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Biomedical subjects

S Lawson

Publications and source records attributed to S Lawson.

At least 19 recordsLinked to original sources
PubMed2007

Development of leiomyosarcoma of the uterus in MMTV-CR-1 transgenic mice.

Overexpression of Cripto-1 (CR-1) in FVB/N mice using the MMTV-LTR promoter results in increased mammary tumourigenesis in these female transgenic mice (MMTV-CR-1). Here, we characterize uterine tumours that developed in 15/76 (19.7%) of MMTV-CR-1 female nulliparous or multiparous mice during 24 months of observation compared with 0/33 (0%) of FVB/N normal control mice observed during the same time period (p < 0.01). The uterine tumours collected from the MMTV-CR-1 mice were classified as leiomyosarcomas and found to express the CR-1 transgene by polymerase chain reaction analysis and immunohistochemistry. Detection by western blot analysis showed higher levels of phosphorylated (P) forms of c-src, Akt, GSK-3beta, and dephosphorylated (DP)-beta-catenin in lysates from MMTV-CR-1 uterine leiomyosarcomas in comparison with lysates from normal control FVB/N uteri. Immunostaining showed increased nuclear localization of beta-catenin in the MMTV-CR-1 uterine leiomyosarcomas. Increased immunostaining for CR-1 was detected in 9/13 (69.2%) cases of human leiomyosarcoma compared with staining in 3/15 (20%) human leiomyoma sections. Stronger immunostaining for P-src, P-Akt, P-GSK-3beta and increased nuclear localization of beta-catenin was also seen in human leiomyosarcomas in comparison with leiomyomas. Normal human uterine smooth muscle (UtSM) cells treated with exogenous soluble rhCR-1 showed increased levels of P-src, P-Akt, P-GSK-3beta and dephosphorylated (DP)-beta-catenin and increased proliferation (p < 0.05) and migration (p < 0.01) in comparison with untreated control UtSM cells. Inhibitors against c-src, Akt or beta-catenin, individually or in combination, significantly reduced CR-1-induced migration. These results suggest a role for CR-1 during uterine tumourigenesis either directly by activating c-src and Akt and/or via cross-talk with the canonical Wnt signalling pathway, as suggested by the increased expression of P-GSK-3beta, DP-beta-catenin, and increased nuclear localization of beta-catenin in human and MMTV-CR-1 mice leiomyosarcomas.

Animals↗
PubMed2006

Risk factors for increased BTEX exposure in four Australian cities.

Benzene, toluene, ethylbenzene and xylenes (BTEX) are common volatile organic compounds (VOCs) found in urban airsheds. Elevated levels of VOCs have been reported in many airsheds at many locations, particularly those associated with industrial activity, wood heater use and heavy traffic. Exposure to some VOCs has been associated with health risks. There have been limited investigations into community exposures to BTEX using personal monitoring to elucidate the concentrations to which members of the community may be exposed and the main contributors to that exposure. In this cross sectional study we investigated BTEX exposure of 204 non-smoking, non-occupationally exposed people from four Australian cities. Each participant wore a passive BTEX sampler over 24h on five consecutive days in both winter and summer and completed an exposure source questionnaire for each season and a diary for each day of monitoring. The geometric mean (GM) and range of daily BTEX concentrations recorded for the study population were benzene 0.80 (0.04-23.8 ppb); toluene 2.83 (0.03-2120 ppb); ethylbenzene 0.49 (0.03-119 ppb); and xylenes 2.36 (0.04-697 ppb). A generalised linear model was used to investigate significant risk factors for increased BTEX exposure. Activities and locations found to increase personal exposure included vehicle repair and machinery use, refuelling of motor vehicles, being in an enclosed car park and time spent undertaking arts and crafts. A highly significant difference was found between the mean exposures in each of the four cities, which may be explained by differences in fuel composition, differences in the mix and density of industry, density of motor vehicles and air pollution meteorology.

Adult↗
PubMed2006

Increased acute GvHD and higher transplant-related mortality in non-caucasians undergoing standard sibling allogeneic stem cell transplantation.

We conducted a retrospective study to compare outcome in Caucasians and non-Caucasians undergoing standard sibling allogeneic SCT. End points of the study were to compare graft-versus-host disease (GvHD) occurrence and transplant-related mortality (TRM). There were 251 patients, 43 non-Caucasian and 208 Caucasian. A higher proportion of non-Caucasian patients developed acute GvHD (aGvHD) grade 2 or greater as compared to the Caucasian group (48 vs 26%, respectively) P = 0.02. With a median follow-up of 27 months, 26% (11/43) of non-Caucasians and 14% (29/208) of Caucasian patients had died from TRM, which accounted for 55% of all deaths in the non-Caucasian group compared to 33% in Caucasians, P = 0.02. Overall survival 12 months post transplant was 64 vs 69% in the non-Caucasian and Caucasian groups, respectively (P = 0.43). Although there were higher numbers of CMV-positive patients in the non-Caucasian group, there were no deaths from CMV reactivation in this subgroup. We conclude that there is increased TRM and aGvHD following standard sibling allograft in the non-Caucasian population and this could be due to either differences in tumour biology or extrinsic factors such as socio-economic factors, nutritional status, post transplant care or presenting with late stage disease.

Acute Disease↗
PubMed2005

Evaluation of hydrogen peroxide vapour as a method for the decontamination of surfaces contaminated with Clostridium botulinum spores.

The aim of this study was to evaluate the efficacy of hydrogen peroxide vapour (HPV) against spores of Clostridium botulinum, for use as a method for decontaminating environments where this pathogen has been handled. Spores were dried onto stainless steel slides and exposed to HPV in a sealed glovebox enclosure, transferred to a quenching agent at timed intervals during the exposure period, before survivors were cultured and enumerated. D-values were calculated from graphs of log10 survivors plotted against time and were found to range from 1.41 to 4.38 min. HPV was found to be effective at deactivating spores of toxigenic Cl. botulinum, non-toxigenic Clostridium spp. and Geobacillus stearothermophilus dried onto stainless steel surfaces. HPV could be used to decontaminate cabinets and rooms where Cl. botulinum has been handled. The cycle parameters should be based on studies carried out with relevant spores of this organism, rather than based on inactivation data for G. stearothermophilus spores, which have been used in the past as a standard biological challenge for disinfection and sterilisation procedures. HPV could provide an attractive alternative to other decontamination methods, as it was rapid, residue-free and did not give rise to the health and safety concerns associated with other gaseous decontamination systems.

Clostridium botulinum↗
PubMed2004

Atypical haemolytic uraemic syndrome as a complication of induction chemotherapy for acute lymphoblastic leukaemia.

This report describes a case of fatal haemolytic uraemic syndrome (HUS) developing in a child with acute lymphoblastic leukaemia (ALL) during induction chemotherapy. The aetiology in this case is uncertain but it may have resulted from treatment with L-asparaginase or vincristine. The possibility of HUS during induction chemotherapy for ALL should be considered early on in the treatment regimen, if clinical signs and symptoms suggest this diagnosis, so that appropriate treatment can be instituted.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Molecular analysis of single colonies reveals a diverse origin of initial clonal proliferation in B-precursor acute lymphoblastic leukemia that can precede the t(12;21) translocation.

The pathogenesis of pediatric B-precursor acute lymphoblastic leukemia is largely unknown, and even with nonrandom chromosomal translocations present, the precise order of clonal molecular events is undefined. We developed an in vitro system using cytokines interleukin (IL)-3, IL-7, IL-10, and FMS-like tyrosine kinase 3 ligand with CD40 ligand-expressing fibroblasts to obtain single blast colonies from which clonal immunoglobulin heavy chain (IgH), T-cell receptor delta gene rearrangements, and, in t(12;21)-positive cases, TEL-AML1 fusion transcripts could be simultaneously PCR amplified. The proliferation of early tumor progenitors increased subclone detection enabling us, in seven diagnostic samples, to determine the stage of differentiation at which each leukemia occurred. Four were derived from the stage before initiation of IgH rearrangement, one during recombination of variable, joining, and diversity segments of the heavy chain gene VDJ(H), and two after completion of IgH rearrangement. Furthermore, analysis of a t(12;21)-positive leukemia with unusually late onset, identified both TEL-AML1-positive and -negative colonies carrying a clonal T-cell receptor delta rearrangement, inferring the presence of clonal expansion before the occurrence of the t(12;21). In contrast, in a typical, early onset t(12;21)-positive leukemia, the t(12;21) appeared to be the first clonal event. In both leukemias, the t(12;21) occurred before recombination of variable, joining and diversity segments of the heavy chain gene VDJ.

B-Lymphocytes↗
PubMed2001

P300 event-related potential decrements in well-functioning university students with mild head injury.

We compared the performance of 10 well-functioning university students who had experienced a mild head injury (MHI) an average of 6.4 years previously and 12 controls on a series of standard psychometric tests of attention, memory, and thinking and on a series of auditory oddball vigilance tasks to which we also took event-related potentials (ERPs). The MHI and Control groups performed equivalently on all the psychometric tasks and on self-report questionnaires of everyday memory and attention difficulties. The MHI group performed more slowly and with lower accuracy on only the most difficult of the oddball tasks, yet they showed substantially and significantly reduced P300 amplitudes and subsequent attentuation on all the oddball tasks, both easy and difficult. There were no alterations of N1, P2, and N2 components. These data suggest that despite excellent behavioral recovery, subtle information processing deficits involving attention nevertheless may persist long after the original injury and may not be apparent on a variety of standard psychometric measures.

Cognition Disorders↗
PubMed2001

Turkey and chicken interferon-gamma, which share high sequence identity, are biologically cross-reactive.

Turkey and chicken interferon-gamma (IFN-gamma) share high identity (96.3% and 97% at the nucleotide and amino acid level, respectively). As such, we predicted that they would be functionally cross-reactive. To test this hypothesis, we produced recombinant turkey and chicken IFN-gamma, and compared their biological properties. Recombinant turkey and chicken IFN-gamma both induce HD11 cells (a chicken macrophage cell line) and LSTC-IAH30 cells (ALV-J-transformed turkey macrophages) to produce nitric oxide (NO), as measured in an avian IFN-gamma bioassay. Polyclonal and monoclonal antibodies, capable of neutralising the effect of chicken IFN-gamma on HD11 cells, were also shown to inhibit the activity of turkey IFN-gamma on these cells. The antibody neutralisation effect on both turkey and chicken IFN-gamma was shown by a significant reduction in NO production by HD11 cells when the neutralising antibodies were present in the bioassay. FACS analysis showed that HD11 and LSTC-IAH30 cells share some cell surface markers.

Animals↗
PubMed2001

Analysis of chimaerism in thalassaemic children undergoing stem cell transplantation.

We have prospectively assessed the relative contribution of host and donor to haemopoiesis following stem cell transplantation (SCT) in children with beta-thalassaemia major (n = 35), using karyotype analysis or Southern blot/polymerase chain reaction analysis of variable number tandem repeats on genomic DNA from peripheral blood. Early haemopoiesis was fully donor in origin in 24 out of 35 cases and remained so throughout the post-transplant course in all but one patient, who evolved to stable mixed chimaerism. The remaining 11 cases (31%) initially showed mixed chimaerism: four of these rejected, one eventually eradicated host haemopoiesis to become fully donor haemopoietic, and the remaining six had persistent mixed chimaerism, with 5--38% host haemopoiesis. The risk of graft rejection was high when > 15% host haemopoiesis was present at 3 months post transplant: four out of six such patients rejected their grafts; conversely, zero out of 29 patients with < 15% host haemopoiesis at 3 months rejected (P < 0.0001). There was a higher incidence of significant acute and chronic graft-versus-host disease in patients with full donor chimaerism. These studies confirm that the mixed chimaeric state is common following SCT for thalassaemia, often persists (with up to 4 years follow-up) and is compatible with long-term cure. Analysis of chimaerism in patients undergoing SCT for beta-thalassaemia enables monitoring of engraftment in the early post-transplant period, provides insight into the biology of engraftment and may be useful in identifying patients at high risk of rejection.

ABO Blood-Group System↗
PubMed2001

Protection of turkeys against Chlamydophila psittaci challenge by parenteral and mucosal inoculations and the effect of turkey interferon-gamma on genetic immunization.

Plasmid DNA (pcDNA1::MOMP A) expressing the major outer membrane protein of an avian Chlamydophila psittaci serovar A strain was tested for its ability to induce protective immunity against challenge with the same C. psittaci serovar. A combined parenteral (intramuscular injection) and mucosal route (DNA drops administered to the nares) of DNA inoculation was compared to three other, different routes of administration (intramuscular inoculation, DNA drops administered to the nares and aerosol immunization). In addition, the effect of turkey interferon gamma (tIFN-gamma) on intramuscular immunization was evaluated by co-expressing pCIneo::tIFN-gamma. A significant level of protection was observed in turkeys immunized via the combined parenteral/mucosal route, the intramuscular route or by aerosol. Severe clinical signs and lesions were observed in the non-vaccinated control groups, in 80% of turkeys inoculated with a mixture of pcDNA1::MOMP A and pCIneo::tIFN-gamma, and in 60% of turkeys vaccinated with DNA drops administered to the nares. The use of MOMP-based DNA vaccination as a means of preventing severe clinical signs and lesions in a turkey model of C. psittaci infection was demonstrated, as was down-regulation of the immune response by co-expression of tIFN-gamma.

Animals↗
PubMed2000

Comparison of allogeneic transplant versus chemotherapy for relapsed childhood acute lymphoblastic leukaemia in the MRC UKALL R1 trial. MRC Childhood Leukaemia Working Party.

BACKGROUND: Although reinduction rates are good for children with relapsed acute lymphoblastic leukaemia there is no consensus on whether bone marrow transplantation (BMT) is the most effective treatment to prolong second remission. PATIENTS AND METHODS: Analyses comparing the outcome of related donor allogeneic BMT (related allograft) with chemotherapy are unreliable because of selection biases. To avoid these biases, the MRC UKALL R1 trial was analysed by HLA-matched donor availability. RESULTS: No significant difference in outcome was found between the donor and no donor groups. The donor group had a non-significant eight-year event-free survival (EFS) advantage of 8%, (95% confidence interval -9%-24%) over the no donor group. Patients with a first remission less than two years appeared to benefit most from having a donor, although the effect was only marginally significantly different from patients with longer first remission. Analysis by treatment received gave similar results, with BMT patients having a 5% (P = 0.8) eight-year EFS advantage over patients who received chemotherapy. CONCLUSIONS: Related allograft was not found to be significantly better than chemotherapy, but there was the possibility of a moderate EFS benefit with related allograft. especially in patients with a short first remission.

Adolescent↗
PubMed2000

Turkey and chicken interleukin-2 cross-react in in vitro proliferation assays despite limited amino acid sequence identity.

We cloned the cDNA of turkey interleukin-2 (IL-2), initially using oligonucleotide primers based on the sequence of the chicken IL-2 gene. Compared with the only other cytokines available for comparison, the interferons (IFN), the coding regions of the turkey and chicken IL-2 genes are much less conserved (86.24% nucleotide identical and 69.93% amino acid identical). The lack of nucleotide conservation was spread across the entire length of the coding region. In comparison, the promoters of the two avian IL-2 genes shared a high degree of identity (95.71% identical over 380 nucleotides). Phylogenetic analysis shows that turkey and chicken IL-2 have diverged to a greater extent than IL-2 from closely related mammalian species. Surprisingly, considering the low level of amino acid identity, including residues known to be important in binding the IL-2 receptor in mammalian species, both turkey and chicken IL-2 cross-react in functional assays.

Amino Acid Sequence↗
PubMed2000

Impact of modifying priming components and fluid administration using miniaturized circuitry in neonatal cardiopulmonary bypass.

Following a succession of changes in circuitry and priming additives between 1993 and 1998, a comprehensive re-evaluation of neonatal cardiopulmonary bypass (CPB) practice was undertaken. Samples from 10 infants (Group 1) undergoing CPB were evaluated for osmolality, oncotic pressure, total protein, hematocrit, glucose, and electrolytes (Na+, K+, iCa2+). These samples were tested at six measurement points: (1) after priming, (2) patient pre-CPB, (3) CPB-start, (4) CPB-mid, (5) CPB-end, and (6) post-modified ultrafiltration (MUF). Prime volumes were also carefully measured as well as the type and amount of volume given during CPB. After evaluating the initial data, changes in protocol regarding mannitol, calcium correction, and oncotic strength on CPB were made. Following implementation of these protocol changes, a second set (Group 2) of 10 infants was identically evaluated. Group 1 prime osmolality was 379 +/- 44 mOsm/kg, while Group 2 prime osmolality was 324 +/- 14 mOsm/kg (p = 0.003). There were no differences in osmolality between groups during bypass and osmolality was unaffected by modified ultrafiltration. Ionized calcium levels were significantly different at the end of bypass between Group 1, 0.6 +/- 0.1 mmol/l; and Group 2, 1.17 +/- 0.24 mmol/l (p < 0.001). In Group 1, there was a 40% drop (p = 0.001) in colloid osmotic pressure (COP) levels from pre-CPB (13.3 +/- 3.4 mmHg) to CPB-end (8.8 +/- 1.2 mmHg). In Group 2, there were no differences in COP during CPB. COP levels of Group 1 and Group 2 at CPB-end were 8.8 +/- 1.2 mmHg and 14 +/- 1.9, respectively (p < 0.0001). Total volume addition during bypass for Group 1 was 363.5 +/- 148.7 ml and for Group 2 was 245.1 +/- 92.2 ml (p < 0.05). In conclusion, progressive changes in neonatal circuits and techniques can have potentially wide-ranging effects on electrolyte and osmotic/oncotic homeostasis. An audit of perfusion management through expanded laboratory tests is recommended, especially in periods of change.

Blood Substitutes↗