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Biomedical subjects

P Tomlinson

Publications and source records attributed to P Tomlinson.

At least 19 recordsLinked to original sources
PubMed2000

Long-term survival but impaired homeostatic proliferation of Naïve T cells in the absence of p56lck.

Interactions between the T cell receptor (TCR) and major histocompatibility complex antigens are essential for the survival and homeostasis of peripheral T lymphocytes. However, little is known about the TCR signaling events that result from these interactions. The peripheral T cell pool of p56lck (lck)-deficient mice was reconstituted by the expression of an inducible lck transgene. Continued survival of peripheral naïve T cells was observed for long periods after switching off the transgene. Adoptive transfer of T cells from these mice into T lymphopoienic hosts confirmed that T cell survival was independent of lck but revealed its essential role in TCR-driven homeostatic proliferation of naïve T cells in response to the T cell-deficient host environment. These data suggest that survival and homeostatic expansion depend on different signals.

Animals↗
PubMed2000

Inducible expression of a p56Lck transgene reveals a central role for Lck in the differentiation of CD4 SP thymocytes.

The T lymphocyte-specific protein tyrosine kinase p56lck (Lck) is an essential component of the TCR-mediated signal transduction complex. Lck knockout mice have reduced numbers of double-positive thymocytes and very few mature single-positive cells, particularly of the CD4 lineage. Here we demonstrate the ability of a tetracycline-based tissue-specific inducible Lck transgene to restore expansion of early thymocytes and maturation of single-positive cells in Lckneg mice upon induction with doxycycline. Restoration of Lck expression is particularly important for positive selection to the CD4+ lineage but has a lesser impact on selection to the CD8+ lineage, suggesting activation of Lck is an important component of the signals involved in lineage choice during thymic differentiation.

Animals↗
PubMed1999

A prospective randomized multicentre comparison of expanded polytetrafluoroethylene and gelatin-sealed knitted Dacron grafts for femoropopliteal bypass.

PURPOSE: To compare graft patency between expanded polytetrafluoroethylene (PTFE) and gelatin-sealed knitted Dacron for femoropopliteal bypass. METHODS: A prospective, multicentre trial was performed in 108 patients randomized to receive either a PTFE or Dacron prosthetic graft. Distal anastomosis was above knee in 75 and below knee in 33 patients. RESULTS: Primary patency at 1, 2 and 3 years was 72, 52 and 52% for PTFE, and 70, 56 and 47% for Dacron (P = 0.87). Secondary patency at 1, 2 and 3 years was 74, 54 and 54% for PTFE and 78, 70 and 53% for Dacron (P = 0.39). The most significant predictors of early graft failure were poor vessel run-off (P = 0.04) and critical limb ischaemia (P = 0.04). CONCLUSION: There was no difference in graft patency between PTFE and Dacron for femoropopliteal bypass.

Aged↗
PubMed1998

Baller-Gerold syndrome associated with congenital portal venous malformation.

We report a 4 year old boy in whom the clinical features of craniosynostosis and bilateral absent radii led to a diagnosis of Baller-Gerold syndrome. Additional congenital abnormalities included midface hypoplasia, atrial and ventricular septal defects, right hydronephrosis, partial sacral agenesis, and anterior ectopic anus. Evidence of portal venous hypertension was present from 8 months and a congenital portal venous malformation was discovered at 2 years. This is the first reported case of Baller-Gerold syndrome associated with a congenital portal venous malformation. We discuss the diagnostic confusion between this syndrome and other overlapping malformation syndromes and propose optimal evaluation strategies aimed at clarifying the nosology of these syndromes.

Abnormalities, Multiple↗
PubMed1997

Combined coronary artery bypass grafting and carotid endarterectomy.

Combined carotid endarterectomy and coronary artery bypass grafting was performed in 52 patients between January 1982 and September 1994. Forty-nine patients had stable or unstable angina and three had symptom-free coronary artery disease detected by stress testing. Thirty-one patients had triple-vessel disease and 17 had left main trunk or left main equivalent coronary artery disease. Five patients had symptom-free carotid artery disease, 12 had non-specific neurological symptoms, and 35 had transient ischaemic attacks. Carotid endarterectomy was performed first, followed by coronary artery bypass grafting. There were three postoperative deaths, two cardiac and one neurological, for a mortality rate of 5.8%. One patient suffered a permanent neurological deficit (1.9%). It is concluded that combined carotid endarterectomy/coronary artery bypass grafting can be performed in selected patients with acceptable neurological morbidity, although cardiac mortality was not eliminated by the combined approach.

Angina Pectoris↗
PubMed1997

HLA-G functions as a restriction element and a transplantation antigen in mice.

HLA-G, a human MHC class I molecule expressed on the trophoblast during pregnancy, was expressed in transgenic mice by recombining the HLA-G gene with a transcriptional promoter from a murine H-2 MHC class I gene. Skin grafts from HLA-G transgenic mice were rejected by non-transgenic mice showing that HLA-G behaves as a xenotransplantation antigen in mice. Further investigation revealed that murine T cells recognize native HLA-G directly as a xenoantigen or they recognize processed peptides derived from HLA-G presented in the context of murine MHC molecules. HLA-G molecules also function as restriction elements capable of presenting peptides to murine T cells since immunization of HLA-G transgenic mice with peptide that binds specifically to HLA-G molecules elicited HLA-G-restricted, cytotoxic T cell responses. In addition, murine T cell responses to human xenoantigens are enhanced when responder cells originated from HLA-G transgenic mice. Based on these observations, we conclude that expression of HLA-G molecules influences selection of the murine T cell repertoire and that HLA-G exhibits immunological properties that are indistinguishable from classical HLA class I molecules when expressed in transgenic mice. Thus, any unique immunological functions mediated by HLA-G must arise from the distinctive, trophoblast-specific pattern of HLA-G expression in humans and not from structural peculiarities of HLA-G molecules.

Animals↗
PubMed1997

Parental experience and meaning construction during a pediatric health crisis.

This study explores parental lived experience following admission of their child to a pediatric intensive care unit. The interview data used were collected from 10 randomly chosen families from the Family Impact of Catastrophic Childhood Illness Project recruited during the early phase of critical care hospitalization of their child. A 3-stage contextual analysis procedure integrating interactional and contextual perspectives into Colaizz's phenomenological approach was used to reduce text data to thematic content. The analysis uncovered a multidimensional and holistic phenomenon consisting of four organizing concepts: initial boundary ambiguity, parents' coping patterns, family resources, and functioning of the family boundary. These results provide evidence of a collective family level perception of stress when experiencing the health crisis of a child and support further use of family stress perception as a family level phenomenon that represents family meaning construction during critical illness of a child.

Adaptation, Psychological↗
PubMed1996

Effects of different antigenic microenvironments on the course of CD8+ T cell responses in vivo.

The influence of microenvironment on the course of CD8 + T cell responses in vivo was investigated by injecting H-2Kb-specific T cells from donor TCR transgenic (TCR-Tg) mice into H-2kb-Tg mice. H-2Kb expression in recipients was either ubiquitous (CBK mice) or restricted to myeloid and erythroid cells (K beta mice). Donor T cells proliferated as extensively and acquired similar surface phenotypes in spleen of both recipient types. Thus, neither the restricted pattern of H-2Kb expression nor the significantly reduced level of H-2Kb expression by myeloid cells in Kbeta recipients affects the ability of the splenic microenvironment to prime T cell proliferation in vivo. However, an unsustained burst of cytolytic activity was generated rapidly in spleen of CBK recipients, whereas relatively little cytolytic activity was generated in K beta spleen. This indicates that effector T cells were not generated efficiently in spleen of Kbeta recipients even though extensive T cell proliferation was taking place in this microenvironment. Furthermore, activated donor T cells dispersed rapidly throughout primary and secondary lymphoid organs of Kbeta recipients, whereas few T cells migrated from spleen in CBK recipients. Consequently, the course of CD8+ T cell responses and the anatomical distribution of activated T cells are profoundly influenced by the nature of the antigenic microenvironment encountered in vivo. We conclude that T cells rapidly proliferate and acquire new tissue-homing characteristics but do not differentiate into cytolytic effector cells at the site of priming when they encounter myeloid cells expressing low levels of antigen in vivo.

Animals↗
PubMed1996

Unprimed T cells are inefficiently stimulated by glycosylphosphatidylinositol-linked H-2Kb because of its lipid anchor rather than defects in CD8 binding.

Many non-classical, or class Ib, MHC molecules, including those linked to the cell membrane via glycosylphosphatidylinositol (GPI) membrane anchors, are poor stimulators of primary cytotoxic T cell responses. Some studies have suggested that certain amino acid substitutions in the alpha 3 domains of class Ib molecules may adversely affect their ability to interact with CD8, thereby affecting their ability to stimulate CD8+ T cells. In this report we show that poor stimulation by GPI-linked class I MHC molecules is not simply due to a failure to interact with CD8, but to a fundamental difference in the way T cells respond to GPI-anchored class I molecules. We have demonstrated this in two ways. Firstly, we have shown that GPI-linked H-2Kb molecules in which the amino acid sequence of the alpha 3 domain is identical to that of transmembrane H-2Kb remain less effective stimulators of a primary T cell response than membrane-spanning H-2Kb molecules. Secondly, using CD8- responder T cell hybridomas and responder T cells from transgenic mice expressing a CD8-independent TCR, we can show that the poor stimulatory ability of GPI-linked H-2Kb molecules is unrelated to their ability to interact with either CD8 or the TCR. These results suggest that the transmembrane linkage of class I MHC molecules plays an important role in the initial priming of T cells.

Amino Acid Sequence↗
PubMed1995

Complications with shunts in adults with spina bifida.

OBJECTIVE: To assess the incidence of malfunction of shunts in adults with spina bifida who have shunts to control hydrocephalus. DESIGN: A retrospective review of the medical notes and contact by questionnaire of adults with spina bifida to assess symptoms, function of shunts, frequency of operative procedures, and follow-up. SUBJECTS: 110 patients with shunts who attended Lord Mayor Treloar College for the physically disabled between 1978 and 1993. RESULTS: The average (range) number of revisions of shunts per person was 3.6 (0-28). Although 37 patients underwent an emergency operation for revision in their first year of life, there was a continuing low incidence, increasing in the early teenage years, which persisted into the third decade. Intervals between emergency revisions varied: 202/320 occurred within one year of the last shunt operation, 56 occurred after five years, 24 after 10 years, and 15 after 15 or more years. Fifteen patients had chronic intermittent headaches, of whom four died and three suffered severe morbidity. Thirteen died; three had raised intracranial pressure, and four died suddenly; these deaths were presumed to be related to their shunts. Up to the age of 16 there was 100% hospital follow up, but after that only 40% of young adults underwent review, including review of their shunt function. CONCLUSION: Shunts to control hydrocephalus may fail after many years without symptoms. This is difficult to diagnose and if missed may lead to chronic morbidity and death. As hospital follow up of this group is falling, both general practitioners and hospital doctors must be aware that a shunt may malfunction after prolonged quiescent periods.

Adolescent↗
PubMed1994

Standard conditions of virus isolation reveal biological variability of HIV type 1 in different regions of the world. WHO Network for HIV Isolation and Characterization.

HIV-1 isolates were obtained from four countries within the framework of the WHO Network for HIV Isolation and Characterization. The use of standard HIV isolation procedures allowed us to compare the biological properties of 126 HIV-1 isolates spanning five genetic subtypes. In primary isolation cultures, viruses from Uganda and Brazil appeared early and replicated without delay, whereas the replication of Thai viruses was delayed by several weeks. Regardless of genetic subtype or country of origin, blood samples collected more than 2 years after seroconversion yielded virus that replicated efficiently in the primary isolation cultures. None of the isolates obtained from Thailand or Rwanda replicated in cell lines, whereas 5 of the 13 Brazilian isolates and 7 of the 11 Ugandan isolates replicated and induced syncytia in MT-2 cells. As expected for virus isolates obtained early in HIV-1 infection (within 2 years of seroconversion), all viruses from Brazil, Rwanda, and Thailand showed a slow/low replicative pattern. For the Ugandan samples, the time from seroconversion was known precisely for a few of the samples and only in one case was less than 2 years. This may explain why the five viruses that were able to replicate in all cell lines, and thus classified as rapid/high, were of Ugandan origin. Viruses able to induce syncytia in MT-2 cells, also induced syncytia in PBMC. However, 8 slow/low viruses (out of 27) gave discordant results, inducing syncytia in PBMC but not in MT-2 cells. Furthermore, using syncytium induction as a marker, changes in virus populations during early in vitro passage in PBMC could be observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Brazil↗
PubMed1994

Leaking mycotic abdominal aortic aneurysm.

A case of leaking mycotic abdominal aortic aneurysm is reported, with a brief review of the literature. A 58 year old female presented with shoulder and abdominal pain associated with diarrhoea, vomiting and fever with leucocytosis. Computed tomography of the abdomen showed pooling of contrast in the retroperitoneum anterior to a non-dilated abdominal aorta. There was considerable retroperitoneal blood accumulating in a mass-like lesion in the right lower abdomen and pelvis obstructing the right renal collecting system. Laparotomy revealed a 4 cm diameter saccular aneurysm of the abdominal aorta, with a 1 cm diameter neck. Culture of the thrombus grew Streptococcus pyogenes.

Aneurysm, Infected↗
PubMed1994

Separation of thymic education from antigen presenting functions of major histocompatibility complex class I molecules.

Participation of transmembrane (TM) and glycosyl-phosphatidylinositol (GPI) anchored H-2Db molecules in antigen presentation and thymic selection events was investigated using transgenic mice. Both GPI-Db and TM-Db can efficiently present H-Y antigen, influenza and lymphocytic choriomeningitis virus (LCMV) peptides to primed cytotoxic, H-2Db-restricted T cells. Transgenic mice expressing GPI-Db, although unable to reject TM-Db skin grafts, nevertheless generate secondary CTL responses which can lyse TM-Db-bearing targets, indicating that GPI-Db mice fail to delete all TM-Db-reactive T cells. Furthermore, double-transgenic mice bearing GPI-Db and a T-cell receptor (TcR) for H-2Db+LCMV do not positively select receptor positive, CD8+CD4- T cells. This paradoxical behaviour of GPI-Db molecules suggests that the structural requirements for antigen presentation and thymic selection by class I molecules are different and may explain why GPI-linked class I molecules, such as Qa-2, do not appear to function as restriction elements in vivo.

Animals↗
PubMed1993

Acute haemodilution in surgery for burns: a preliminary report.

Blood loss is a major problem in the management of patients with burns treated by early excision and grafting. Acute normovolaemic haemodilution has been successfully used in cardiac surgery for many years but has not been reported previously in surgery for burns. The technique has been used in six patients with burns undergoing early excision and grafting, with no obvious morbidity and an apparent reduction in homologous blood requirements.

Adolescent↗
PubMed1993

Immunological consequences of T cell-specific expression of H-2Kb molecules in transgenic mice.

CBA (H-2k) mice carrying a H-2Kb transgene (CD2Kb) linked to transcriptional control elements from the human CD2 gene express H-2Kb at high levels on all thymocytes and peripheral T cells. However, skin grafts from two independent transgenic lineages, CD2Kb-2 and CD2Kb-3, are not rejected by recipient CBA mice. Although mice from both lineages tolerate H-2Kb disparate skin grafts, tolerance is maintained by different mechanisms because H-2Kb-specific cytotoxic T cells cannot be generated in vitro using CD2Kb-2 responder spleen cells, but can be generated when responder cells are from CD2Kb-3 mice. Furthermore, H-2Kb-restricted cytotoxic T cell responses directed against minor histocompatibility antigens can be obtained from CD2Kb-2 responder mice. Thus, negative and positive selection of immature thymocytes seems to take place in CD2Kb-2 mice, even though the pattern of H-2Kb expression is modified by the CD2Kb transgene. In contrast, H-2Kb-specific cytotoxic T cell precursors are not eliminated in CD2Kb-3 mice, even though all thymocytes express H-2Kb in these mice. However, these potentially autoreactive H-2Kb-specific T cells are apparently inactive in vivo and fail to lyse syngeneic CD2Kb-3 target cells in vitro, even when activated to lyse other H-2Kb-expressing cells. These results reveal that tolerance in CD2Kb-3 mice is induced either by a non-deletional mechanism or by partial elimination of a subset of cytotoxic T cell precursors capable of recognizing H-2Kb as a target antigen.

Animals↗
PubMed1993

Urinary excretion and clearance of insulin in diabetic and normal children and adolescents.

Seventy-two diabetic (38 males) and 86 normal (41 males) children provided timed overnight urine collections. Fourteen of the diabetic and 33 of the normal children had concurrent overnight plasma insulin profiles. Urinary insulin clearance in the diabetic subjects was compared with excretion of albumin, growth hormone, retinol-binding protein, and N-acetyl-beta-D-glucosaminidase. In the normal subjects, urinary insulin excretion correlated with mean overnight plasma levels in the boys (r = 0.82, p < 0.001) but not in the girls (r = 0.32), and varied with puberty stage in the boys. Insulin clearance was greater in boys than girls during puberty, and fell in both sexes with advancing puberty. Insulin excretion was greater in diabetic than normal children in both sexes at all puberty stages. Insulin clearance was also greater in diabetic than normal subjects (1.05 +/- 0.1 ml min-1 1.73 m-2 vs 0.48 +/- 0.05 ml min-1 1.73 m-2, p < 0.001). Insulin excretion as a percentage of the filtered load was also greater in diabetic than normal subjects (1.9 +/- 0.27% vs 0.85 +/- 0.09%, p < 0.01). In the diabetic children, there was a correlation between urinary insulin and growth hormone excretion (r = 0.52, p < 0.02), and retinol-binding protein in those (n = 10) with higher retinol binding protein excretion (r = 0.76, p = 0.01). The value of urinary insulin excretion as a measure of free plasma insulin levels in normal and diabetic children may be limited by sex differences in renal insulin clearance, and by proximal renal tubular dysfunction in children with diabetes.

Acetylglucosaminidase↗