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P Pavli

Publications and source records attributed to P Pavli.

At least 19 recordsLinked to original sources
PubMed2007

Perioperative acute upper gastrointestinal haemorrhage in older patients with hip fracture: incidence, risk factors and prevention.

BACKGROUND: No specific preventive strategy exists for acute gastrointestinal haemorrhage in hip fracture patients. AIMS: To determine the effectiveness of prophylactic use of proton pump inhibitors in patients with risk factors for acute gastrointestinal haemorrhage. METHODS: Prospective two-stage study of 822 consecutive older (> or =60 years) hip fracture patients. RESULTS: Acute gastrointestinal haemorrhage occurred in 16 (3.9%) of 407 patients and was associated with increased length of hospital stay (28.7 vs. 15.9; P = 0.0027) and mortality (18.8% vs. 4.3%; P = 0.043). Multiple analysis identified five independent risk factors for acute gastrointestinal haemorrhage: pre-existing peptic ulcer (OR 4.3; P = 0.043), current smoking (OR 3.1; P = 0.023), post-operative use of an antiplatelet agent (OR 6.5; P = 0.046), post-operative use of non-steroidal anti-inflammatory drug/cyclo-oxygenase-2 inhibitor (OR 4.9; P = 0.06) and blood group O (OR 1.7; P = 0.046). These risk factors were highly sensitive and had a negative predictive value of 99.8%. Prophylactic use of proton pump inhibitors in patients with risk factor for acute gastrointestinal haemorrhage significantly reduced the incidence of this complication (0.72% in treated patients vs. 13.4% in untreated; P < 0.001); the number needed to treat was 7.9. Conclusions In older hip fracture patients perioperative acute gastrointestinal haemorrhage occurs in 3.9% and is associated with poor outcome. Preventive proton pump inhibitor therapy in patients at risk of acute gastrointestinal haemorrhage is effective and safe.

Aged↗
PubMed2005

The IBD international genetics consortium provides further evidence for linkage to IBD4 and shows gene-environment interaction.

BACKGROUND AND AIMS: The inflammatory bowel diseases (IBDs) Crohn's disease (CD) and ulcerative colitis are complex disorders with an important genetic determinant. One gene associated with CD has been identified: NOD2/CARD15. Two independent genome-wide scans found significant evidence (logarithm of odds [LOD] 3.6) and suggestive evidence (LOD 2.8) for linkage on locus 14q11-12, also known as the IBD4 locus. To further characterize this locus, we assessed gene-environment interaction (IBD4 x smoking) and phenotypic heterogeneity in a large cohort of IBD-affected sibling pairs as part of an ongoing international collaborative effort. PATIENTS AND METHODS: A total of 733 IBD families, comprising 892 affected sibling pairs, were genotyped for microsatellites D14S261, D14S283, D14S972, and D14S275, spanning the IBD4 locus. Information on gender, ethnicity, age at onset, smoking at diagnosis, extraintestinal manifestations, and disease location was available. RESULTS: A significant distortion in the mean allele sharing (MAS) between affected siblings was observed for CD patients only at each of the four markers (54.6%, 52.8%, 50.4%, and 53.3%, respectively). Maximum linkage for CD was observed at marker D14S261 (multipoint nonparametric linkage score 2.36; P </= 0.01; MAS 54.6%). MAS was higher in CD families in which all siblings or at least one sibling smoked compared with nonsmoking CD families (MAS, 58.90%, 57.50%, and 52.80%, respectively). CONCLUSIONS: The IBD International Genetics Consortium replicated the IBD4 locus on chromosome 14q for CD and also showed evidence for a gene-environment interaction at this locus. Further studies are needed to explore the mechanism by which smoking influences IBD4.

Adolescent↗
PubMed2003

CARD15/NOD2 risk alleles in the development of Crohn's disease in the Australian population.

We have previously reported strong evidence for linkage between IBD1 and Crohn's disease (CD) in Australian Crohn's disease families. Three risk alleles for Crohn's disease, (Arg702Trp (C/T), Gly908Arg (G/C) and 980fs981 (-/C), were recently identified in the CARD15/NOD2 gene on chromosome 16, implicating this as the IBD1 locus. Using a novel diagnostic PCR-RFLP, we have examined the frequency of these alleles in 205 multiplex IBD families, 107 sporadic Crohn's disease cases and 409 normal individuals. We demonstrate that the three risk alleles are more frequent in Crohn's disease, than in controls, with allelic frequencies of 0.11, 0.02 and 0.07 respectively. Heterozygosity for individual variants conferred a three-fold increase in risk for Crohn's disease while substantially higher risks were associated with being homozygous or compound heterozygous. Despite a significantly lower population allele frequency for the frameshift mutation than reported by other groups, we see a similar contribution by this allele to the risk of developing Crohn's disease. While the three risk alleles influence susceptibility to Crohn's disease in Australia, we show that these alleles do not fully explain the linkage evidence and suggest that there are very likely additional IBD1 susceptibility alleles yet to be described in Australian CD at the NOD2 locus. We also show a second linkage peak in Australian CD that provides some support for a second disease susceptibility locus on chromosome 16.

Alleles↗
PubMed2001

Dextran sulphate sodium-induced colitis is ameliorated in interleukin 4 deficient mice.

The importance of IL-4 and its effects in inflammatory bowel disease (IBD) was studied using the dextran sulphate sodium-induced model of experimental colitis. The model resembles ulcerative colitis in humans. IL-4 deficient mice and IL-4+/+ littermates were used to induce colitis. Activity of disease, extent of tissue damage, immunoglobulin isotypes, IFNgamma and IL-10 production was assessed. Both disease activity index (DAI) and histological scores were consistently lower in the IL-4 deficient mice than in the IL-4+/+ littermates. Furthermore, the lower histological scores reflected the milder inflammatory lesions and decreased ulceration found in the IL-4 deficient mice. Analysis of immunoglobulin subtypes showed that IgG1 was almost absent in the sera of IL-4 deficient mice. IFNgamma contents was much higher in colonic tissues from IL-4 deficient mice. Dextran sulphate sodium-induced colitis is ameliorated in IL-4 deficient mice. IL-4 either directly or through its effects on T and B cells influences its severity. It is unclear if the higher immunoglobulin-producing cells in the colonic tissues of IL-4 deficient mice before colitis was induced could have influenced the outcome of the disease. The high IFNgamma contents in colonic tissues of IL-4 deficient mice argue against the role of this cytokine as a crucial mediator of tissue damage during the acute phase of colitis.

Animals↗
PubMed2000

Eosinophilia is attenuated in experimental colitis induced in IL-5 deficient mice.

Tissue eosinophilia is a feature of idiopathic inflammatory bowel disease and other forms of colonic inflammation but it is not clear whether the role of eosinophils in the disease process is to contribute to tissue damage. Interleukin 5 (IL-5) stimulates production and activation of eosinophils in vitro and enhances immunoglobulin A (IgA) production. As very little is known about the function of IL-5 in the colon, the aim of this study was to assess its role in colonic inflammation. IL-5 deficient mice were studied using the dextran sulphate sodium (DSS)-induced colitis model and the results compared to a congenic IL-5+/+ strain. The absence of IL-5 resulted in reduction of tissue eosinophilia (P < 0.0001) but was not reflected in differences in the severity of the disease (P > 0.5) or in the extent of tissue damage in this model of colitis. Numbers of immunoglobulin-containing cells in IL-5 deficient mice were similar to those in the IL-5+ mice. We conclude that the main role of IL-5 in DSS-induced colonic inflammation is to attract a population of eosinophils which do not appear to contribute significantly to the initiation or development of tissue damage in this model of colitis.

Animals↗
PubMed1999

Dextran sodium sulphate-induced colitis activity varies with mouse strain but develops in lipopolysaccharide-unresponsive mice.

Bacteria and their products have been implicated in the pathogenesis of chronic Inflammatory Bowel disease. The aim of this study was to investigate the potential role of lipopolysaccharides (LPS) in the development of intestinal injury by comparing the effects of the dextran sodium sulphate (DSS)-induced model of colitis in LPS-sensitive and -insensitive mice. Experimental colitis was induced in LPS-sensitive mice (C3H/He) and their LPS-insensitive congenic strain (C3H/HeJ). Colitis was assessed clinically using a disease activity index (derived from the three main clinical signs; diarrhoea, rectal bleeding and weight loss) and by histological scoring of the diseased colon. The clinical signs and disease activity index did not differ between the LPS-sensitive and -insensitive costrains. Similarly, histological scores did not differ significantly for either C3H strain at any time point during exposure to DSS. However, there were differences in the inflammatory response when different strains were compared (C3H vs CBA): the effects of DSS in C3H mice were immediate, more severe and mainly involved the caecum and ascending colon. These findings suggest that LPS from colonic bacteria do not play a primary role in the initiation of DSS-induced colitis and demonstrate clear differences in the responsiveness of different mouse strains to DSS.

Animals↗
PubMed1998

Analysis of Australian Crohn's disease pedigrees refines the localization for susceptibility to inflammatory bowel disease on chromosome 16.

A number of localizations for the putative susceptibility gene(s) have been identified for both Crohn's disease and ulcerative colitis. In a genome wide scan, Hugot et al. (1996) identified a region on chromosome 16 which appeared to be responsible for the inheritance of inflammatory bowel disease in a small proportion of families. Subsequent work has suggested that this localization is important for susceptibility to Crohn's disease rather than ulcerative colitis (Ohmen et al. 1996; Parkes et al. 1996). We investigated the contribution of this localization to the inheritance of inflammatory bowel disease in 54 multiplex Australian families, and confirmed its importance in a significant proportion of Crohn's disease families; we further refined the localization to a region near to D16S409, obtaining a maximum LOD score of 6.3 between D16S409 and D16S753.

Australia↗
PubMed1997

Ulcerative colitis: a genetic disease?

A number of lines of evidence support the hypothesis that ulcerative colitis is an inherited disorder in a proportion of cases. First, there is a pattern of familial aggregation. Second, there are differences in the prevalence of the disease in different ethnic groups. Finally, the concordance rate in monozygotic twin pairs is higher than that of dizygotic twin pairs, although not as high as the concordance rates observed in Crohn's disease. Genetic models of the inheritance patterns suggest that ulcerative colitis is probably caused by one major gene, although that gene (or genes) remains to be identified. While at least one localization for susceptibility to Crohn's disease now seems certain, efforts to localize and characterize the susceptibility genes involved in the inheritance of ulcerative colitis are still underway. While the genes of the major histocompatibility complex have been imputed as causal in susceptibility to ulcerative colitis, a consensus of proof continues to elude us.

Chromosomes, Human, Pair 6↗
PubMed1997

Toxocara canis infection and granulomatous hepatitis.

This report describes possible involvement of Toxocara canis in granulomatous hepatitis in three patients who presented with varied clinical features; two were being treated for other diagnoses until Toxocara serology became available. Despite initial nonspecific therapy, there was clinical improvement in all patients and complete resolution of symptoms and abnormal liver biochemistry in two. T. canis infection should be considered in cases of granulomatous hepatitis.

Adult↗
PubMed1996

Enhanced expression and production of monocyte chemoattractant protein-1 in inflammatory bowel disease mucosa.

Peripheral blood monocytes are recruited to the inflamed mucosa of inflammatory bowel disease but the specific chemotactic signals responsible for their attraction are not known. Monocyte chemoattractant protein-1 (MCP-1) is a chemokine with potent monocyte attracting and activating properties and the aim of this study was to examine its expression and production in inflammatory bowel disease. In situ hybridization demonstrated mRNA for MCP-1 in macrophages, some of which had been recently recruited from the circulation as demonstrated by their co-expression of the monocyte marker CD 14, as well as in smooth muscle and endothelial cells in inflamed mucosa. Immunohistochemical studies showed a corresponding distribution of MCP-1 protein production by macrophages, smooth muscle, and endothelial cells. By contrast minimal MCP-1 mRNA expression and protein were found in histologically normal mucosa. Macrophages isolated from surgically resected inflammatory bowel disease colons and examined by Northern analysis expressed MCP-1 mRNA significantly more frequently (15/24 vs. 0/19, P< 0.0001) than macrophages from histologically normal mucosa from colon cancer resections. Blood monocytes stimulated by lipopolysaccharide and treated with hydrocortisone, 5-aminosalicylic acid, or cyclosporin A showed reduced MCP-1 expression and production in the presence of these agents. This study demonstrates increased expression of MCP-1 mRNA and protein and cells of origin of MCP-1 in inflamed intestinal mucosa. Together with the demonstrated influence of therapeutic agents on monocyte MCP-1 production the findings suggest a role for MCP-1 in monocyte attraction to the mucosal lesion of inflammatory bowel disease.

Adolescent↗
PubMed1996

Distribution of human colonic dendritic cells and macrophages.

To define the phenotype of intestinal dendritic cells and macrophages, resected colonic specimens were used to obtain lamina propria cell suspensions by EDTA treatment, then enzymatic digestion. The phenotype of dendritic cell-enriched suspensions was compared with that of macrophage-enriched populations by immunocytochemistry using the avidin-biotin-peroxidase (ABC) system and immunoelectron microscopy. Dendritic cells expressed HLA-DR (L243) and HLA-DQ-associated (RFD) antigens and CD68 in a perinuclear distribution. Staining for S100 was weak or absent. Macrophages also expressed HLA markers (L243 and RFD1) and CD68. The 25F9 antigen was expressed strongly, whilst CD14 was absent from cells isolated from noninflamed tissues. To determine their anatomic distribution, immunohistochemistry was performed using single- and double-labelling techniques (ABC +or- alkaline phosphatase anti-alkaline phosphatase method). Mutually exclusive subsets of 25F9+ and S100+ cells were seen: 25F9+ macrophages were concentrated in a band immediately beneath the luminal epithelium; S100+/HLA-DR+ dendritic cells formed a reticular network throughout the lamina propria and beneath the basement membrane of the crypts. This distribution suggests that macrophages may help regulate intestinal responses by acting as the first line of defence against the entry of luminal antigens. A breach of the macrophage 'barrier' by invading antigens may necessitate the recruitment of T cell responses by immunostimulatory dendritic cells.

Cell Adhesion↗
PubMed1996

Interleukin 8: cells of origin in inflammatory bowel disease.

Neutrophils are important cellular mediators in inflammatory bowel disease (IBD). Interleukin (IL)8, a powerful neutrophil chemoattractant, is found in increased quantities in inflamed mucosa, but the cells of origin are uncertain. IL8 gene expression was studied by in situ hybridisation in uninflamed intestinal tissue resected for colon carcinoma (n = 7) and in inflamed colonic tissue resected for IBD (n = 11). Immunohistochemistry was used to assess the phenotype of IL8 expressing macrophages and the production of IL8 protein. Macrophages isolated from intestinal resections and lipopolysaccharide stimulated peripheral blood monocytes treated with 5-aminosalicylic acid, hydrocortisone, and cyclosporin A were examined for IL8 mRNA by northern blotting and IL8 secretion by enzyme linked immunosorbent assay (ELISA). In all cases IL8 mRNA was detected by in situ hybridisation in macrophages and neutrophils adjacent to ulceration in inflamed bowel, but not detected in uninflamed mucosa from carcinoma resections. Recently recruited CD14 positive macrophages were responsible for some of this IL8 expression. IL8 protein was present in the same distribution as mRNA. Epithelial cells in normal and inflamed tissue showed neither mRNA nor protein. IL8 mRNA was expressed significantly more commonly by macrophages from IBD affected than from normal mucosa, and IL8 secretion by IBD but not normal colon macrophages was augmented significantly by lipopolysaccharide treatment. IL8 expression and production by lipopolysaccharide treated blood monocytes was inhibited by the therapeutic agents tested. These results show that neutrophils and recently recruited macrophages are responsible for production of IL8 in IBD, suggesting a mechanism for a continuing cycle of neutrophil attraction. Agents used therapeutically in these diseases may be effective in part by disrupting this cycle.

Adolescent↗