Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn's disease

The inflammatory bowel diseases (IBDs), Crohn's disease (CD) and ulcerative colitis, are chronic inflammatory disorders of the digestive tract. The pathogenesis of IBD is complicated, and it is widely accepted that immunologic, environmental and genetic components contribute to its etiology. To identify genetic susceptibility factors in CD, we performed a genome-wide association study in Japanese patients and controls using nearly 80,000 gene-based single nucleotide polymorphism (SNP) markers and investigated the haplotype structure of the candidate locus in Japanese and European patients. We identified highly significant associations (P = 1.71 x 10(-14) with odds ratio of 2.17) of SNPs and haplotypes within the TNFSF15 (the gene encoding tumor necrosis factor superfamily, member 15) genes in Japanese CD patients. The association was confirmed in the study of two European IBD cohorts. Interestingly, a core TNFSF15 haplotype showing association with increased risk to the disease was common in the two ethnic groups. Our results suggest that the genetic variations in the TNFSF15 gene contribute to the susceptibility to IBD in the Japanese and European populations.     

Effects of endoscopic variceal treatment on oesophageal function: a prospective, randomized study

AIM : Endoscopic methods are currently the most widely used techniques for the treatment of bleeding oesophageal varices (BOV). However, a number of complications may limit their usefulness. We conducted a prospective, randomized comparison of variceal ligation versus sclerotherapy in cirrhotics after the control of variceal haemorrhage to study the relative short-term risks of these two procedures with respect to oesophageal motility and gastro-oesophageal reflux. METHODS : Seventy-three patients with established cirrhosis and an episode of variceal bleeding controlled by one session of endoscopic therapy were randomized to treatment with sclerotherapy or ligation until variceal eradication. In 60 of these patients, oesophageal manometry and 24-h intra-oesophageal pH monitoring were performed at inclusion and 1 month after variceal eradication. RESULTS : After variceal eradication with sclerotherapy, peristaltic wave amplitude decreased from 76.2 +/- 14.7 mmHg to 61.6 +/- 17.7 mmHg (P = 0.0001), simultaneous contractions increased from 0% to 37.9% (P = 0.0008), and the percentage of time with pH < 4 increased from 1.60 +/- 0.25 to 4.91 +/- 1.16% in channel 1 (P = 0.0002) and from 1.82 +/- 0.27 to 5.69 +/- 1.37% in channel 2 (P = 0.0006). In contrast, the above parameters were not disturbed with ligation. CONCLUSION : Our data define the advantages of ligation over sclerotherapy with respect to post-treatment oesophageal dysmotility and associated gastro-oesophageal reflux.     

Diastolic cardiac dysfunction is a predictor of dismal prognosis in patients with liver cirrhosis

Background and purpose

Left ventricular diastolic dysfunction (LVDD) constitutes the prominent characteristic of cirrhotic cardiomyopathy, but its relevance on the clinical course of cirrhotic patients has not been clearly defined. The aim of the study was to evaluate the relationship of LVDD with the severity and etiology of liver disease and to investigate whether it affects the outcome of cirrhotic patients.

Methods

Cardiac function of 45 cirrhotics was studied by a tissue Doppler imaging echocardiography. Diagnosis of LVDD was made according to the latest guidelines of the American Society of Echocardiography. All patients were followed up for a period of 2 years. Death or liver transplantation was the endpoint of the study.

Results

LVDD was found in 17 (38 %) of 45 patients. Its presence was not found to be associated with the etiology and stage of cirrhosis, but its severity was directly correlated with the Child-Pugh score. At the end of follow-up, 14 patients had died; 9 had LVDD (9/17, 53 %) and 5 had not (5/28, 18 %). Patients who died at the beginning of observation period had a higher Child-Pugh and MELD score, higher BNP, lower albumin and more prolonged QTc. On Kaplan-Meier analysis, patients with LVDD had statistically significantly worse prognosis compared to those without (p = 0.013, log rank: 5.495). Low albumin values (p = 0.003) and presence of LVDD (p = 0.017) were independent predictive factors of mortality.

Conclusions

LVDD is a common complication of cirrhosis. As its development seems to be related to a worse prognosis, patients with LVDD must be under a strict follow-up.     

Bacterial infection in cirrhosis impairs coagulation by a heparin effect: a prospective study

BACKGROUND: Bacterial infections have been postulated as a trigger for variceal bleeding in cirrhotic patients, and impair coagulation evaluated by thrombelastography (TEG). Endogenous heparinoids have been detected after variceal bleeding and during liver transplantation in some cirrhotics using heparinase-modified-TEG. AIM: To assess if bacterial infection is associated with endogenous heparinoids in cirrhotics, thus impairing coagulation. METHODS: Native and heparinase-modified-TEG (cleavage of heparin and heparan-sulphate) was performed in 60 cirrhotics (Grade A, 2; B, 30; C, 28): 30 infected [septicaemia, 6 (culture positive); 6 (culture negative); spontaneous bacterial peritonitis, 10; chest infection, 4; others, 4], 30 not infected, and five infected patients without liver diseases, comparing TEG parameters r, alpha, and ma. Eight cirrhotics were studied before and after infection. The diagnosis of presence and type of infection was based on international standard criteria. RESULTS: A significant heparin effect was found only in infected cirrhotics (28 of 30) with significant changes in r (P=0.0003), alpha (P<0.0001), and ma (P<0.0001), but in none of those not infected. This effect completely reversed in the eight evaluated after resolution of infection. There was no heparin effect in infected non-cirrhotics. CONCLUSIONS: A heparin effect was only found in cirrhotic patients with infection, further confirming that infection significantly modifies coagulation in cirrhotic patients.     

Analysis of reelin as a candidate gene for autism

Genetic studies indicate that chromosome 7q is likely to contain an autism susceptibility locus (AUTS1). We have followed a positional candidate gene approach to identify relevant gene(s) and report here the analysis of reelin (RELN), a gene located under our peak of linkage. Screening RELN for DNA changes identified novel missense variants absent in a large control group; however, the low frequency of these mutations does not explain the relatively strong linkage results on 7q. Furthermore, analysis of a previously reported triplet repeat polymorphism and intragenic single nucleotide polymorphisms, using the transmission disequilibrium test, provided no evidence for association with autism in IMGSAC and German singleton families. The analysis of RELN suggests that it probably does not play a major role in autism aetiology, although further analysis of several missense mutations is warranted in additional affected individuals.