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Biomedical subjects

P Dobson

Publications and source records attributed to P Dobson.

At least 19 recordsLinked to original sources

Txp40, a ubiquitous insecticidal toxin protein from Xenorhabdus and Photorhabdus bacteria.

Xenorhabdus and Photorhabdus are gram-negative bacteria that produce a range of proteins that are toxic to insects. We recently identified a novel 42-kDa protein from Xenorhabdus nematophila that was lethal to the larvae of insects such as Galleria mellonella and Helicoverpa armigera when it was injected at doses of 30 to 40 ng/g larvae. In the present work, the toxin gene txp40 was identified in another 59 strains of Xenorhabdus and Photorhabdus, indicating that it is both highly conserved and widespread among these bacteria. Recombinant toxin protein was shown to be active against a variety of insect species by direct injection into the larvae of the lepidopteran species G. mellonella, H. armigera, and Plodia interpunctella and the dipteran species Lucilia cuprina. The protein exhibited significant cytotoxicity against two dipteran cell lines and two lepidopteran cell lines but not against a mammalian cell line. Histological data from H. armigera larvae into which the toxin was injected suggested that the primary site of action of the toxin is the midgut, although some damage to the fat body was also observed.

Animals↗

Anthocyanins from red wine--their stability under simulated gastrointestinal digestion.

The stability of anthocyanins from red wine was assessed using an in vitro digestion system that simulated the physiochemical changes that occur in the upper gastrointestinal tract. Anthocyanins in red wine were stable to gastric conditions whereas there was a small loss in total phenol content. After pancreatic digestion, the total anthocyanins were very poorly recovered compared to the bulk phenols in the IN sample, which was previously described as the "serum-available" fraction, and the majority of the anthocyanins and phenols were recovered in the OUT fraction, previously described as the "colon-available" fraction. Removing alcohol from the wine samples prior to the procedure did not markedly affect this pattern. The composition of anthocyanins in the post gastric, IN and OUT samples was analysed using liquid chromatography mass-spectrometry. The red wine used contained over 20 identifiable anthocyanins of which the main components were 3-O-glucosides of malvidin, peonidin, petundin, delphidin and cyanidin. Coumaroylated-glucoside derivatives of malvidin, petundin, peonidin, and delphinidin were observed and acetylated glucosides of peonidin, petundin and malvidin were also identified. Anthocyanins with modified aglycones similar to vitisin A derivatives of delphinidin, peonidin, petunidin and malvidin were also identified. After the in vitro digestion procedure, only five anthocyanins could be detected in the IN (serum-available) and the OUT (colon-available) fractions, which were confirmed as malvidin-3-O-glucoside and the vitisin A adducts of malvidin-3-O-glucoside, malvidin-3-O-acetylglucoside, malvidin-3-O-coumaroylglucoside and peonidin-3-O-glucoside. Malvidin-3-O-glucoside was recovered at 0.2% in the IN fraction and 0.9% in the OUT fraction. However, the vitisin derivatives were much more stable to pancreatic digestion. Assuming that the vitisin A derivatives display similar biological properties to their parent anthocyanins, their enhanced gastrointestinal stability could lead to enhanced bioavailability and bio-effectiveness in vivo.

Anthocyanins↗

An isolated osteochondroma with underlying non-Hodgkin's lymphoma of bone.

Osteochondroma is the most common benign bone tumour. The risk of sarcomatous change in an isolated lesion is approximately 1%. We report a case of an isolated osteochondroma which appeared benign on clinical and plain radiographic examination but routine histological analysis revealed non-Hodgkin's lymphoma in the underlying bone. This association has not previously been reported and the case emphasises the importance of routine histological analysis, even if a lesion appears benign.

Adult↗

Impact of hydroxychloroquine therapy on chronic urticaria: chronic autoimmune urticaria study and evaluation.

BACKGROUND: Chronic urticaria (CU) imposes profound impairment on quality of life. Up to 60% of idiopathic CU is associated with autoimmune phenomena, and may respond to immunomodulation. Hydroxychloroquine offers potential efficacy for CU and is relatively benign compared with most other therapeutic approaches. OBJECTIVE: The aim of the chronic autoimmune urticaria study and evaluation was to evaluate the efficacy of hydroxychloroquine in patients with chronic idiopathic urticaria. METHODS: Twenty-one patients referred to the Immunology and Allergy Unit at John Hunter Hospital, New South Wales, Australia, with idiopathic CU were randomised to receive treatment with standard urticaria therapies (corticosteroids, H2-antihistamines, H1--antihistamines, doxepin) with or without hydroxychloroquine. Markers of autoimmunity, thyroid disease and mast-cell autoreactivity (autologous serum skin-prick testing (ASPT)) were assessed. Measures of urticaria control were compared at baseline and at 12 weeks for the 18 individuals who completed the study. These included urticaria scores, medication scores and quality-of-life indices. RESULTS: The hydroxychloroquine-treated group achieved significant improvements in quality of life as assessed by the global symptom severity score and the LAMY-7 (a quality of life index designed by Lamy, 7th revision) at 12 weeks (P < 0.01 and P < 0.05, respectively). No significant treatment effect on medication requirements or urticaria score was detected, although differences between treatment groups approached statistical significance for urticaria score and medication requirements (0.05 < P < 0.10). ASPT-reactivity did not correlate to hydroxychloroquine-responsiveness. Hydroxychloroquine was well tolerated. CONCLUSION: Immunomodulation with hydroxychloroquine is safe and appears to offer some efficacy as an intervention in CU.

Adult↗

Efficacy of nitenpyram as a systemic flea adulticide in dogs and cats.

In a clinical trial involving 123 cats and 88 dogs, the efficacy of tablets containing nitenpyram against natural flea infestations was investigated. The animals were selected from the routine cases of nine veterinary clinics in the UK and 143 were treated with the tablets and 68 control animals were treated with placebo tablets. Each animal was maintained in an individual cage. The time when the first fleas fell off each animal was recorded between 30 minutes and five hours after treatment, and six hours after treatment the numbers of live, moribund or dead fleas on each animal were determined, and the flea survival rate was calculated. The drug's efficacy was assessed by comparing the mean survival rates of fleas on the treated and control animals. Fleas started to fall from the animals 30 minutes after treatment and two hours after treatment some fleas had detached from 81 per cent of the treated animals. After six hours the efficacy of the drug reached 96.7 per cent on dogs and 95.2 per cent on cats, and 85.9 per cent of the fleas were found off the treated animals, compared with 1.8 per cent in the controls. No adverse drug reactions were recorded during the trial.

Animals↗

The efficacy of autologous blood transfusion in bilateral total knee arthroplasty.

A controlled, randomised, prospective study was undertaken to assess the efficacy of the use of a blood re-infusion device in the reduction of allogenic blood requirements of patients undergoing bilateral simultaneous total knee replacements. Thirty-three consecutive patients were randomised to receive allogenic blood only, or a combination of collected and re-infused blood. An average of 1000 ml of drainage blood was salvaged in the study group, resulting in a significant reduction in allogenic blood requirements from 6.3 to 3.8 units in total (P value=0.002). No patients suffered transfusion reactions. We conclude that autologous re-infusion is a safe and effective method of reducing allogenic blood requirements, and as a result, reducing the risks of transmission of infection, and the rate of post-operative infection.

Journal Article↗

Enuresis treatment in the UK.

The Enuresis Resource and Information Centre (ERIC) is a UK-based charity that works with parents, carers, professionals, and children with nocturnal enuresis (NE). The charity has recently commissioned York University's centre for reviews and dissemination to undertake a detailed analysis of studies that measure the effectiveness of the most common psychological and pharmacological treatments for NE. This included reviewing 960 research articles from around the world. The resulting review will direct thinking in the UK towards the most effective treatment approaches. A brief summary presented at conferences in addition to data from ERIC's own clinical practice database shows the distribution and type of enuresis clinic currently being run within the UK.

Child↗

Constitutive activation of a slowly migrating isoform of Stat3 in mycosis fungoides: tyrphostin AG490 inhibits Stat3 activation and growth of mycosis fungoides tumor cell lines.

Mycosis fungoides (MF) is a low-grade cutaneous T cell lymphoma of unknown etiology. In this report, the Jak/Stat (Janus kinase/signal transducer and activator of transcription) signaling pathway was investigated in tumor cell lines established from skin biopsy specimens from a patient with MF. Jaks link cytokine receptors to Stats, and abnormal Jak/Stat signaling has been observed in some hemopoietic cancers. In MF tumor cells, a slowly migrating isoform of Stat3, Stat3(sm), was found to be constitutively activated, i.e., (i) Stat3(sm) was constitutively phosphorylated on tyrosine residues, and tyrosine phosphorylation was not enhanced by growth factor stimulation; (ii) band shift assays and immunoprecipitations of DNA/Stat complexes showed constitutive DNA-binding properties of Stat3(sm); and (iii) Stat3(sm) was constitutively associated with Jak3. The abnormal activation of Stat3(sm) was highly specific. Thus, neither the fast migrating isoform of Stat3 (Stat3(fm)) nor other Stats (Stat1, Stat2, and Stat4 through Stat6) were constitutively activated. The Jak kinase inhibitor, tyrphostin AG490, blocked the constitutive activation of Stat3(sm) and inhibited spontaneous as well as interleukin 2-induced growth of MF tumor cells. In conclusion, we have provided evidence for an abnormal Jak/Stat signaling and growth regulation in tumor cells obtained from affected skin of an MF patient.

Cell Division↗

Protein phosphatase 2A plays a critical role in interleukin-2-induced beta 2-integrin dependent homotypic adhesion in human CD4+ T cell lines.

Besides its function as a growth factor for T lymphocytes, interleukin 2 (IL-2) induces beta 2-integrin mediated adhesion, migration, and extravasation of T lymphocytes. It is, however, largely unknown how IL-2 receptors (IL-2R) are coupled to the beta 2-integrin adhesion pathway. Because IL-2 modulates enzymatic activity and/or subcellular distribution of serine/threonine phosphatases 1 and 2A (PP1/PP2A) in T cells, we examined the role of these phosphatases in IL-2 induced homotypic adhesion in antigen specific human CD4+ T cell lines. We show that calyculin A, a potent inhibitor of PP1 and PP2A, blocks PP1/PP2A activity and IL-2 induced adhesion, whereas cyclosporin A, an inhibitor of protein serine/threonine phosphatase 2B (PP2B), does not, suggesting that PP1 and/or PP2A are involved in IL-2 induced adhesion. Endothall, which preferentially inhibits PP2A, strongly inhibited cytokine induced adhesion, whereas the structurally related compound 1,4-dimethylendothall had no effect on either phosphatase activity or the adhesion response. Okadaic acid, which preferentially inhibits PP2A, almost completely blocked IL-2-induced adhesion, whereas tautomycin, a potent inhibitor of PP1, had no inhibitory effect on cytokine induced adhesion at concentrations which strongly inhibited phosphatase activity. In conclusion, these data provide evidence that PP2A plays a critical role in IL-2-induced beta 2-integrin-dependent adhesion of human T cell lines.

CD18 Antigens↗

Interleukin 2 induces a transient downregulation of protein phosphatase 1 and 2A activity in human T cells.

Stimulation of human CD4+ T cell lines with interleukin 2 (IL-2) induces tyrosine, serine and threonine phosphorylation of a series of proteins involved in the IL-2 receptor (IL-2R) signaling pathway. Here, we examined whether IL-2 induces changes in the activity of protein serine/threonine phosphatases in antigen specific, CD4+ human T cell lines. Using inhibitors of protein phosphatases 1 (PP1, PP2A, and PP2B, we provide evidence, that IL-2 induces a downregulation of PP activity in the cytoplasmic/membrane fraction. Thus, IL-2R ligation for 30 min triggers a 16 percent decrease in total PP2A activity (p < 0.0005, n = 17) and a seven percent decrease in PP1 activity (p < 0.00005, n = 17). Cytokine-induced downregulation of PP2A activity reaches a maximum 60 min after IL-2R ligation, and returns to baseline levels within two hours. Downregulation of PPI activity reaches a maximum after 30 min and is largely reversed one hour after IL-2 stimulation. As determined from immunoblotting experiments using a specific anti-PP1 or anti-PP2A antibody, the amount of PPI and PP2A recovered from cytosolic/membrane fraction remains unchanged after IL-2 treatment suggesting that the drop in PP1/PP2A activity might be due to a regulatory change rather than to a change in the amount of PP1 and PP2A. In conclusion, we provide evidence, for the first time, that IL-2 induces a transient downregulation of PP2A activity in T cells. In addition, our findings indicate that cytoplasmic PP1 activity is transiently downregulated following IL-2R ligation in antigen-specific, human CD4+ T cells.

CD4-Positive T-Lymphocytes↗

IL-2 induces beta2-integrin adhesion via a wortmannin/LY294002-sensitive, rapamycin-resistant pathway. Phosphorylation of a 125-kilodalton protein correlates with induction of adhesion, but not mitogenesis.

Besides its function as a growth factor, IL-2 induces beta2-integrin-dependent, homotypic adhesion of IL-2R-positive T cells. In this study, we investigated how IL-2R are functionally and biochemically linked to the beta2-integrin adhesion pathway. After a lag period of 15 to 20 min, IL-2 induces beta2-integrin-dependent, homotypic adhesion in Ag-specific, human T cell lines. The IL-2 adhesion response is blocked by wortmannin and LY294002, inhibitors of phosphatidylinositol-3 (PI-3) kinase activity. In contrast, rapamycin strongly inhibits IL-2-induced proliferation without inhibiting IL-2-induced adhesion. Herbimycin A and genestein, inhibitors of protein tyrosine kinases, inhibit cytokine-induced adhesion and mitogenesis in parallel, whereas cytochalasin E, an inhibitor of actin polymerization, almost completely blocks the adhesion response at concentrations that have little effect on mitogenesis. IL-2R ligation rapidly (<5 min) induces tyrosine phosphorylation of several proteins, the most prominent being signal transducer and activator of transcription (Stat) proteins, the p85 subunit of the PI-3 kinase, and an as yet unidentified 125-kDa protein (p125). Wortmannin, LY294002, and cytochalasin E almost completely inhibit cytokine-induced tyrosine phosphorylation of p125, whereas tyrosine phosphorylation of PI-3 kinase, Janus kinases, Stat3, Stat5, and other proteins is unaffected. In contrast, rapamycin has little effect on IL-2-induced phosphorylation of p125. Taken together, these data suggest that 1) IL-2R ligation induces homotypic adhesion through a wortmannin/LY294002-sensitive, rapamycin-resistant pathway, 2) tyrosine kinases play a critical role in cytokine-induced adhesion, and 3) adhesion, but not mitogenesis, correlates with enhanced tyrosine phosphorylation of an as yet unidentified protein of 125 kDa.

CD18 Antigens↗

Advanced maternal age and smoking: risk factors for admission to a neonatal intensive care unit.

The aim of this study was to assess if advanced maternal age and cigarette smoking increased the requirement for admission to the neonatal intensive care unit (NICU) and if those factors acted synergistically. Retrospective analysis was made of 3518 singleton pregnancies receiving antenatal care and delivering at King's College Hospital from 1 January 1992 to 31 December 1992. The maternal age was greater than 35 years in 356 women (10.1% of the total) and 49 (13.8%) of those were cigarette smokers. There was an inverse relationship between maternal age and smoking. Two hundred and fifty-nine infants were admitted to the NICU. Logistic regression analysis revealed a significant relationship between maternal age and admission (p < 0.05), but no independent effect of maternal smoking. The proportion of infants from smoking mothers of advanced age (> 35 years) admitted to the NICU, however, was greater than that from young (< or = 35 years) smoking mothers (p < 0.05). Advanced maternal age does increase the requirement for NICU admission and this effect is enhanced by smoking.

Adolescent↗