Biomedical subjects
Publications and source records attributed to G Owen.
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This study was designed to determine the range of oxygen saturation levels encountered in normal sleeping children up to 10 years of age in their own home environment. Subjects were chosen by stratified random sampling from the general practice list of the town of Frome, Somerset, UK. Analysis of overnight pulse oximetry recordings allowed a normal range for the following parameters of oxygen saturation level to be reported: mean, median, mode, maximum, fifth centile, upper and lower quartiles and the number of greater than 4% dips in oxygen saturation per hour. As a consequence of this study the values given can now be used to identify those children with abnormal sleep patterns.
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Ligation of surface immunoglobulin (sIg) on certain murine B-lymphoma lines has been shown to initiate a programme leading to growth arrest and death of the cells by apoptosis. The cell lines WEHI 231 and CH33 which respond in this way to receptor cross-linking have phenotypic characteristics resembling those of immature normal B cells, and their responses have been taken to model those responsible for clonal deletion or anergy. Cross-linking of sIg on normal neonatal B cells has also been shown to inhibit their responsiveness to polyclonal activators. We have examined the ability of various co-stimuli to modify the response of growth-inhibitable B lymphoma lines to sIg cross-linking. Our findings indicate that cell-cell contact between cells of the WEHI 231 or CH33 lines and activated T cells rescues these cells from growth arrest and apoptosis. Cell-free supernatants from some T-cell lines were also protective although recombinant IL-4 had no effect. Analysis of the most effective signals and timing for inducing this protection suggested that it might, in part, be mediated by CD40 ligand (CD40L) expressed on or secreted by activated T cells. Using a soluble recombinant CD40L-CD8 fusion protein we have now shown that co-ligation of CD40 is sufficient to rescue WEHI231 and CH33 cells from anti-Ig-induced apoptosis. In contrast, the inhibitory effect of anti-Ig antibodies on the lipopolysaccharide (LPS)-driven proliferation of neonatal B cells was not relieved by co-ligation of CD40 with CD40L. These findings bring into question the usefulness of 'immature' B-cell lines as models for tolerance induction.
The reproducibility of urinary growth hormone levels in normal children and in children undergoing adenotonsillar surgery was investigated. Thirty normal children and 32 children pre- and post-adenotonsillectomy had overnight urinary growth hormone levels measured on two consecutive nights using the technique of immunoradiometric assay. There was no significant difference when levels in each of these groups were compared. Therefore, the results were pooled (n = 94) and the correlation coefficient comparing levels obtained on the first and the second consecutive nights sample was calculated, r = 0.644 (P < 0.001). This work suggests that studies of urinary growth hormone levels in children give reproducible results. Further investigation of this technique as a screening or diagnostic procedure in the clinical setting can now be more widely evaluated.
The prevalence of OSA increases with age depending on the techniques used and criteria accepted for definition of the condition. In children there may be a relationship of snoring to parental smoking. Night time problems may be worsened by use of anti-histamine sympathomimetic amine medication or cough suppressants. Disorders of sleep affect not only the child but also the parents and family. Progression to right heart failure is very rare and more likely in syndromic conditions. Whilst polysomnography will detect most of the changes of OSA, pulse oximetry may detect only two-thirds of adults with the condition and until now there has been no data for normal children examined at home.
Intraosseous infusion is a potential route for intravenous access in the child with burns who required vascular access that cannot be achieved in a timely manner via another route. Drugs, fluid and blood can be given via this route and marrow aspirate drawn for laboratory analysis. It is a reliable, safe procedure with a low incidence of complications.
DNA from the bone marrow of a child with haemophagocytic lymphohistiocytosis was examined by polymerase chain reaction for evidence of rearrangement of the T-cell receptor delta chain gene. Evidence of clonal rearrangement was detected, supporting a role for abnormalities of T-cell function in the pathogenesis of this disorder.
The effects of epidermal growth factor (EGF), transforming growth factor alpha (TGF alpha), insulin-like growth factor (IGF) I and II, acidic fibroblast growth factor (FGF), tumour necrosis factor alpha (TNF alpha), macrophage inhibitory protein 1 alpha (MIP-1 alpha) (LD78), and TGF beta-1 on cell proliferation in the crypts of the small intestine of mice were investigated. Various doses and dosing regimens were tested. Three in vivo assays were developed, in each case involving detailed cell positional analysis of methyl tritiated thymidine labelling and mitotic activity. These allowed deductions to be made about the regions of the crypt and hence regions of the proliferative hierarchy (stem cells versus dividing transit cells) that are affected by treatment with growth factors. The assays involved: (1) normal untreated mice (an assay most likely to be effective for detecting inhibitors); (2) mice shortly after whole body irradiation when compensatory proliferation has been endogenously triggered (another assay for inhibitory factors, possibly ones associated specifically with the regenerative process); and (3) mice at late times (96 hours) after irradiation in the regression phase after a proliferative overshoot (an assay designed to detect stimulators). Little effect was seen after treatment with acidic FGF, TNF alpha, or MIP-1 alpha but EGF, IGF-I and II, and TGF alpha can all be seen to exert some stimulatory effects on labelling or mitosis. EGF and IGF-I stimulate both unirradiated mice and 96 hour recipients, while TGF alpha had a greater effect on the 96 hour animals. In all cases, multiple doses were used. TGF beta-1 was an effective inhibitor of proliferation in unirradiated and early regenerating (18 hour) animals. EGF was the most effective of the stimulators, raising the levels of proliferation at all positions in the crypt, but particularly in the upper crypt. IGF-I also exerted its effect predominantly in the upper crypt, while TGF alpha raised proliferation at all cell positions. TGF beta-1 tended to have its strongest inhibitory effects in the lower (stem cell) regions of the crypt.
A molecular analysis was carried out in 63 sequentially diagnosed childhood acute lymphoblastic leukemia (ALL) patients and 1011 controls to investigate the homozygosity rate for HLA-DR53. HLA-DR53 is associated with acute myeloblastic leukemia at the protein level, and our previous study has shown its association with early-onset chronic myeloid leukemia only in homozygous form at the DNA level. In the present study, the homozygosity rates for DR53 were 17.5 and 13.6% in patients and controls, respectively. Ten of the 11 homozygous patients were boys. In the common ALL group (n = 40), all seven DR53 homozygous patients were boys, and among 19 girls this genotype was not observed (P = 0.006). For males, homozygosity for DR53 revealed a relative risk (RR) of 3.29 (P = 0.008) for common ALL. Five of the 11 relapsed patients were homozygous for DR53. Heterozygous frequencies for HLA-DR53 were not different between patients and controls. Homozygosity for DR53 was associated with a very high relapse rate (45.5 vs 7.7%, P = 0.002, RR = 9.1). These results extended our findings in chronic myeloid leukemia and showed the recessive nature and the male predominance of the interactive HLA influence on the development of childhood leukemia. Molecular mimicry of an HLA-DR53 epitope by oncogenic (retro)viruses or putative susceptibility genes in linkage disequilibrium with HLA-DR53 may be responsible for this association.
Patients who have received cytotoxic therapy for primary neoplastic disease are at an increased risk of developing secondary (therapy-related) acute myeloid leukaemia (AML) or myelodysplasia (MDS). RAS and FMS mutations have been observed in patients with AML and MDS. It has been suggested that the mutational status within these genes may be predictive of early secondary leukaemic disease. In this study we have screened 50 haematologically normal patients in complete remission from childhood acute lymphoblastic leukaemia (ALL) for activating point mutations in the RAS and FMS proto-oncogenes. Such patients may be considered at risk of therapy-related disease. Codons 12, 13 and 61 were screened in RAS and codon 969 in FMS using the polymerase chain reaction (PCR) followed by oligonucleotide hybridization (ONH). Three of the 50 patients (6%) were found to harbour N12 RAS mutations. One of these three patients (2%) had both a N12 RAS and FMS 969 mutation. Upon sequencing the RAS mutations, substitutions of serine, cysteine and aspartic acid for glycine were identified. The FMS 969 mutation was also confirmed, by sequencing, as a histidine substitution. RAS mutations were not detected in presentation samples indicating that these lesions have been somatically acquired presumably subsequent to cytotoxic therapy for the primary disease. Continued follow-up of these patients may indicate a role for these mutations in the development of secondary malignancies.
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Pokeweed (Phytolacca americana) lectin was found to stain the secretory granules in epithelial Paneth cells of small intestine in mice and rats. The distribution of Paneth cells stained with this lectin was identical to that obtained by another immunohistochemical marker for lysozyme. However, in comparison with other immunohistochemical markers, Pokeweed lectin is a more robust method for identifying Paneth cells in histological sections and for studying their secretory granules. Co-expression of the Pokeweed lectin binding sites in some oligomucous cells within the crypts suggested a close developmental link between these two cell types. Only one other non-epithelial cell type was stained by this lectin, and these were migratory lymphocytes found within the villus epithelium and lamina propria. Approximately 20% of these lymphocyte cells were also positive for the expression of CD3+. Pokeweed lectin was therefore used to study changes in the frequency of Paneth cells and intra-epithelial lymphocytes in normal and immunologically compromised animals (following infection with a parasite worm Trichuris muris and in a model of graft-versus-host rejection). This study confirmed that the population of Paneth cells turns over slowly even during conditions of inflammation.
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Neuronal microtubule-associated proteins (MAPs) are important components of neurons and are believed to regulate neuronal function and development by controlling the assembly of microtubules and the interaction of microtubules with other cytoplasmic organelles. We studied the immunohistochemical localization of MAPs 1, 2, 5, and tau in the intestinal tissues of five patients with Hirschsprung's disease and in five normal controls using monoclonal antibodies. Microtubule-associated proteins 5 and tau proved to be excellent enteric neuronal markers; they were specifically located in the nerve cell bodies and processes of normal intestine as well as in the abnormal hypertrophied nerve fibers of aganglionic colon. Fine fibrillar structures in the neuroplasm were revealed in greater detail than were those obtained from studies with conventional markers, including neuron-specific enolase, S-100 protein, and neurofilament protein. A slight reduction of MAPs 5 and tau immunoreactivity was observed in the aganglionic colon compared with normal colon. Microtubule-associated proteins 1 and 2 were absent from the nerve fibers in both normal and aganglionic colon. This study suggests that immunostaining for MAPs 5 and tau may be superior to other immunohistochemical methods for diagnosing Hirschsprung's disease; however, in view of its limited retrospective nature these findings need to be corroborated by a large prospective evaluation.