical informatics.

Learning and teaching of health and medical Informatics is currently supported by web based material, which in the main has been derived from traditional texts. Aided by contributions from the expert community, the web site of the handbook of Medical Informatics has been developed to incorporate increased interactivity (with question and answers related to each section). This approach has proved beneficial to both student and teacher. To further increase the interactivity of the WWW we investigate the suitability of authoring tools for developing complex simulations and interactive tutorials, using an example from the area of quantitative decision support (Bayes Theorem). We propose that these tools provide a suitable platform for the preparation and delivery of collaboratively produced HMI courses, which address open and distance learning and pedagogic issues.

Bayes Theorem↗
PubMed2000

Modelling of peripheral lymphocyte migration: system identification approach.

This is the first application of the prediction error method (PEM) of system identification to modelling lymphocyte migration through peripheral lymphoid tissue. The PEM was applied to the emergence of labelled lymphocytes from the efferent lymphatic of a lymph node following their intravenous administration. Advantages of PEM included the capacity to calculate the response to a unit impulse stimulus, unavailable to direct observation, and to allow for the return to the node of labelled cells that had already recirculated once. Calculation of the system delay (time between introduction of cells into the blood and their first appearance in lymph) indicated 4.67 +/- 1.05 h for the total lymphocyte population. The peak in efferent lymph occurred at 11.91 +/- 4.68 h, much earlier than previous reports, which were affected by cells that had already recirculated. While 75% of labelled cells had emerged in efferent lymph by 20.77 +/- 5.62 h, 86.38 +/- 29.44 h was required for 100% emergence. The considerable heterogeneity in migratory behaviour is likely to reflect frequency and duration of binding of lymphocytes by dendritic cells in paracortical cord corridors. It is proposed that differences in the speed with which lymphocytes pass along corridors depend on their functional status, in particular whether they are naïve or memory cells.

Animals↗
PubMed1999

The cloning, mapping and expression of a novel gene, BRL, related to the AF10 leukaemia gene.

The MLL gene is reciprocally translocated with one of a number of different partner genes in a proportion of human acute leukaemias. The precise mechanism of oncogenic transformation is unclear since most of the partner genes encode unrelated proteins. However, two partner genes, AF10 and AF17 are related through the presence of a cysteine rich region and a leucine zipper. The identification of other proteins with these structures will aid our understanding of their role in normal and leukaemic cells. We report the cloning of a novel human gene (BRL) which encodes a protein containing a cysteine rich region related to that of AF10 and AF17 and is overall most closely related to the previously known protein BR140. BRL maps to chromosome 22q13 and shows high levels of expression in testis and several cell lines. The deduced protein sequence also contains a bromodomain, four potential LXXLL motifs and four predicted nuclear localization signals. A monoclonal antibody raised to a BRL peptide sequence confirmed its widespread expression as a 120 Kd protein and demonstrated localization to the nucleus within spermatocytes.

Amino Acid Motifs↗
PubMed1999

Tumour responding accessory cells in testicular seminoma: an immunohistochemical study.

AIM: To investigate the role of accessory cells (and other chronic inflammatory cells) in the host immune response to testicular seminoma by defining their immunophenotypic characteristics and topographical arrangement. METHODS AND RESULTS: A panel of antibodies applicable to paraffin-embedded tissues was employed to characterize the host chronic inflammatory response in eight cases of classical testicular seminoma. The antibodies were directed against CD45RO, CD20, CD68, acid cysteine proteinase inhibitor (ACPI), MAC387, muramidase (MUR), S100 protein, Factor XIIIa, CD21 and HLA Class II. In all cases the majority of the inflammatory cells were T-lymphocytes situated mainly in areas of apparent tumour destruction. Large numbers of macrophages/dendritic cells which had not been evident by conventional light microscopy were also demonstrated. In particular, an immunophenotypically distinct population of accessory cells showing a specific pattern of distribution was revealed. It clearly rimmed islands of tumour and showed strong positive staining for CD68, MAC387 and HLA Class II. CONCLUSION: The study has identified an immunophenotypically distinct population of accessory cells showing a characteristic topographical arrangement. It is proposed that it represents a subpopulation of macrophages which are responding directly to the tumour and are likely to play a part in influencing tumour dynamics.

Adult↗
PubMed1999

Model of lymphocyte migration in Merino ewes under physiological conditions.

The paper presents an example of a new type of a structured model containing time delays in parallel branches. This model was selected as optimal to describe mathematically the lymphocyte migration between the venous blood and prescapular lymph in Merino ewes under physiological conditions. The model allowed to identify and quantify several lymphocyte fractions exhibiting different migration dynamics.

Animals↗
PubMed1998

Cellular interactions during the development of autoimmunity in a fetal lamb model of self-antigen deprivation.

Anti-thyroid autoimmune responses have been examined in fetal lambs, the immune systems of which had matured in the absence of exposure to thyroid-specific antigens. The lymphocytic infiltrate in self-thyroid tissue reintroduced into autoimmune lambs showed well-differentiated B and T cell domains. However, T cells from these fetuses were not sensitized against ovine thyroglobulin nor did serum antibodies appear against ovine thyroglobulin or thyroid peroxidase. In the light of these observations, it is inferred that the primary abnormality in the immune systems of fetuses deprived of exposure to thyroid autoantigens is likely to be a failure of the development of a normal T cell subpopulation responsible for down-regulation of autoreactivity. It is also concluded that overt autoimmunity develops only when these fetuses are challenged with thyroid tissue and that B cells may undertake an antigen-presentation role in its induction.

Animals↗
PubMed1998

Observational learning and the fearful child: influence of peer models on swimming skill performance and psychological responses.

This study examined the role of peer mastery and coping models on children's swimming skills, fear, and self-efficacy. Children (N = 24; M age = 6.2 years), who were identified as fearful of the water, were matched to control, peer-mastery, or peer-coping model conditions. Day 1 included a preintervention assessment. Days 2-4 included exposure to model conditions followed by a 20-min swimming lesson, Day 5 consisted of postintervention assessments, and a follow-up test was conducted 4 days later. Data were analyzed in a series of 3 x 3 (Model Type x Assessment Period) repeated measures analyses of variance on the dependent variables. Results revealed differences between modeling and control groups at postintervention and follow-up, but the small sample size and large within-group variability compromised many statistically significant findings. Calculation of effect sizes indicated moderate-to-large pre- to posintervention differences between control and modeling groups on skill, self-efficacy, and fear of swimming. These findings suggest that a modeling intervention combined with swimming lessons is a more effective behavior change agent for fearful children than swimming lessons alone.

Adaptation, Psychological↗
PubMed1997

Learning versus correct models: influence of model type on the learning of a free-weight squat lift.

It has been assumed that demonstrating the correct movement is the best way to impart task-relevant information. However, empirical verification with simple laboratory skills has shown that using a learning model (showing an individual in the process of acquiring the skill to be learned) may accelerate skill acquisition and increase retention more than using a correct model. The purpose of the present study was to compare the effectiveness of viewing correct versus learning models on the acquisition of a sport skill (free-weight squat lift). Forty female participants were assigned to four learning conditions: physical practice receiving feedback, learning model with model feedback, correct model with model feedback, and learning model without model feedback. Results indicated that viewing either a correct or learning model was equally effective in learning correct form in the squat lift.

Analysis of Variance↗
PubMed1996

Gene BR140, which is related to AF10 and AF17, maps to chromosome band 3p25.

The genes AF10 and AF17 have been identified as the basis of the t(10;11) and t(11;17) translocations, events that result in their fusion to the MLL/HRX gene in acute myeloid leukaemias. AF10 and AF17 bear significant homology to each other within their putative zinc finger and leucine zipper domains, although they are diverged outside these regions. The BR140 gene encodes a 140 kDa protein of unknown function that contains a putative zinc finger domain, a leucine zipper region, and, in addition, a bromo domain. The zinc finger and leucine zipper domains of BR140 have significant homology to those of AF10 and AF17, suggesting that it belongs to this newly described gene family and, therefore, could be a target for chromosome translocation. To assess the potential involvement of BR140 in chromosome translocations in leukaemia, the chromosomal location of the BR140 gene has been determined by using several independent methods. A combination of Southern analysis, polymerase chain reactions (PCR) on monochromosomal cell hybrids, and fluorescence in situ hybridisation (FISH) has been used to show that the BR140 gene maps to chromosome band 3p25.

Blotting, Southern↗
PubMed1995

Expression and regulation of anti-thyroid autoimmunity directed against cultivated rat thyrocytes.

Lymph node cells from DA rats that had been exposed in utero to 131I in doses sufficient to interrupt thyroid development, attacked monolayers of normal syngeneic thyrocytes in vitro. Lymph node cells from normal DA rats did not damage syngeneic thyrocyte monolayers. Thyrocytes could be protected from damage provided they had been incubated with lymph node cells from normal syngeneic rats before the introduction of lymph node cells from 131I exposed rats. Spleen cells from both 131I exposed and normal rats attacked syngeneic thyrocytes. It is concluded that normal rats possess cells capable of downregulating anti-thyroid autoimmunity.

Animals↗
PubMed1995

Suppression of anti-thyrocyte autoreactivity by the lymphocytes of normal fetal lambs.

We have devised an experimental strategy to determine whether the developing immune system of normal fetal animals can spontaneously acquire the capacity to inhibit autoimmune responses by its cells as it matures. Whilst the existence of cells with the capacity to exert negative regulation and to curtail autoimmune responses has been demonstrated previously in response to the experimental induction of these responses, the relevance of such regulatory processes to the prevention of overt autoimmunity in normal animals has not been established. We have produced pairs of identical twin fetal lambs by splitting blastocysts and have subsequently deprived one of each pair of exposure to thyroid-specific antigens by surgical thyroidectomy before development of immunological self recognition. Thyroidectomized fetuses developed T lymphocytes autoreactive against self thyrocytes. However, their normal, identical co-twins were found to acquire a class of T lymphocytes with the capacity to block anti-thyrocyte autoreactive cells from the thyroidectomized fetal co-twin. Blocking of anti-thyroid autoreactivity required preliminary contact between these normal T lymphocytes and the target thyrocytes. Substitution of an allograft of fetal thyroid tissue for a fetal lamb's own thyroid gland failed to prevent the development of autoreactivity against autologous thyrocytes by the recipient's lymphocytes. However, the reactivity of those lymphocytes against thyrocytes from the specific allogeneic thyroid donor was markedly curtailed.

Animals↗