A Hereditary Enteropathy Caused by Mutations in the SLCO2A1 Gene, Encoding a Prostaglandin Transporter.

Previously, we proposed a rare autosomal recessive inherited enteropathy characterized by persistent blood and protein loss from the small intestine as chronic nonspecific multiple ulcers of the small intestine (CNSU). By whole-exome sequencing in five Japanese patients with CNSU and one unaffected individual, we found four candidate mutations in the SLCO2A1 gene, encoding a prostaglandin transporter. The pathogenicity of the mutations was supported by segregation analysis and genotyping data in controls. By Sanger sequencing of the coding regions, 11 of 12 other CNSU patients and 2 of 603 patients with a diagnosis of Crohn's disease were found to have homozygous or compound heterozygous SLCO2A1 mutations. In total, we identified recessive SLCO2A1 mutations located at seven sites. Using RT-PCR, we demonstrated that the identified splice-site mutations altered the RNA splicing, and introduced a premature stop codon. Tracer prostaglandin E2 uptake analysis showed that the mutant SLCO2A1 protein for each mutation exhibited impaired prostaglandin transport. Immunohistochemistry and immunofluorescence analyses revealed that SLCO2A1 protein was expressed on the cellular membrane of vascular endothelial cells in the small intestinal mucosa in control subjects, but was not detected in affected individuals. These findings indicate that loss-of-function mutations in the SLCO2A1 gene encoding a prostaglandin transporter cause the hereditary enteropathy CNSU. We suggest a more appropriate nomenclature of "chronic enteropathy associated with SLCO2A1 gene" (CEAS).

Differentiation-inducing factor-3 inhibits intestinal tumor growth in vitro and in vivo.

Differentiation-inducing factor-1 (DIF-1) produced by Dictyostelium discoideum strongly inhibits the proliferation of various types of cancer cells by suppression of the Wnt/ß-catenin signal transduction pathway. In the present study, we examined the effect of differentiation-inducing factor-3 (DIF-3), a monochlorinated metabolite of DIF-1 that is also produced by D. discoideum, on human colon cancer cell lines HCT-116 and DLD-1. DIF-3 strongly inhibited cell proliferation by arresting the cell cycle at the G0/G1 phase. DIF-3 reduced the expression levels of cyclin D1 and c-Myc by facilitating their degradation via activation of GSK-3ß in a time and dose-dependent manner. In addition, DIF-3 suppressed the expression of T-cell factor 7-like 2, a key transcription factor in the Wnt/ß-catenin signaling pathway, thereby reducing the mRNA levels of cyclin D1 and c-Myc. Subsequently, we examined the in vivo effects of DIF-3 in Mutyh(-/-) mice with oxidative stress-induced intestinal cancers. Repeated oral administration of DIF-3 markedly reduced the number and size of cancers at a level comparable to that of DIF-1. These data suggest that DIF-3 inhibits intestinal cancer cell proliferation in vitro and in vivo, probably by mechanisms similar to those identified in DIF-1 actions, and that DIF-3 may be a potential novel anti-cancer agent.

Patients' assessment of adalimumab self-injection for Crohn's disease: a multicenter questionnaire survey (The PEARL Survey).

BACKGROUND/AIMS: Adalimumab (ADA) is a self-injectable anti-tumor necrosis factor-α antibody used for treating Crohn's disease (CD). Although self-injecting ADA may be convenient for patients, few reports have assessed patients receiving ADA self-injection therapy. METHODOLOGY: We conducted a questionnaire survey involving outpatients on ADA self-injection therapy at four university hospitals. We analyzed the degree of satisfaction with and adherence to the self-injection therapy and performed sub-analyses. RESULTS: Responses were obtained from 124 patients. Before treatment initiation, 38% patients replied that they were unwilling to accept the self-injection therapy. However, after treatment initiation, 75% patients were satisfied with the treatment. 66 patients previously treated with infliximab (IFX), the degree of treatment satisfaction was significantly higher in patients who felt burdened to the time required for IFX infusion than in those who had not felt burdened (P < 0.05). Patient adherence to ADA was high (85%). Multivariate analysis regarding adherence revealed that duration of disease (OR, 0.99), degree of treatment efficacy satisfaction (OR, 13.42), and schedule registration (OR, 7.95) were significant. Safety assessment results were within the range of those already reported. CONCLUSIONS: ADA self-injection was thought to have good adherence and a safe administration method according to patients' assessments.

Chronic nonspecific multiple ulcer of the small intestine segregates in offspring from consanguinity.

BACKGROUND AND AIMS: Chronic nonspecific multiple ulcer of the small intestine is a recently proposed enteropathy characterized by persistent blood and protein loss from the small-bowel. We examined possible segregation of the disease in family pedigrees. METHODS: All cases of the disease diagnosed at our institution were reviewed with respect to particular focuses on the presence of close consanguinity in the families, the enteroscopic findings and the long-term clinical course. The diagnosis was based on persistent occult gastrointestinal bleeding and hypoproteinemia for more than 5 years, and irregularly shaped shallow ulcers in the ileum. RESULTS: During a 45-year-period, 13 patients were diagnosed as having the disease. There were 11 females and 2 males, with ages ranging from 8 to 37 years at the time of the initial presentation and with those from 13 to 38 years at the diagnosis. Enteroscopy performed in 11 patients with a time duration ranging from 0.5 to 44 years after the diagnosis revealed active ileal ulcers in 10 patients. Parents' consanguineous marriage was verified in 6 patients, two of whom also had siblings with the enteropathy. Another patient without consanguinity had a sibling with protein-losing enteropathy. CONCLUSION: Chronic nonspecific multiple ulcer of the small intestine seems to segregate in offspring from consanguineous marriage.

Endoscopic findings under narrow band imaging colonoscopy in ulcerative colitis.

Narrow band imaging (NBI) depicts distinct intramucosal vascular network and pit pattern without any use of dye technique. It is thus suggested that NBI can be used for the assessment of severity in inflammatory bowel diseases, especially in ulcerative colitis (UC). In the active UC, NBI colonoscopy depicts friability as a black area. In the inflamed granular mucosa, crypt openings and villous structure become evident through the procedure. In the inactive UC, there are two types of mucosal vascular pattern; one being composed of deep, green vessels and superficial, black vessels, and the other lacking in superficial vessels. With used of a magnifying instrument, the mildly active mucosa can be classified into the mucosa with obvious crypt openings and that with villous structure. Mucosal vascular pattern in the inactive mucosa is shown as a honeycomb-like structure or irregular, tortuous structure under magnifying NBI observation. Furthermore, such NBI findings show close correlations with histologic findings including crypt distortion, goblet cell depletion and basal plasmacytosis. Therefore, NBI colonoscopy might be of value for the precise assessment of histologic severity in mildly active and inactive UC.

Computed tomographic and magnetic resonance features of inflammatory myofibroblastic tumor of the lung in children.

We report two cases of inflammatory myofibroblastic tumor (IMT) of the lung in a 4-year-old boy and a 7-year-old girl. We performed dynamic contrastenhancement computed tomography in both of our cases and dynamic contrast enhancement magnetic resonance imaging (MRI) in one case. These dynamic studies showed a demarcated mass with delayed enhancement in both cases. A T1-weighted MR image shows a mass with homogeneous low signal intensity, and a T2- weighted image shows a mass with slightly high signal intensity. A post-contrast-enhanced T1-weighted image demonstrates homogeneous enhancement. We speculate that the delayed enhancement could be attributed to the abundant fibrous tissue, which was the main structural material of the tumor. This same finding has been described in previous reports of IMT in other organs.