Acute renal artery occlusion following infliximab infusion.

We report the case of a 44-year-old male patient who presented with acute renal artery occlusion, 3 d after first injection of infliximab for steroid refractory attack of ulcerative colitis. Extensive work-up provided no evidence of predisposing factors for arterial thrombosis. Infliximab was thus suspected in the genesis of thrombosis, based on both intrinsic and extrinsic criteria. At month 3 after thrombosis with ongoing anticoagulation, angio-tomodensitometry showed complete revascularization of the left renal artery with renal atrophy. Renal function remained normal and the patient was still in steroid free remission on mercaptopurin monotherapy at maximal follow-up. Few thromboembolic events have been described with anti- tumor necrosis factor (TNF) agents, but it is the first case reported of renal artery thrombosis after infliximab infusion. In addition, we review thrombosis associated with anti-TNF agents.

Role of toll like receptors in irritable bowel syndrome: differential mucosal immune activation according to the disease subtype.

BACKGROUND: The irritable bowel syndrome (IBS) is a functional gastrointestinal disorder whose pathogenesis is not completely understood. Its high prevalence and the considerable effects on quality of life make IBS a disease with high social cost. Recent studies suggest that low grade mucosal immune activation, increased intestinal permeability and the altered host-microbiota interactions that modulate innate immune response, contribute to the pathophysiology of IBS. However, the understanding of the precise molecular pathophysiology remains largely unknown. METHODOLOGY AND FINDINGS: In this study our objective was to evaluate the TLR expression as a key player in the innate immune response, in the colonic mucosa of IBS patients classified into the three main subtypes (with constipation, with diarrhea or mixed). TLR2 and TLR4 mRNA expression was assessed by real time RT-PCR while TLRs protein expression in intestinal epithelial cells was specifically assessed by flow cytometry and immunofluorescence. Mucosal inflammatory cytokine production was investigated by the multiplex technology. Here we report that the IBS-Mixed subgroup displayed a significant up-regulation of TLR2 and TLR4 in the colonic mucosa. Furthermore, these expressions were localized in the epithelial cells, opening new perspectives for a potential role of epithelial cells in host-immune interactions in IBS. In addition, the increased TLR expression in IBS-M patients elicited intracellular signaling pathways resulting in increased expression of the mucosal proinflammatory cytokines IL-8 and IL1ß. CONCLUSIONS: Our results provide the first evidence of differential expression of TLR in IBS patients according to the disease subtype. These results offer further support that microflora plays a central role in the complex pathophysiology of IBS providing novel pharmacological targets for this chronic gastrointestinal disorder according to bowel habits.

Long term efficacy of gastric electrical stimulation in intractable nausea and vomiting.

BACKGROUND: Although the efficacy of gastric electrical stimulation has been reported in short-term studies, there is a lack of data on the long-term improvement of nausea and vomiting by gastric electrical stimulation in patients with delayed or normal gastric emptying. METHODS: Thirty-one patients were implanted at our centre for medically refractory severe and chronic nausea and/or vomiting. Patients were evaluated at baseline, 6 months then 5 years after implantation (mean follow-up 80±4 months) using a symptomatic and quality of life scores. KEY RESULTS: Amongst the 31 patients, 4 were lost to follow-up, 6 explanted due to lack of improvement, and 1 patient died. Out of the 20 patients evaluated over 5 years, the quality of life score showed 27% improvement (p<0.01), including nausea (62%; p<0.01), vomiting (111%; p=0.03), satiety (158%; p<0.01), bloating (67%; p<0.01) and epigastric pain (43%; p=0.03). Over 5 years, 15/20 patients reported a 50% improvement with a global satisfaction rated at 64±6%. Therefore, 15/27 patients (56%) were improved by gastric electrical stimulation over 5 years in intention to treat. Improvement of nausea 6 months after implantation was predictive of 5-year success of gastric electrical stimulation (p=0.04). Finally, patients with delayed gastric emptying or with normal gastric emptying rate before surgery were similarly improved over 5 years (60% versus 50% respectively). CONCLUSION: Gastric electrical stimulation is safe and effective in the long term in patients with medically refractory nausea and vomiting, with an efficacy over 50% beyond 5 years in intention to treat. Gastric emptying measured before implantation did not influence the response rate over 5 years.

The expression and the cellular distribution of the tight junction proteins are altered in irritable bowel syndrome patients with differences according to the disease subtype.

OBJECTIVES: Recent studies have suggested that an increased intestinal permeability is involved in the pathophysilogy of irritable bowel syndrome (IBS). However, the differential expression of tight junctions (TJs) proteins according to IBS subtypes and symptoms remained unknown. The objective of this study was to study zonula occludens-1 (ZO-1), occludin, and claudin-1 in the colonic mucosa of patients with IBS. METHODS: Fifty IBS patients fulfilling the Rome III criteria and 31 controls were included. All types of IBS patients participated with predominant diarrhea (IBS-D, n=19), predominant constipation (IBS-C, n=14), constipation alternating with diarrhea (IBS-A, n=15), or unclassified (IBS-U, n=2). IBS symptom intensity was quantified on 10-cm Visual Analog Scale (VAS). TJ proteins (claudin-1, ZO-1, occludin) were quantified by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), western blot, while their localization was determined by immunofluorescence. RESULTS: ZO-1 and occludin expression was lower in IBS patients compared with controls, whereas only a trend for a decrease of claudin-1 was observed. The mRNA levels remained unaffected. In the subgroup analyses, occludin and claudin-1 expression was decreased in IBS-D patients but not in IBS-C and IBS-A patients. The subcellular distribution of these three proteins was altered in IBS-C and IBS-D patients. Occludin (r=0.40, P<0.01) and claudin-1 (r=0.46, P<0.01) expression was correlated with the duration of symptoms. The expression of occludin was lower in patients with an abdominal pain intensity higher than 6 on the VAS (P<0.05). CONCLUSIONS: Occludin and claudin-1 appeared markedly affected in IBS-D patients. In addition, our results suggest that alteration of TJ proteins may be involved in the initiation of IBS and contribute to visceral hypersensitivity.

Increased proteasome-mediated degradation of occludin in irritable bowel syndrome.

OBJECTIVES: Proteasome-mediated protein degradation may contribute to the regulation of intestinal inflammation. At the same time, low-grade inflammation and increased intestinal permeability seem to be involved in the pathophysiology of irritable bowel syndrome (IBS). Thus, we aimed to evaluate proteasome composition and activities in colonic mucosa of IBS patients and its putative pathogenic role. METHODS: Proteasome activities and proteasome subunit expression were measured in colonic mucosa of IBS, Crohn's disease (CD), and control patients by fluorometric assays and western blot, respectively. Expression of inhibitor of kappa B factor (IkappaB alpha) and occludin, a tight junction protein, was also evaluated in colonic biopsies. The degradation of recombinant occludin incubated with protein extracts from colonic mucosa was evaluated in the presence or absence of proteasome inhibitor, MG132. RESULTS: Proteasome trypsin-like activity was increased in IBS patients compared with CD and controls, whereas chymotrypsin-like activity was upregulated in CD patients only. Caspase-like activity was reduced both in IBS and CD patients. IkappaB alpha expression was similar between IBS and controls. In contrast, occludin expression was lower in IBS than in controls, but occludin mRNA level was similar. Protein extracts from IBS patients but not from controls degraded recombinant occludin (20% over 160 min), which was blocked by MG132. Although mast cell number was increased in IBS patients, no correlation was found between this number and proteasome alterations. CONCLUSIONS: Our study shows that proteasome alterations are present in the colonic mucosa of IBS patients and may contribute to the pathophysiology of IBS by increasing occludin degradation.