Background: The cationic trypsinogen (PRSS1) R122H mutation causes autosomal dominant hereditary pancreatitis (HP) with multiple attacks of acute pancreatitis, but the penetrance, frequency, and ...severity of attacks are highly variable. HP twins study suggests that modifier genes influence severity but not penetrance. Aim: To investigate potential trypsin associated factors in subjects with the PRSS1 R122H mutation and phenotypic non-penetrance. Methods: Two subjects from HP families (including a 93 year old subject with PRSS1 R122H without pancreatitis), one with chronic pancreatitis and one with a normal pancreas, were studied. Relative expression of: (a) the PRSS1 R122 and H122 alleles; and (b) the PRSS1 and SPINK1 genes in pancreatitis were determined using complementary methods. Results:PRSS1 wild-type (R122) and mutant (H122) allele expression was equivalent in multiple (>3) samples from the phenotypically affected and non-penetrant subjects with R122H genotypes using allele specific quantitative reverse transcription-polymerase chain reaction (RT-PCR) and intron spanning nested RT-PCR followed by cDNA sequencing. Compared with PRSS1 mRNA levels, SPINK1 mRNA levels were low in normal appearing tissue but markedly increased in samples with chronic inflammation, independent of PRSS1 genotype. Conclusion: Attacks of acute pancreatitis in HP subjects appear to be independent of the relative expression of the mutant PRSS1 H122 allele or SPINK1 gene expression. The marked increase in SPINK1 gene expression with inflammation is consistent with its regulation as an acute phase protein.
Genetic polymorphisms in alcoholic pancreatitis Hanck, Christoph; Schneider, Alexander; Whitcomb, David C
Baillière's best practice & research. Clinical gastroenterology,
08/2003, Letnik:
17, Številka:
4
Journal Article
Recenzirano
Chronic, excessive alcohol consumption is clearly associated with acute and chronic pancreatitis. However, both clinical and laboratory studies have demonstrated that alcohol consumption alone does ...not directly cause pancreatitis. Growing evidence suggests that environmental and possibly genetic cofactors must also be present before the mechanisms protecting the pancreas from pancreatitis are circumvented and pancreatitis develops. The discovery that mutations in the cationic trypsinogen gene (R122H, N29I) predisposed to acute and chronic pancreatitis focused attention on possible genetic predispositions. Mutations in the cationic trypsinogen gene, however, are rarely associated with alcoholic chronic pancreatitis. Mutations in the SPINK1 gene (e.g. N34S) provide a threefold increased risk, and cystic fibrosis transmembrane conductance regulator (CFTR) mutations continue to be investigated. However, the major cofactor associated with alcoholic chronic pancreatitis is yet to be identified.
We propose an IV panel unit root test robust to nonstationary error volatility. Its finite-sample performance is convincing even for many units and strong cross-correlation. An application to GDP ...prices illustrates the inferential impact of nonstationary volatility.
► We propose an IV panel unit root test robust to nonstationary error volatility. ► Its finite-sample performance is good even for many units and strong correlation. ► An application to GDP prices illustrates the impact of nonstationary volatility.
Using PIRLS (Progress in International Reading Literacy Study) data, we investigate which countries' schools can be classified as significantly better or weaker than Germany's as regards the reading ...literacy of primary school children. The ‘standard’ approach is to conduct separate tests for each country relative to the reference country (Germany) and to reject the null of equally good schools for all those countries whose
p-value satisfies
p
i
⩽
0.05. We demonstrate that this approach ignores the multiple testing nature of the problem and thus overstates differences between schooling systems by producing unwarranted rejections of the null. We employ various multiple testing techniques to remedy this problem. The results suggest that the ‘standard’ approach may overstate the number of significantly different countries by up to 30%.
► International school comparisons statistically test for "significant" differences. ► These tests usually do not take the multiplicity of tests performed into account. ► This approach may overstate the differences between countries' schools. ► We use multiple testing techniques to control for this problem. ► Using PIRLS data, we find up to 30% fewer significantly different countries.
There is evidence that TNF‐α contributes to the pathogenesis of chronic viral hepatitis. The cellular effects of this cytokine are regulated by two specific receptors, and membranous shedding of ...these receptors reflects activation of the TNF system. We performed a study of TNF‐α and functionally active soluble TNF‐receptors (TNFR‐p55 and ‐p75) in 105 patients with chronic HCV infection. In HCV RNA‐positive patients a significant enhancement of TNF‐α and both receptor types was observed compared with controls (TNF‐α 83.8 ± 91.7 pg/ml versus 18.8 ± 8.4 pg/ml, P < 0.001; TNFR‐p55 1.4 ± 0.4 ng/ml versus 0.9 ± 0.2 ng/ml, P < 0.0001; TNFR‐p75 6.4 ± 2.4 ng/ml versus 2.9 ± 0.6 ng/ml, P < 0.0001, respectively). The enhanced serum levels of TNF‐α and TNFRs were reflected by a significant expression of TNFR‐specific mRNA in peripheral mononuclear cells of HCV‐infected patients (P < 0.001). Serum aminotransferases correlated with soluble TNFR‐p75 (P < 0.001) but not with TNFR‐p55 and TNF‐α. We demonstrated an association of the degree of histological inflammation with both TNFRs (P < 0.01). Furthermore, enhanced hepatocellular expression of TNF‐α and TNFRs could be demonstrated by immunohistochemical staining in HCV‐infected patients. Sixty‐eight out of 105 patients were treated with interferon‐alpha (IFN‐α) (3 × 106 U × 3/week). Pretreatment levels of TNF‐α and TNFRs did not differ between responders and non‐responders. Our results demonstrate that TNF‐α and TNFRs are enhanced in chronic HCV infection and reflect histological activity of the disease. This up‐regulation of TNFRs might modify host response and potentially contribute to liver damage in chronic HCV infection.
Cytokines and plasma endotoxin were measured in a consecutive series of patients with alcoholic cirrhosis (AC). Endotoxaemia was found to be strongly correlated to increased plasma levels of ...functionally active tumour necrosis factor (TNF) receptors -p55 and -p75, TNF-α, and the Child-Pugh stage of the disease. Our data support the hypothesis of the pathogenic role of lipopolysaccharide in hepatocellular damage of patients with AC.
BACKGROUND Most patients with alcohol induced cirrhosis (AC) and chronic endotoxinaemia are not suffering from clinically evident systemic inflammatory reactions. This may be due to altered gene ...expression of cytokines, possibly related to endotoxin (for example, tolerance and sensitisation). Interleukin 18 (IL-18; interleukin γ inducing factor) modulates local cytokine production in response to endotoxin (lipopolysaccharide (LPS)). AIM To investigate the systemic immune response of patients with AC and to see if unstimulated peripheral blood mononuclear cells (PBMC) from patients with AC are activated and contribute to gene expression of IL-18. METHODS Plasma levels of endotoxin (LPS) and serum levels of IL-18 were measured by enzyme linked immunoassay and the amoebocyte lysate test in 74 abstinent patients with different stages of AC (Child-Pugh stage A, n=18; B, n=22; C, n=34) and compared with healthy controls (n=43). Gene expression of IL-18 was assessed by semiquantitative reverse transcription-polymerase chain reaction in freshly isolated unstimulated PBMC of a subgroup of 14 patients with AC compared with five healthy controls. RESULTS Gene expression of IL-18 specific mRNA in unstimulated PBMC was significantly enhanced in patients with advanced AC (Child-Pugh stage C) and correlated with plasma LPS and serum CD14 levels (Spearman rank correlation factors r=0.76 andr=0.72). Serum concentrations of IL-18 were also elevated compared with healthy controls (p<0.001) but correlation with serum levels of CD14 and plasma levels of LPS was much weaker compared with mRNA data (Spearman rank correlation factorsr=0.47 andr=0.26). CONCLUSIONS Our in vivo data suggest a presensitisation of “unstimulated” PBMC in the circulation of patients with AC by endotoxin. The term “unstimulated” may be inadequate in patients with AC. Further investigations are needed to define the exact mechanisms and localisation of sensitisation of PBMC in vivo.
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