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D Pilling

Publications and source records attributed to D Pilling.

At least 37 records · Page 2Linked to original sources
PubMed1998

Fetal lung abnormalities--what do they mean?

Antenatal diagnosis of lung abnormalities by ultrasound has been a much more frequent occurrence in recent years. There is a range of appearances from uniform increased echogenicity through to lesions containing large echo-free areas. Bilateral uniformly increased echogenicity has a poor outlook but in all other situations outcome cannot be accurately predicted from an early second trimester scan. Follow-up through pregnancy often allows a fairly accurate prognosis to be made but the appearance of the lesion does not accurately predict histology. A conservative approach to the antenatal management of unilateral lesions is recommended with long-term postnatal follow-up for all lesions because of the unknown long-term outcome for the lesions, many of which are symptomatic postnatally.

Cystic Adenomatoid Malformation of Lung, Congenita↗
PubMed1997

Inhibition of T cell apoptosis in the rheumatoid synovium.

Synovial T cells in rheumatoid arthritis are highly differentiated and express a phenotype suggesting susceptibility to apoptosis (CD45RB dull, CD45RO bright, Bcl-2 low, Bax high, Fas high). However, no evidence of T cell apoptosis was found in synovial fluid from any of 28 patients studied. In contrast, synovial fluid from 10 patients with crystal arthritis showed substantial levels of T cell apoptosis. The failre of apoptosis was not an intrinsic property of rheumatoid synovial T cells, as they showed rapid spontaneous apoptosis on removal from the joint. Synovial T cells from rheumatoid arthritis and gout patients could be rescued from spontaneous apoptosis in vitro either by IL-2R gamma chain signaling cytokines (which upregulate Bcl-2 and Bcl-XL) or by interaction with synovial fibroblasts (which upregulates Bcl-xL but not Bcl-2). The phenotype of rheumatoid synovial T cells ex vivo (Bcl-2 low, Bcl-xL high) suggested a fibroblast-mediated mechanism in vivo. This was confirmed by in vitro culture of synovial T cells with fibroblasts which maintained the Bcl-xL high Bcl-2 low phenotype. Synovial T cells from gout patients were Bcl-2 low Bcl-xL low and showed clear evidence of apoptosis in vivo. Inhibition experiments suggested that an integrin-ligand interaction incorporating the Arg-Gly-Asp motif is involved in fibroblast-mediated synovial T cell survival. We propose that environmental blockade of cell death resulting from interaction with stromal cells is a major factor in the persistent T cell infiltration of chronically inflamed rheumatoid synovium.

Apoptosis↗
PubMed1996

Interleukin-2 receptor common gamma-chain signaling cytokines regulate activated T cell apoptosis in response to growth factor withdrawal: selective induction of anti-apoptotic (bcl-2, bcl-xL) but not pro-apoptotic (bax, bcl-xS) gene expression.

Cytokine deprivation from activated T cells leads to apoptosis associated with down-regulation of the bcl-2 gene product. It is not clear, however, how cytokines other than interleukin-2 (IL-2) may affect this process and regulate the involvement of other apoptosis-modulating genes. We show that a group of cytokines including IL-2 (IL-2R gamma), prevent the apoptosis of IL-2-deprived activated T cells. This rescue involves the induction of the anti-apoptosis genes bcl-2 and bcl-xL), but causes little change in expression of bax and bcl-xS, which promote apoptosis. Furthermore, the prevention of apoptosis and induction of proliferation by the common gamma chain cytokines can be dissociated. Thus, when proliferation is blocked, the common gamma chain cytokines still induce up-regulation of bcl-2 relative to bax and retard apoptosis. These cytokines can thus regulate the persistence or removal of effector T cells by coordinating the balance between genes which promote and those which inhibit apoptosis, events which are probably mediated at least in part by signals through the common gamma chain. These data also implicate inappropriate T cell apoptosis resulting from a dysfunctional common gamma-chain as part of the pathophysiological defect in patients with X-linked severe-combined immunodeficiency (SCID).

Apoptosis↗
PubMed1996

Fibroblasts prevent apoptosis of IL-2-deprived T cells without inducing proliferation: a selective effect on Bcl-XL expression.

The apoptosis of human cytokine-deprived activated T cells can be prevented by a soluble mediator secreted by fibroblasts, epithelial and endothelial cells, and this rescue occurs with fibroblasts from different species. Fractionation of W138 fibroblast-conditioned medium indicated that the survival-promoting agent(s) were > 30,000 MW. The continuous presence of the survival factor was required for prevention of apoptosis, which did not involve the induction of proliferation. Nevertheless, the co-cultured T cells remained in a primed state. The expression of the apoptosis-inducing proteins Bax and CD95 (Fas/Apo-1) was either unchanged or slightly increased in fibroblast-rescued T cells, suggesting that constraints on survival still existed after co-culture. A fundamental observation in the present study was that although Bcl-2 was reduced, the levels of Bcl-XL was maintained in cytokine-deprived T cells by fibroblast co-culture. This suggests that fibroblasts and/or other stromal cells may promote activated T-cell survival by a selective effect on Bcl-XL expression, which is consistent with histological examination of activated T cells within lymphoid tissue in vivo. The rescued T cell could be re-activated by CD3 antibody, but only in the presence of CD28 co-stimulation, which induced both Bcl-2 and Bcl-XL expression and also proliferation. Thus, survival signals from stromal cells in tissue microenvironments may enable activated T-cell persistence in a primed but quiescent state, and our data suggest that the regulation of Bcl-XL expression may be central in this process. The further characterization of this process is essential to clarify how signals from stromal cells can influence the resolution and/or chronicity of immune responses in different tissues in vivo.

Apoptosis↗
PubMed1996

CD4+ CD45RA+ T cells from adults respond to recall antigens after CD28 ligation.

The leukocyte common antigen isoforms CD45RA and CD45RO have long been used to discriminate human naive and memory T cells respectively. This model was largely based on the observation that CD45RO+ T cells respond preferentially to and show a higher frequency of precursors specific for recall antigens. However, CD45RA+ T cells have more stringent requirements for stimulation and standard in vitro assays may favour CD45RO+ cells in this respect. We tested the hypothesis that CD45RA+ T cells respond poorly to in vitro stimulation with recall antigens because of inadequate stimulation rather than a lack of precursors. Limiting dilution analyses (LDA) for tetanus toxoid (TT)-specific T cells were performed in the presence or absence of exogenous anti-CD28 antibody. Addition of anti-CD28 yielded no proliferation in the absence of specific antigen. The precursor frequency for TT in the CD4+ CD45RO+ population was approximately 1:4000, while the frequency of CD4+ CD45RA+ T cells specific for TT was 4- to > 20-fold lower. Addition of anti-CD28 antibody did not significantly alter the apparent precursor frequency for CD45RO+ cells but yielded an enhancement of the value for CD45RA+ cells by 3- to > 5-fold. No enhancement of antigen-specific proliferation by anti-CD28 was observed with CD45RA+ T cells derived from cord blood, although phytohemagglutinin responses of these cells were amplified by CD28 antibody. These results indicate that conventional LDA underestimate the true precursor frequency of antigen-specific cells within the adult CD45RA+ population and support the possibility that a small number of cells revert from a primed (CD45RO+) to an unprimed (CD45RA+) state. The majority of memory T cells, however, appear to reside in the CD45RO+ population.

Adult↗
PubMed1996

Growth impairment in very low birthweight children at 12 years: correlation with perinatal and outcome variables.

AIM: To compare the growth of very low birthweight (VLBW) children in early adolescence with that of their normal birthweight peers; to examine the role of factors contributing to growth-parental height, perinatal variables, bone maturity and sexual maturation; to examine the correlation between head growth and cognitive and educational outcome. METHODS: Standing and sitting heights, weight, occipito-frontal circumference (OFC), skinfold thicknesses and pubertal staging were assessed in 137 VLBW children and 160 controls at 11-13.5 years of age. Ninety six (70%) of the VLBW children had their bone age assessed using the TW2 method. Reported parental heights were obtained by questionnaire. All children had standardised tests of cognitive and educational ability. Perinatal data had been collected prospectively as part of a longitudinal study. RESULTS: VLBW children had lower heights, weight, and OFC. Skinfold thicknesses were no different. The children's short stature was not accounted for by difference in parental height, degree of pubertal development, or by retarded bone age. Indeed, the TW2 RUS score was significantly advanced in the VLBW children. Using the bone ages to predict final adult height, 17% have a predicted height below the third centile and 33% below the tenth. Weight was appropriate for height, but there was a residual deficiency in OFC measurements after taking height into account. In the VLBW group smaller head size was associated with lower IQ and mathematics and reading scores. CONCLUSIONS: Growth problems persist in VLBW children and final heights may be even more abnormal than present heights suggest. VLBW children have smaller OFCs than expected from their short stature alone and this may be associated with poorer educational and cognitive outcomes.

Adolescent↗
PubMed1994

Genetic typing of patients with inflammatory arthritis at presentation can be used to predict outcome.

OBJECTIVE: To test the hypothesis that genetic characterization of patients at the time they present with inflammatory arthritis can predict subsequent destructive disease. METHODS: We evaluated 177 patients with early arthritis. Patients were serologically tested for rheumatoid factor (RF) and were DNA oligotyped for the presence of conserved base sequences in the third hypervariable region (HVR3) of the DRB1 gene, previously shown to be associated with severe rheumatoid arthritis (RA). Homozygosity in the patient's genotype was confirmed using restriction fragment length polymorphism analysis. The main outcome measure was radiologic erosions at 1 year. RESULTS: At presentation, 120 patients fulfilled the American College of Rheumatology 1987 criteria for RA, 64% of whom possessed the conserved base sequences, compared with 45% of 347 healthy controls (P < 0.001) and with 56% of 57 patients with other inflammatory arthritis (P not significant). Within the RA population, the frequency of Dw4/Dw14 compound heterozygotes was disproportionately increased. The presence of either HVR3 or RF had a relative risk of 13.49 for erosions, with a sensitivity of 95% (specificity 39%); the presence of both HVR3 and RF had a relative risk of 8.13, with a specificity of 88% (sensitivity 53%). All but 1 patient with the Dw4/Dw14 genotype developed erosions within 1 year. CONCLUSION: Knowledge of a patient's HLA-DR type and RF status allows clinically useful prediction of erosive disease; patients possessing Dw4/Dw14 represent a particularly high-risk subgroup.

Alleles↗
PubMed1994

The progressive differentiation of primed T cells is associated with an increasing susceptibility to apoptosis.

Recent studies have suggested that T cell memory for recall antigens resides in clones of primed T cells with a short inter-mitotic half-life. In humans such cells express an isoform of the leukocyte common antigen termed CD45RO. Nevertheless, little is known of the fate of these primed T cells after initial activation, since no markers are available to distinguish recently primed cells from long-established clones. This report is focused on a spectrum of primed CD4+ T cells characterized by an inverse relationship between the expression of two CD45 epitopes: CD45RB and CD45RO. We show that primed CD4+ T cells progress through many cycles of division from a CD45RBbrightOdull to a CD45RBdullObright state, resulting in a highly skewed distribution of the T cell receptor variable region usage within this particular population. The progressive differentiation defined by the shift from CD45RBbright to CD45RBdull is paralleled by the gradual loss of bcl-2 and gain of Fas expression, two features associated with an increased propensity for apoptosis. At the same time, the highly differentiated CD45RBdull cells selectively lose the capacity to synthesize interleukin (IL)-2, a cytokine which is particularly effective in preventing T cell apoptosis, although they produce high levels of IL-4. The inability to produce adequate levels of IL-2 leads to the apoptosis of primed CD45RBdull cells, when they are stimulated in the absence of exogenous IL-2. These observations show the crucial dependence of highly differentiated T cells on the availability of exogenous IL-2, and suggest both a major constraint for the persistence of T cell memory maintained by continually cycling primed cells, and an important mechanism contributing to the maintenance of T cell homeostasis in vivo.

Apoptosis↗
PubMed1994

CD57+ T lymphocytes are derived from CD57- precursors by differentiation occurring in late immune responses.

CD3+ T cells expressing the 110-kDa CD57 antigen are found in survivors of renal, cardiac and bone marrow transplants, in patients with acquired immune deficiency syndrome and in patients with rheumatoid arthritis. They are also present in normal individuals and expand upon ageing. They do not grow in culture and their role in the immune response is poorly understood. The expression of the various isoforms of the leukocyte common antigen (CD45) identifies a spectrum of differentiation in CD4+ and CD8+ T cells ranging from naive (CD45RA+CD45RBbrightCD45RO-) through early primed cells (CD45RA-RBbrightROdull) to highly differentiated memory cells which are CD45RA-RBdullRObright. CD45 isoforms expressed by CD57+ T cells showed distinct differences between CD4+ and CD8+ populations, but in each case indicated an advanced state of differentiation. The expression of T cell receptor V beta families was highly variable between individuals, but both CD57+ and CD57- cells show a full range of the specificities tested. V beta expression was more closely related within either the CD4+ or the CD8+ subsets, irrespective of CD57 expression, than between these subsets, suggesting a relationship between CD57+ and CD57- cells within the same T cell pool. This possibility was supported by experiments showing that CD3+CD57+ lymphocytes were similar to CD3+CD57- T cells in terms of the production of basic T cell cytokines [interleukin (IL)-2, IL-4, and interferon-gamma]. Furthermore, in vitro stimulation of CD3+CD57- T cells in secondary mixed leukocyte reaction or by co-culture with IL-2 and IL-4 induced the appearance of CD3+CD57+ cells with phenotypic and functional similarities to in vivo CD3+CD57+ cells. These data strongly suggest that the expression of CD57 is a differentiation event which occurs on CD57- T cells late in the immune response.

Antigens, CD↗
PubMed1994

Isolated choroid plexus cysts--the need for routine offer of karyotyping.

The management of isolated fetal choroid plexus cysts remains controversial. We have prospectively studied 15,565 pregnancies at two large obstetric units for the presence of choroid plexus cysts. In all cases where cysts were present at 19 weeks' gestation or greater, and were multiple, bilateral or solitary and greater than 5 mm maximum diameter, women were offered amniocentesis or placental biopsy, irrespective of the presence or absence of other abnormalities. Choroid plexus cysts were present in 152 (0.98 per cent) of cases. Four cases (2.6 per cent) of autosomal trisomy (three of trisomy 18, one of trisomy 21) were detected on prenatal karyotyping. In all cases, choroid plexus cysts were the only detectable prenatal anomaly. This study and a review of other large studies do not support the view that isolated choroid plexus cysts are a benign variant, the risk of trisomy being 1 in 82. Until further evidence is available, we recommend that cases of isolated fetal choroid plexus cysts at 19 weeks' gestation or greater should be offered prenatal karyotyping.

Amniocentesis↗
PubMed1993

The significance of low bcl-2 expression by CD45RO T cells in normal individuals and patients with acute viral infections. The role of apoptosis in T cell memory.

The bcl-2 gene product has been shown to prevent apoptotic cell death. We have now investigated the bcl-2 protein expression by resting and activated mature T cell populations. Freshly isolated CD45RO+ T cells within CD4+ and CD8+ subsets expressed significantly less bcl-2 than CD45RO- (CD45RA+) T cells (p < 0.001). When CD45RA+ T cells within both CD4+ and CD8+ subsets were activated in vitro, the transition to CD45RO phenotype was associated with a decrease in bcl-2 expression. Patients with acute viral infections such as infectious mononucleosis caused by Epstein-Barr virus infections or chickenpox, resulting from varicella zoster virus infection, had circulating populations of activated CD45RO+ T cells which also showed low bcl-2 expression. In these patients, a significant correlation was seen between low bcl-2 expression by activated T cells and their apoptosis in culture (r = 0.94, p < 0.001). These results suggest that the primary activation of T cells leads to the expansion of a population that is destined to perish unless rescued by some extrinsic event. Thus the suicide of CD45RO+ T cells could be prevented by the addition of interleukin 2 to the culture medium which resulted in a concomitant increase in the bcl-2 expression of these cells. Alternatively, apoptosis was also prevented by coculturing the activated T lymphocytes with fibroblasts, which maintained the viability of lymphoid cells in a restinglike state but with low bcl-2 expression. The paradox that the CD45RO+ population contains the primed/memory T cell pool yet expresses low bcl-2 and is susceptible to apoptosis can be reconciled by the observations that maintenance of T cell memory may be dependent on the continuous restimulation of T cells, which increases their bcl-2 expression. Furthermore, the propensity of CD45RO+ T cells to extravasate may facilitate encounter with fibroblast-like cells in tissue stroma and thus be an important additional factor which promotes the survival of selected primed/memory T cells in vivo.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Subpopulations of primed T helper cells in rheumatoid arthritis.

OBJECTIVE: To analyze subsets of primed T helper cells, defined by expression of the CD45RB isoform of the leukocyte common antigen, in the blood and synovial fluid (SF) of patients with rheumatoid arthritis (RA). METHODS: Three-color immunofluorescence was used to study CD45 isoform expression by peripheral blood and SF CD4+ T cells. RESULTS: CD45 isoform expression in the peripheral blood of patients with either RA or reactive arthritis did not differ from that in healthy controls. SF T cells from both RA patients and reactive arthritis patients were almost exclusively primed (CD45RO+) cells. RA SF T cells expressed very low levels of CD45RB; this is the most highly differentiated subset of primed cells. Patients with acute reactive arthritis showed higher levels of CD45RBbright cells in their synovial fluid. CONCLUSION: The highly selected cell population in SF, representing one subset of primed cells, may relate to the apparent functional abnormalities of cells from this site in patients with RA.

Adult↗
PubMed1993

The value of baseline CT head scans in the assessment of shunt complications in hydrocephalus.

The purpose of this study was to determine the value of a baseline CT head scan in the assessment of patients who subsequently presented with symptoms which may have been due to shunt complications (such as blockage or infection). In all these patients the shunt had been inserted in the treatment of hydrocephalus. We conclude that the presence of a baseline scan does not add to the interpretation of CT scans done when the patient presents with symptoms of possible shunt malfunction.

Brain↗
PubMed1992

MHC restriction of synovial fluid lymphocyte responses to the triggering organism in reactive arthritis. Absence of a class I-restricted response.

Synovial fluid mononuclear cells (SFMC) from patients with reactive arthritis (ReA) show marked proliferative responses to preparations of the organism triggering the arthritis. Initial studies with MHC-specific MoAbs have indicated that a significant element of these proliferative responses is mediated by class II MHC-restricted CD4+ T cells. It is imperative to establish the presence or absence of a class I-restricted response, for two reasons. Firstly, the association of ReA with the MHC class I molecule, HLA B27, raises the possibility of there being a B27-restricted response to the triggering organism. Secondly, a number of the organisms associated with ReA are intracellular pathogens, whose antigens might be expected to be presented by class I MHC molecules. In an effort to identify a class I MHC-restricted pathogen-specific response in the SFMC of ReA patients, we have assessed the proliferative responses of SFMC depleted of CD4+ T cells. Responses were grossly diminished by CD4+ T cell depletion. We also investigated Chlamydia-specific cytotoxicity in the SFMC of patients with sexually acquired ReA in a system using productive chlamydial infection to produce both targets and effectors. Significant antigen specific cytotoxicity was not seen. These experiments do not provide evidence to support the existence of pathogen-specific responses by CD8+, class I-restricted synovial fluid T cells in ReA.

Arthritis, Reactive↗
PubMed1991

Human CD4+CD45R0+ and CD4+CD45RA+ T cells synergize in response to alloantigens.

Alloantigens, unlike recall antigens, activate both CD45RA+ (naive) and CD45R0+ (memory) CD4+ cells to the same extent. These T cell subsets may therefore interact with each other in response to alloantigens on transplanted grafts. We have investigated if the ability of activated CD4+CD45RA+ and CD4+CD45R0+ T cells to produce and respond to interleukin 2 (IL2) and IL4 may be involved in this interaction. After activation, both subsets up-regulate their IL2 receptor (IL2R) and IL4R expression, yet IL4 substantially enhanced the proliferation of the CD4+CD45RA+ but not of the CD4+CD45R0+ T cell subset, while IL2 increased the proliferation of CD4+CD45R0+ but not of the CD4+CD45RA+ T cells. Significantly, the CD4+CD45RA+ T cells synthesized two- to threefold more mRNA for IL2 than the CD4+CD45R0+ subset, while the CD4+CD45R0+ T cells synthesized mRNA for IL4 and interferon-gamma exclusively. The addition of IL2 to alloactivated CD4+CD45R0+ T cells further up-regulated their production of all three lymphokine mRNA; in contrast, IL4 induced an increase in mRNA for IL2 in only the alloactivated CD4+CD45RA+ subset. The reciprocity in the ability of both these CD4+ T cells to synthesize and respond to IL2 and IL4 may provide a rationale for the regulation of lymphokine interactions in vivo. Furthermore, the synergy between these subsets in response to alloantigens, which was directly quantitated by co-culturing CD4+CD45RA+ and CD4+CD45R0+ cells together prior to activation, may potentiate the alloreactivity against transplanted grafts in vivo.

Antigens, CD↗
PubMed1991

The empty rectum on plain X-ray. Does it have any significance in the neonate?

The absence of rectal gas is said to be a sign of Hirschsprung's disease, especially when there is also gaseous distension of the bowel proximally. This paper reviews 136 neonates who had plain abdominal radiographs. There were 83 patients with multiple examinations, of which 52 (63%) showed variability in the presence of rectal gas on the radiographs. Fifty-seven of the total babies (42%) had significant bowel distension and of these 42 (74.5%) had absence of rectal gas. Only one of these cases had Hirschsprung's disease, most of the remaining having either generalized sepsis (42%) or necrotizing enterocolitis (25.5%).

Diagnosis, Differential↗