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Biomedical subjects

P McCullagh

Publications and source records attributed to P McCullagh.

At least 19 recordsLinked to original sources
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↗
PubMed1994

Retarded and excessive development of skin appendages in fetal lambs in response to thyroidectomy before wool follicle appearance.

The impact on wool follicles of development in an athyroid environment was studied in a series of twin fetal lambs by surgically thyroidectomizing one of each pair before the appearance of follicle buds and comparing development of epidermal appendages in it with their development in the normal co-twin. Thyroidectomy was undertaken at 51 to 54 days' gestation, i.e. after approximately one-third of the gestation period. Each treated fetus was then replaced in the uterus, allowing pregnancy to continue. Eight pairs of twins were removed at intervals from 67 to 122 days' gestation and skin samples from the thyroidectomized and the intact twins were compared. Micromorphometric examination of the samples was used to assess quantitatively the effects of thyroid deprivation on wool follicle development. In thyroidectomized fetuses there was a failure of keratinization in primary wool follicles, an absence of secondary follicles, a tendency to excessive follicular branching and sweat gland development, and a paucity of sebaceous gland formation. The density of wool follicles was substantially increased, but the mean cross-sectional area of these follicles was reduced. The effects of very early thyroidectomy imply that the thyroid plays a role in the stimulation and regulation of wool follicle differentiation. To test the reversibility of the effects observed in the skin of thyroidectomized fetuses, grafts from these animals were transplanted to normal, young fetal lambs. Subsequent examination of grafted skin revealed that complete keratinization had occurred but that none of the other abnormal features had been reversed.

Animals↗
PubMed1994

Evaluation of a transgenic mouse model for alpha-1-antitrypsin (AAT) related liver disease.

We have attempted to produce a transgenic mouse model of the neonatal liver disease associated with the human PIZ allele. Analysis of a number of transgenic mouse lines carrying either a normal human PIM gene construct or the mutant Z is reported. Using isoelectric focusing analysis of plasma from transgenic mice, we have shown that the human AAT proteins produced in mice are processed in a similar way to their counterparts in humans. By comparing the level of M and Z mRNA in liver with the levels of M and Z proteins in plasma we have inferred that, as in humans, the mutant protein tends to accumulate within the hepatocyte. Accumulation of Z protein has also been demonstrated by immunocytochemistry. Two of the M transgenic lines produce such high levels of the human protein that it, like the Z protein, accumulates as globules. Histological features of livers from 116 mice of different ages and genotypes were examined: 37 non-transgenic, 62 Z transgenic (23 low expressing and 39 high expressing) and 17 M transgenic mice, all high expressing. Cirrhosis or fibrosis was not seen in any animal and we were unable to find any evidence for neonatal liver disease. Some necrosis was seen in all genotypes and this increased significantly with age with one Z line showing significantly more frequent necrosis than any other group. This line, the highest expressing Z line, was back crossed onto 7 different genetic backgrounds but no major differences between the back crosses with respect to liver disease were observed. The mouse model we have developed is compared with other transgenic Z mouse models; none of these is representative of human neonatal liver disease. Our view is that the transgenic animals generated in these experiments may be most useful for investigating the liver manifestations that almost invariably occur in ZZ adults. Alteration of additional factors other than accumulation of Z protein, for example inactivation of the endogenous mouse genes or some environmental challenge, might produce a mouse model with more relevance to neonatal liver disease.

Animals↗
PubMed1993

Proliferation of reactive and neoplastic human tissue mast cells. An immunohistochemical study using the antibody PC10 (anti-PCNA).

Studies on the proliferative compartment of human tissue mast cells (MCs) and their tumours (mastocytosis) have not been performed. We have used the monoclonal antibody PC10 to study MCs in reactive or hyperplastic states (chronic non-specific lymphadenitis, n = 10; benign and malignant solid tumours, n = 5) and in the various subtypes of mastocytosis (urticaria pigmentosa, n = 22; solitary mastocytoma of the skin, n = 7; systemic mastocytosis; n = 8; malignant mastocytosis, n = 4). The identification of PC10-positive MC nuclei was achieved by double staining. We found no PC10-positive MCs in reactive or hyperplastic states, or in 14 of 22 cases of urticaria pigmentosa. PC10-positive MCs could be identified in all other mastocytosis but mostly in very low numbers. The mean percentages of PC10-positive MCs amounted to 0.5 in eight positive cases of urticaria pigmentosa, 1.2 in mastocytoma, 0.7 in systemic mastocytosis, and 4.0 in malignant mastocytosis. The difference between the latter form of mastocytosis and each of the other subtypes proved to be significant (P < 0.05). The very small proliferative compartment in the cutaneous and systemic variants of mastocytosis is in accord with their favourable prognosis. Most of the patients with systemic mastocytosis in the present study are all alive and well up to 12 years after diagnosis. In contrast, most of the patients with malignant mastocytosis died within 1 year of diagnosis.

Adult↗
PubMed1993

The failure of a combination of thyroid and thymus allografts to prevent the development of autoimmunity in thyroidectomized foetal lambs.

Previous experiments have shown that surgical removal of the thyroid gland from the foetal lamb one third of the way through gestation prevents the development of self tolerance towards thyroid-specific determinants. As a result, self thyroid tissue reintroduced into the foetal lamb after maturation of the immune system is not recognized as self and is subject to autoimmune thyroiditis. Furthermore, the transplantation of a thyroid allograft into a foetal lamb immediately after extirpation of its own gland has been shown not to direct the development of self tolerance to thyroid determinants. In the present experiment, foetal lambs were submitted to removal of the entire thyroid gland and the majority of the thymus gland, at 51-54 days of gestation followed by the immediate implantation of thyroid and thymic allografts. The additional implantation of thymus tissue did not affect the previously observed incapacity of a thyroid allograft to facilitate induction of organ-specific tolerance by the thyroid allograft. It was inferred that any T lymphocytes generated within the thymus graft and tolerant of thyroid-specific determinants had not had the capacity to suppress the activity of autoreactive cells generated in the host's thymus.

Animals↗