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Biomedical subjects

S Poole

Publications and source records attributed to S Poole.

At least 73 records · Page 4Linked to original sources
PubMed1998

E-cadherin/catenin complex in benign and malignant melanocytic lesions.

E-cadherin is a calcium-dependent cell-cell adhesion molecule expressed by melanocytes and responsible for their adhesion to keratinocytes in vitro. In this study, the expression of E-cadherin and its associated cytoplasmic proteins alpha-, beta-, and gamma-catenin was evaluated in melanocytic lesions by immunohistochemistry. E-cadherin expression was evaluated in 70 malignant melanomas and the catenins in 35 of these specimens. Twenty benign melanocytic naevi were also evaluated for E-cadherin and catenin expression. In normal epidermis, E-cadherin/catenin immunostaining was localized at the intercellular borders. In melanomas, a differential loss of E-cadherin expression was observed. Membranous E-cadherin staining was absent in dermal nests of melanomas in their radial growth phase and in Clark level II and III lesions, whereas it was present in a high proportion of melanomas in their vertical growth phase, in Clark level IV and V lesions and in metastasizing melanomas. In contrast, superficial compartments of naevi showed membranous E-cadherin immunoreactivity and junctional naevus cell nests displayed heterogeneous or diffuse cytoplasmic staining. Cytoplasmic alpha- and beta-catenin, but not gamma-catenin staining were detected in all benign and malignant lesions. These findings indicate that qualitative changes in the expression and cellular localization of E-cadherin and of alpha-, beta-, and gamma-catenin occur in melanocytic lesions and may reflect different stages in their progression.

Adult↗
PubMed1998

Cytokine degradation by biofilms of Porphyromonas gingivalis.

The aim of this study was to determine whether biofilms of Porphyromonas gingivalis could proteolytically degrade the cytokines interleukin (IL)-1beta, IL-6, or IL-1 receptor antagonist (IL-1ra). Biofilms were grown on membrane filters on the surface of Wilkins-Chalgren blood agar. The biofilms were removed from the plates, and solutions containing 2.5 microg/ml of each cytokine were added. Following incubation for up to 4.0 h, supernatants from the biofilms were subjected to SDS-PAGE. The separated proteins were transferred by Western blotting to PVDF membranes and probed with peroxidase-conjugated antibodies recognizing both the intact cytokines and their degradation products. After 2 h, no intact IL-1beta, IL-6, or IL-1ra were detectable. Cytokine proteolysis also occurred in the presence of horse serum. These results demonstrate that biofilm-grown P. gingivalis can degrade both pro- and anti-inflammatory cytokines and so may be able to perturb cytokine networks in vivo by eliminating cytokines from the local environment.

Biofilms↗
PubMed1998

p53 mutation is a poor prognostic indicator for survival in patients with hepatocellular carcinoma undergoing surgical tumour ablation.

Forty-two patients with hepatocellular carcinoma (HCC) were resected and their tumours were analysed for p53 mutations by GC-clamped denaturing gradient gel electrophoresis (DGGE), single-strand conformation polymorphism (SSCP) and gene sequencing. All the exons have been analysed in this study. Eight of 12 HCCs with cirrhosis due to viral hepatitis and the two patients with sarcomatoid changes displayed p53 mutations. In contrast, no mutation was observed in the fibrolamellar variant (n = 9), non-cirrhotics (n = 13) and alcoholic cirrhosis (n = 6). The mutations observed were in exons 5-8. Two mutations were observed in codons 136 and 213 as well as a T insertion between residues 156 and 157 (exon 5) and these are reported for the first time in HCC. Likewise, the silent mutation polymorphism in codon 213 was noticed in 3 of the 42 patients. Survival analysis of these patients after surgery showed the mean and median survival in patients with wild-type p53 to be 60 and 43 months respectively. In the group with p53 mutations, the mean and median survival was 15 and 12 months. The difference was statistically significant (P= 0.003).

Adolescent↗
PubMed1998

Development of an instrument to assess stress levels and quality of life in children with asthma.

The purpose of this study was to develop and evaluate a new instrument, About My Asthma (AMA), to assess stressors affecting quality of life in children with asthma. The AMA is a 55-item, 4-point Likert-type scale. Concurrent validity was established by comparing the AMA with the Pediatric Asthma Quality of Life Questionnaire (PAQLQ). Increased levels of stress measured by the AMA correlated with a decreased quality of life measured by the PAQLQ. We conclude that the AMA is a valid and reliable instrument to measure the quantity and type of stressors experienced by children who have asthma.

Asthma↗
PubMed1998

Biological activity and brain actions of recombinant rat interleukin-1alpha and interleukin-1beta.

IL-1alpha and IL-1beta have potent effects on the central nervous system resulting in fever, activation of the hypothalamic-pituitary-adrenal axis and behavioural depression. These effects have mainly been studied in rats, using recombinant human and mouse IL-1. Because IL-1alpha and IL-1beta show some species specificity in the potency of their biological activities, the objective of the present work was to directly compare the effects of recombinant rat IL-1alpha and IL-1beta in the rat system as a first step to dissect out the mechanisms that are involved in these effects. In vitro, recombinant rat IL-1alpha and IL-1beta bound with the same affinity as human IL-1 to the rat insulinoma Rin m5F cell line that mainly expresses type I IL-1 receptors. This binding activated IL-1 receptors, as shown by induction of the synthesis of TNF-alpha mRNA. In vivo, recombinant rat IL-1alpha and IL-1beta enhanced body temperature, increased plasma levels of corticosterone and ACTH, and depressed social behaviour. All these effects were obtained at doses 100-1,000 fold lower when IL-1 was injected centrally than when it was administered peripherally, indicating that they are centrally mediated. The relative potencies of recombinant rat IL-1alpha and IL-1beta were not the same depending on the endpoint and the route of injection, indicating that different mechanisms are likely to be involved in the various effects of IL-1 on the brain.

Animals↗
PubMed1997

Abnormal immunoreactivity of the E-cadherin-catenin complex in gastric carcinoma: relationship with patient survival.

BACKGROUND & AIMS: The E-cadherin-catenin complex plays a critical role in the maintenance of normal tissue architecture. Mutation of any of its components is believed to result in loss of cell-cell adhesion and contribute to neoplasia. The aim of this study was to examine the expression of E-cadherin and alpha-, beta-, and gamma-catenin in gastric carcinoma and dysplasia and determine any relationship with tumor characteristics and survival. METHODS: Immunoperoxidase staining of E-cadherin and alpha-, beta-, and gamma-catenin was performed using 89 gastric carcinomas, lymph node metastases, and gastric biopsy specimens from 14 patients with dysplasia and 10 healthy controls. RESULTS: Membranous staining was observed in control biopsy specimens for all components of the complex. Up to 57% of gastric dysplasia and 90% of tumors stained abnormally for one or more components of the cadherin-catenin complex. Abnormal E-cadherin and gamma-catenin staining occurred more frequently in diffuse than intestinal tumors (P < 0.0005 and < 0.05, respectively). No association with tumor grade or stage was found. A survival advantage was noted in intestinal and diffuse tumors retaining membranous expression of beta-catenin, independent of tumor type, grade, or stage (P < 0.005). CONCLUSIONS: Abnormal expression of the E-cadherin-catenin complex occurs frequently in gastric carcinoma. The close correlation with poor survival suggests that abnormal beta-catenin may be a useful prognostic marker.

Adult↗
PubMed1997

Hyperalgesia induced by low doses of thymulin injections: possible involvement of prostaglandin E2.

Thymulin injection into rats (20-150 ng) i.p. caused a significant reduction in both mechanical (paw pressure test) and thermal (hot plate and tail flick tests) nociceptive thresholds. Thymulin injection also doubled IL-1beta level in the liver of these animals. Induced hyperalgesia was reversed completely by alpha-MSH related tripeptide, Lys-D-Pro-Val in low doses, which is known to antagonize IL-1beta and PGE2 induced hyperalgesia, but was only partly reversed by IL-1beta related tripeptide, Lys-D-Pro-Thr at high doses, which is known to antagonize IL-1beta induced hyperalgesia only. We conclude from these results that thymulin causes hyperalgesia and that this effect is at least in part mediated via PGE2 and its effectiveness at low concentration implies a physiological role for this thymic hormone.

Animals↗
PubMed1997

Cytokines, nerve growth factor and inflammatory hyperalgesia: the contribution of tumour necrosis factor alpha.

1. Peripheral inflammation is characterized by heightened pain sensitivity. This hyperalgesia is the consequence of the release of inflammatory mediators, cytokines and growth factors. A key participant is the induction of the neurotrophin nerve growth factor (NGF) by interleukin-1 beta (IL-1 beta). 2. Tumour necrosis factor alpha (TNF alpha) has been shown both to produce hyperalgesia and to upregulate IL-1 beta. We have now examined whether the induction of TNF alpha in inflammatory lesions contributes to inflammatory sensory hypersensitivity by inducing IL-1 beta and NGF. 3. The intraplantar injection of complete Freund's adjuvant (CFA) in adult rats produced a localized inflammation of the hindpaw with a rapid (3 h) reduction in withdrawal time in the hot plate test and in the mechanical threshold for eliciting the flexion withdrawal reflex. 4. The CFA-induced inflammation resulted in significant elevation in the levels of TNF alpha, IL-1 beta and NGF in the inflamed paw. In the case of TNF alpha, an elevation was detected at 3 h, rose substantially at 6 h, peaked at 24 h and remained elevated at 5 days, with similar but smaller changes in the contralateral non-inflamed hindpaw. No increase in serum TNF alpha was detected at 24 h post CFA injection. 5. Intraplantar recombinant murine TNF alpha injections produce a short-lived (3-6 h) dose-dependent (50-500 ng) increase in thermal and mechanical sensitivity which was significantly attenuated by prior administration of anti-NGF antiserum. 6. Intraplantar TNF alpha (100-500 ng) also elevated at 6 but not 48 h the levels of IL-1 beta and NGF in the hindpaw. 7. A single injection of anti-TNF alpha antiserum, 1 h before the CFA, at a dose sufficient to reduce the effects of a 100 ng intraplantar injection of TNF alpha, significantly delayed the onset of the resultant inflammatory hyperalgesia and reduced IL-1 beta but not NGF levels measured at 24 h. 8. The elevation of TNF alpha in inflammation, by virtue of its capacity to induce IL-1 beta and NGF, may contribute to the initiation of inflammatory hyperalgesia.

Animals↗
PubMed1997

Role of lipocortin-1 in the anti-hyperalgesic actions of dexamethasone.

1. The effect of dexamethasone, lipocorton-1(2-26) and an antiserum to lipocortin-1(2-26) (LCPS1) upon the hyperalgesic activities in rats of carrageenin, bradykinin, tumour necrosis factor alpha (TNF alpha), interleukin-1(2), interleukin-6 (IL-6), interleukin-8 (IL-8), prostaglandin E beta (PGE2) and dopamine were investigated in a model of mechanical hyperalgesia. 2. Hyperalgesic responses to intraplantar (i.pl.) injections of carrageenin (100 micrograms), bradykinin (500 ng), TNF alpha (2.5 pg), IL-1 beta (0.5 pg), and IL-6 (1.0 ng), but not responses to IL-8 (0.1 ng), PGE2 (100 ng) and dopamine (10 micrograms), were inhibited by pretreatment with dexamethasone (0.5 mg kg-1, subcutaneously, s.c., or 0.04-5.0 micrograms/paw). 3. Inhibition of hyperalgesic responses to injections (i.pl.) of bradykinin (500 ng) and IL-1 beta (0.5 pg) by dexamethasone (0.5 mg kg-1, s.c.) was reversed by LCPS1 (0.5 ml kg-1, injected s.c., 24 h and 1 h before hyperalgesic substances) and hyperalgesic responses to injections (i.pl.) of bradykinin (500 ng), TNF alpha (2.5 pg) and IL-1 beta (0.5 pg), but not responses to PGE2 (100 ng), were inhibited by pretreatment with lipocortin-1(2-26) (100 micrograms/paw). Also, lipocortin-1(2-26) (30 and 100 micrograms ml-1 and dexamethasone (10 micrograms ml-1) inhibited TNF alpha release by cells of the J774 (murine macrophage-like) cell-line stimulated with LPS (3 micrograms ml-1), and LCPS1 partially reversed the inhibition by dexamethasone. These data are consistent with an important role for endogenous lipocortin-1(2-26) in mediating the anti-hyperalgesic effect of dexamethasone, with inhibiton of TNF alpha production by lipocortin-1(2-26) contributing, in part, to this role. 4. Although arachidonic acid by itself was not hyperalgesic, the hyperalgesic response to IL-1 beta (0.25 pg, i.pl.) was potentiated by arachidonic acid (50 micrograms) and the potentiated response was inhibited by dexamethasone (50 micrograms, i.pl.) and lipocortin-1(2-26) (100 micrograms, i.pl.). Also, lipocortin-1(2-26) (30 and 100 micrograms ml-1) inhibited/abolished PGE2 release by J774 cells stimulated with LPS (3 micrograms ml-1). These data suggest that, in inflammatory hyperalgesia, inhibition of the induction of cyclo-oxygenase 2 (COX-2), rather than phospholipase A2, by dexamethasone and lipocortin-1(2-26) accounts for the anti-hyperalgesic effects of these agents. 5. The above data support the notion that induction of lipocortin by dexamethasone plays a major role in the inhibition by dexamethasone of inflammatory hyperalgesia evoked by carrageenin, bradykinin and the cytokines TNF alpha, IL-1 beta and IL-6, and provides additional evidence that the biological activity of lipocortin resides within the peptide lipocortin-1(2-26). Further, the data suggest that inhibition of lipocortin-1(2-26) of eicosanoid production by COX-2 also contributes to the anti-hyperalgesic effect of lipocortin-1.

Animals↗
PubMed1997

Staphylococcus epidermidis produces a cell-associated proteinaceous fraction which causes bone resorption by a prostanoid-independent mechanism: relevance to the treatment of infected orthopaedic implants.

Staphylococcus epidermidis is the most commonly isolated coagulase-negative staphylococcus from the skin, gut and upper respiratory tract. Although it is less virulent than Staphylococcus aureus, it has emerged in recent years as an important causative agent of infections associated with metal implants, prosthetic devices and i.v. lines. We have previously demonstrated that a saline wash of S. aureus contained proteins which had potent bone-resorbing activity in vitro. The purpose of this study was to determine whether gently washing S. epidermidis in saline also released osteolytically active proteins. The so-called surface-associated material (SAM) eluted from S. epidermidis in saline was able to induce osteolysis, and activity was heat and trypsin sensitive, suggesting that the active component was proteinaceous. Fractionation studies have suggested that activity is due to a small number of cationic proteins. This SAM-induced bone resorption was not inhibited by the cyclo-oxygenase inhibitor, indomethacin, or the 5-lipoxygenase inhibitors BWA70C and MK886. However, it was partially inhibited by high concentrations of interleukin-1 receptor antagonist and was completely blocked by a neutralizing antibody to tumour necrosis factor-alpha. Thus, the SAM from this organism is a potent osteolytic agent which differs from that of S. aureus SAM in not being inhibited by cyclo-oxygenase inhibitors. As adjunctive therapy is becoming necessary in infectious diseases, either as a result of the side-effects of antibiotics or their lack of efficacy, consideration should be given to the future treatment of bone infections with staphylococci in the light of the different mechanisms of action of the surface proteins produced by these bacteria.

Animals↗
PubMed1997

Ileal endometriosis masquerading as Crohn's ileitis.

Endometriosis is usually confined to the pelvis but may involve distant organs. When the small bowel is affected, endometriosis has a propensity to develop in the distal ileum, which may lead to fibrosis and stricture formation that can be confused with Crohn's disease. Here were describe two women, one with antecedent Crohn's colitis in whom ileal endometriosis mimicked obstructing Crohn's disease of the terminal ileum. These reports illustrate that ileal endometriosis must be considered in the differential diagnosis of Crohn's disease of the ileum, even in the presence of Crohn's disease elsewhere in the gastrointestinal tract.

Adult↗
PubMed1997

Interactions between periodontopathogenic bacteria and cytokines.

Cytokines produced in response to plaque bacteria clearly play a key role in the periodontal diseases. However, we know very little about the interactions between cytokines and periodontopathogenic bacteria. The aims of this study were to determine whether the key pro-inflammatory cytokines interleukin-1 beta (IL-1 beta) and IL-6 could affect the growth of Actinobacillus actinomycetemcomitans or Porphyromonas gingivalis and to determine whether these organisms could hydrolyse IL-1 beta, IL-6 or the anti-inflammatory IL-1 receptor antagonist (IL-1ra). Culture medium containing up to 100 ng/ml of IL-1 beta or IL-6 was inoculated with A. actinomycetemcomitans (serotypes a, b and c) or P. gingivalis and growth was monitored by measuring changes in electrical conductivity every 3 min for up to 48 h. IL-1 beta, IL-6 or IL-1ra were added to culture supernatants and incubated for up to 24 h. Samples were taken at various times, analysed by SDS-PAGE and the separated proteins transferred by Western blotting to PVDF membranes and probed with anti-cytokine antibodies. None of the cytokines tested had any effect on the rate of growth or yield of A. actinomycetemcomitans or P. gingivalis. Supernatants from P. gingivalis cultures, but not those from A. actinomycetemcomitans, hydrolysed IL-1 beta, IL-6 and IL-1ra. The hydrolysate from the P. gingivalis supernatant-treated IL-1 beta was unable to stimulate the release of IL-6 from human gingival fibroblasts showing that it had lost biological activity. These results suggest that P. gingivalis can perturb the cytokine network, not only by stimulating the release of cytokines from host cells, but also by removing them from its local environment.

Aggregatibacter actinomycetemcomitans↗
PubMed1997

Role of circulating endotoxin and interleukin-6 in the ACTH and corticosterone response to intraperitoneal LPS.

Peripheral administration of lipopolysaccharide (LPS) may activate the hypothalamus-pituitary-adrenal (HPA) axis by way of both neural and humoral mechanisms. We have investigated whether biologically active endotoxin appears in the general circulation after intraperitoneal administration of LPS (5 or 100 micrograms/kg) to rats and whether this is a prerequisite for activation of this HPA axis. Within 15 min, endotoxin appeared in the general circulation, whereas elevations of plasma adrenocorticotropic hormone (ACTH), corticosterone, and interleukin (IL)-6 concentrations were not detected until 90 min after LPS injection. At this time, a marked interindividual variation was observed in plasma concentrations of endotoxin, ACTH, corticosterone, and IL-6. Elevated levels of plasma endotoxin were associated with elevated levels of ACTH, corticosterone, and IL-6. Intravenous administration of the LPS antagonist cationic antimicrobial protein 18 (5 mg/kg), which did not affect cytokine production in the peritoneal cavity, markedly reduced plasma ACTH, corticosterone, and IL-6 levels after 5 micrograms/kg LPS. Our results suggest that circulating endotoxin is required for the activation of the HPA axis. They also favor a role for circulating IL-6 in this response.

Adrenocorticotropic Hormone↗
PubMed1997

Cytoplasmic antineutrophil cytoplasmic antibody-positive vasculitis associated with ulcerative colitis.

The case of a man with poorly controlled ulcerative colitis, who developed a cytoplasmic antineutrophil cytoplasmic antibody-positive systemic vasculitis, causing small bowel infarction is reported. Antineutrophil cytoplasmic antibodies occur in 50-70% of patients with ulcerative colitis, but are usually of the perinuclear or atypical pattern; the cytoplasmic pattern seen in this case is indicative of systemic vasculitis. A variety of vasculitic diseases have been reported as occurring rarely with ulcerative colitis, but this report is the first description of a cytoplasmic antineutrophil cytoplasmic antibody-positive vasculitis with this association.

Adult↗
PubMed1996

Peripheral cell types contributing to the hyperalgesic action of nerve growth factor in inflammation.

The contribution of nerve growth factor (NGF) to inflammatory hyperalgesia potentially could be mediated by any of the three peripheral cell types that express trkA, the high-affinity NGF receptor: inflammatory cells, sympathetic neurons, and primary sensory neurons. To investigate their relative involvement, the effects of sympathectomy and mast cell degranulation were examined on the local inflammation produced by an intraplantar injection of complete Freund's adjuvant in the adult rat. Sympathectomy, produced by neonatal guanethidine treatment, elevated basal NGF levels in the skin but did not attenuate a further increase in NGF during inflammation. Although the onset of inflammatory hyperalgesia was delayed in sympathectomized animals, peak sensitivity was not affected and was still NGF-dependent. In contrast, mast cell degranulation produced by several days of treatment with the cationic secretagogue compound 48/80, while also increasing basal NGF levels, prevented a further increase in NGF levels and attenuated hypersensitivity during inflammation. Neither manipulation modified the inflammatory upregulation of interleukin-1beta. We conclude that sympathetic neurons contribute transiently to inflammatory hyperalgesia, but that mast cells and sensory neurons are important sites for the sustained action of NGF in producing increased sensitivity during inflammation.

Animals↗
PubMed1996

Surface-associated material from the bacterium Actinobacillus actinomycetemcomitans contains a peptide which, in contrast to lipopolysaccharide, directly stimulates fibroblast interleukin-6 gene transcription.

The oral commensal Gram-negative bacterium Actinobacillus actinomycetemcomitans is believed to be the causative organism of localized juvenile periodontitis, a disease in which there is rapid loss of alveolar bone supporting the teeth. Previously, we have reported that gentle saline extraction of this bacterium removed a loosely adherent proteinaceous fraction from the cell surface of the bacterium, which we have termed surface-associated material. This material contained potent bone-resorbing activity. We now report that surface-associated material is also a potent stimulator of cytokines, and in particular, interleukin-6 (IL-6) synthesis, while the lipopolysaccharide from this bacterium is only a weak stimulator of IL-6 synthesis by fibroblasts and monocytes. In contrast to enteric lipopolysaccharide (LPS), which induces fibroblast IL-1, IL-6 and tumour necrosis factor (TNF) alpha synthesis, surface-associated material stimulated gingival fibroblasts to synthesize only IL-6, with no induction of IL-1 or TNF (the normal inducers of IL-6 synthesis). Reverse transcriptase PCR also failed to detect mRNA for IL-1 or TNF in surface-associated-material-stimulated fibroblasts, although both mRNAs were present in Escherichia coli LPS-stimulated cells. Neutralizing antibodies to IL-1 and/or TNF or the natural IL-1 receptor antagonist (IL-1ra) inhibited enteric LPS-induced IL-6 synthesis, but did not inhibit surface-associated-material-induced synthesis. In addition, dexamethasone, which completely suppressed LPS-induced IL-6 synthesis, only inhibited surface-associated-material-induced IL-6 synthesis by 50%. This suggests that the active constituent in the surface-associated material stimulates IL-6 gene transcription by a transcriptional control mechanism distinct to that of E. coli LPS. The IL-6 stimulating activity of the surface-associated material is inhibited by both heat and trypsin, suggesting that it is proteinaceous. The activity has been isolated using anion-exchange, reverse-phase and size-exclusion HPLC. The active moiety is a peptide of molecular mass 2kDa which may be the product of a bacterial short open reading frame.

Aggregatibacter actinomycetemcomitans↗