Congenital anaemia associated with loss-of-function variants in DNA polymerase epsilon 1.

DNA polymerase epsilon (Pol ε), a component of the core replisome, is involved in DNA replication. Although genetic defects of Pol ε have been reported to cause immunodeficiency syndromes, its role in haematopoiesis remains unknown. Here, we identified compound heterozygous variants (p.[Asp1131fs];[Thr1891del]) in POLE, encoding Pol ε catalytic subunit A (POLE1), in siblings with a syndromic form of severe congenital transfusion-dependent anaemia. In contrast to Diamond-Blackfan anaemia, marked reticulocytopenia or marked erythroid hypoplasia was not found. Their bone marrow aspirates during infancy revealed erythroid dysplasia with strongly positive TP53 in immunostaining. Repetitive examinations demonstrated trilineage myelodysplasia within 2 years from birth. They had short stature and facial dysmorphism. HEK293 cell-based expression experiments and analyses of patient-derived induced pluripotent stem cells (iPSCs) disclosed a reduced mRNA level of Asp1131fs-POLE1 and defective nuclear translocation of Thr1891del-POLE1. Analysis of iPSCs showed compensatory mRNA upregulation of the other replisome components and increase of the TP53 protein, both suggesting dysfunction of the replisome. We created Pole-knockout medaka fish and found that heterozygous fishes were viable, but with decreased RBCs. Our observations expand the phenotypic spectrum of the Pol ε defect in humans, additionally providing unique evidence linking Pol ε to haematopoiesis.

Prognosis of pediatric ulcerative colitis after infliximab failure: A multicenter registry-based cohort study.

BACKGROUND AND AIM: Even with increasing numbers of biologic agents available for management of ulcerative colitis (UC), infliximab (IFX) retains an important place in treatment of pediatric patients with this disease. As few reports have addressed outcomes in pediatric UC patients who had to discontinue IFX, we examined clinical course and prognosis after IFX failure in pediatric UC. METHODS: A prospective cohort study of pertinent cases enrolled in the Japanese Pediatric Inflammatory Bowel Disease Registry between 2012 and 2020 was conducted to determine outcomes for pediatric UC patients who received IFX but required its discontinuation during follow-up (IFX failure). RESULTS: Of the 301 pediatric UC patients in the registry, 75 were treated with IFX; in 36 of these, IFX was discontinued during follow-up. Severity of UC at onset and absence of concomitant immunomodulator therapy were significant risk factors for IFX failure (P = 0.005 and P = 0.02, respectively). The cumulative colectomy rate after IFX failure was 41.3% at 1 year and 47.5% at 2 years. Colectomy was significantly more frequent when IFX was discontinued before June 1, 2018, than when IFX was discontinued later (P = 0.013). This difference likely involves availability of additional biologic agents for treatment of UC beginning in mid-2018 (P = 0.005). CONCLUSION: In pediatric UC patients, approximately 50% underwent colectomy during a 2-year interval following IFX failure. Prognosis after IFX failure appeared to improve with availability of new biologic agents and small-molecule drugs in mid-2018.

Evaluation of Deficient Nutrients in Infants and Toddlers Mainly Taking Amino Acid-Based Elemental Formulas: An Exploratory Study.

INTRODUCTION: This study evaluated nutrient deficiencies in infants and toddlers with inflammatory bowel disease (IBD) and eosinophilic gastrointestinal disorders (EGIDs), whose primary nutritional source is elemental formulas (EFs). METHODS: The nutrient status of children with IBD and EGID aged 6 months to 6 years was evaluated. RESULTS: Twenty-one children fed with EFs (EF group) and 25 controls (CL group) were enrolled. The selenium level in the EF group was lower than that in the CL group (2.2 µg/dL vs. 9.3 µg/dL; p < 0.01). Although fat-soluble vitamins were deficient in some EF group participants, no significant differences were observed in their concentration and insufficiency proportion. However, ascorbic acid deficiency was more frequent in the EF group, with significantly lower levels (8.6 µg/mL vs. 12.0 µg/mL; p < 0.01). The triene:tetraene ratio was significantly higher in the EF group (0.046 vs. 0.010; p < 0.01). Asparagine and taurine levels were significantly lower in the EF group (asparagine: p < 0.01; taurine: p < 0.01) and tyrosine and phenylalanine levels were higher in the EF group, resulting in a lower Fisher's ratio (p < 0.01). CONCLUSION: Long-term feeding with EFs can cause deficiencies in essential fatty acids, selenium, and ascorbic acid and also carries a risk of amino acid imbalance in infants and toddlers.

Monogenic inflammatory bowel disease with STXBP2 mutations is not resolved by hematopoietic stem cell transplantation but can be alleviated via immunosuppressive drug therapy.

STXBP2, encoding syntaxin-binding protein 2, is involved in intracellular organelle trafficking and is associated with familial hemophagocytic lymphohistiocytosis type 5. Although STXBP2 mutations reportedly cause monogenic inflammatory bowel disease, the clinical course and underlying pathogenic mechanisms remain unclear. We identified a novel mutation in STXBP2 [c.1197delC, p.Ala400fs] in a boy with congenital intractable diarrhea and hemophagocytic lymphohistiocytosis (HLH). HLH was treated with intravenous prednisolone, cyclosporine, and dexamethasone palmitate. Hematopoietic stem cell transplantation (HSCT) along with prophylaxis for graft-versus-host-disease was performed at 5 months of age. Additionally, colonoscopies done before and after HSCT showed mild colitis with cryptitis. The patient showed elevated fecal calprotectin levels and persistent diarrhea even after HSCT and required partial parenteral nutrition. While anti-inflammatory treatment reduced diarrhea, it was not completely normalized even after HSCT, suggesting that the pathogenesis of inflammatory bowel disease associated with STXBP2 mutations involves both hyperinflammation and functional epithelial barrier defects.

Tolerability and safety of a new elimination diet for pediatric eosinophilic gastritis and duodenitis.

BACKGROUND: Non-esophageal eosinophilic gastrointestinal disorders (non-EoE EGIDs) are chronic inflammatory disorders with massive infiltration of eosinophils into the gastrointestinal tract. Food elimination diets are potentially effective treatments. But the existing dietary therapies have various weak points. We developed a new regimen to compensate for the shortcomings of the elemental diet and 6-food elimination diet. The new regimen consists of an amino-acid-based formula, potatoes, vegetables, fruits and restricted seasonings. We named it the "Rainbow Elimination Diet (ED)." The aims of this study were to evaluate the tolerability and safety of this diet. METHODS: A retrospective medical record examination was conducted at the National Center for Child Health and Development covering the period from January 2010 through December 2018. The medical records of patients (age 2-17 y) with histologically diagnosed non-EoE EGIDs were reviewed. The tolerability, nutritional intake, symptoms, and blood test findings were evaluated. RESULTS: Nineteen patients were offered several kinds of food-elimination diets. Seven patients (eosinophilic gastritis: 5; gastroenteritis: 1; duodenitis: 1) were treated with Rainbow ED. Six patients were compliant with this diet. The median duration of the diet induction phase was 15 days (range 14-30). All 5 patients who had had symptoms just before the induction phase became symptom-free. The body weight decreased in 5 patients (median -0.6 kg), probably because the serum protein increased, resulting in reduced edema. All 5 patients with hypoproteinemia had elevated serum albumin (median 2.9-3.5 g/dL). The ingested nutritional elements were calculated, and most of them were sufficient, except for fat and selenium. CONCLUSIONS: The Rainbow ED was well-tolerated and safe for pediatric non-EoE EGIDs.

Novel biallelic mutations in the DUOX2 gene underlying very early-onset inflammatory bowel disease: A case report.

Genetic variants affecting the function of dual oxidase 2 (DUOX2), the catalytic subunit of membrane-bound enzymes that produce hydrogen peroxide, are associated with very early-onset inflammatory bowel disease (VEO-IBD). We report the case of a 1-year-old boy diagnosed with VEO-IBD after presenting with bloody diarrhea. He had pancolitis and an extensive small intestinal ulcerative lesion at age 4 years. Infliximab treatment was successful but was discontinued due to delayed reaction. At age 7 years, treatment with ustekinumab was started, and remission has been maintained for more than 2 years. Whole-exome sequencing identified compound heterozygous missense DUOX2 variants of unknown significance (p.[R1212H];[F1490Y]). Protein expression in the whole-cell lysate and plasma membrane was lower in F1490Y-DUOX2 than in wild-type (WT)-DUOX2. Hydrogen peroxide generation upon ionomycin stimulation was lower in cells expressing R1212H-DUOX2 and F1490Y-DUOX2 than in those expressing WT-DUOX2. The novel, inherited, biallelic DUOX2 mutations may be molecular risk factors of VEO-IBD.

Qing-Dai for pediatric ulcerative colitis multicenter survey and systematic review.

BACKGROUND: Pediatric ulcerative colitis (UC) is more challenging to treat than adult UC. Qing-Dai therapy is effective in adults but reports of its efficacy in children are unavailable. We conducted a questionnaire survey on Qing-Dai use among pediatric patients with UC in Japan to determine its efficacy and safety. METHODS: Questionnaires were sent to 31 high-volume centers treating pediatric patients with inflammatory bowel disease. The number of patients using Qing-Dai, short-term and long-term effects, and adverse events were assessed. A systematic review of studies on the efficacy and safety of Qing-Dai usage for UC was also performed. RESULTS: Overall, 29/31 facilities (93.5%) responded, Qing-Dai was used in 107 patients with UC, and 84/107 patients (78.5%) initiated treatment. Within 6 months, 81/101 (80.2%) patients had clinical remission, while 59/92 (64.1%) patients had no relapse and 29/92 (31.5%) experienced only one to two relapses yearly. Eighty-seven percent of the patients underwent regular follow ups for adverse events, among whom one patient was diagnosed with pulmonary arterial hypertension (PAH), five with enteritis, and one with headache. In the systematic review, the clinical remission rate was 50-80%, and PAH was observed in 14 of 1,158 patients (1.2%). CONCLUSIONS: Qing-Dai is highly effective in treating pediatric UC. However, Qing-Dai should be administered with caution as it may cause adverse events such as PAH.

Intestinal outcome of bone marrow transplantation for monogenic inflammatory bowel disease.

BACKGROUND: Some monogenic inflammatory bowel diseases (IBDs) are known to be refractory to conventional treatments. Although allogeneic hematopoietic stem-cell transplantation (allo-HSCT) has become a curative therapeutic option for certain monogenic IBDs, its effectiveness regarding endoscopic improvements has not been clarified. METHODS: The clinical course and endoscopic findings of patients with monogenic IBDs who were treated with allo-HSCT between December 2017 and November 2018 at the National Center for Child Health and Development, were retrospectively reviewed. The clinical disease activity was assessed using the weighted Pediatric Crohn's Disease Activity Index (wPCDAI) and the endoscopic finding was evaluated using the Simple Endoscopic Score for Crohn's Disease (SES-CD). Clinical remission was defined as a wPCDAI <10 and endoscopic remission was defined as an SES-CD of 2 or less. RESULTS: Four patients with severe monogenic IBDs, including three with X-linked inhibitors of apoptosis protein (XIAP) deficiency and one with interleukin-10 signaling defect, were treated with allo-HSCT with reduced-intensity conditioning. In four patients, the maximum scores of wPCDAI and SES-CD before allo-HSCT ranged from 67.5 to 120 and 20 to 34, respectively. After allo-HSCT, all four patients showed a significant improvement in intestinal inflammation and achieved both clinical and endoscopic remission. Although patients with XIAP deficiency presented with post-transplant hemophagocytic lymphohistiocytosis and a relatively late engraftment, all patients achieved prolonged clinical remission, and IBD medications were successfully discontinued in all patients. CONCLUSION: Allo-HSCT for monogenic IBD resulted in complete clinical resolution with endoscopically confirmed mucosal healing.

Safety and efficacy of the endoscopic delivery of capsule endoscopes in adult and pediatric patients: Multicenter Japanese study (AdvanCE-J study).

BACKGROUND AND AIM: We retrospectively determined the safety and efficacy of the endoscopic delivery (ED) of capsule endoscopes. METHODS: We enrolled 10,156 patients who underwent small bowel capsule endoscopy (SBCE), 3182 who underwent patency capsule (PC), and 1367 who underwent colon capsule endoscopy (CCE), at 11 gastroenterological and nine pediatric centers. RESULTS: Small bowel capsule endoscopies, PCs, and CCEs were endoscopically delivered to 546 (5.4%), 214 (6.7%), and 14 (1.0%) patients, respectively. Only mild complications occurred for 21.6% (167/774), including uneventful mucosal damage, bleeding, and abdominal pain. Successful ED of SBCE to the duodenum or jejunum occurred in 91.8% and 90.7% of patients aged <16 years and ≥16 years, respectively (P = 0.6661), but the total enteroscopy rate was higher in the first group (91.7%) than in the second (76.2%, P < 0.0001), for whom impossible ingestion (87.3%) was significantly more common than prolonged lodging in the stomach (64.2%, P = 0.0010). Successful PC and CCE delivery to the duodenum occurred in 84.1% and 28.6%, thereafter the patency confirmation rate and total colonoscopy rate was 100% and 61.5%, respectively. The height, weight, and age cutoff points in predicting spontaneous ingestion were 132 cm, 24.8 kg, and 9 years 2 months, respectively, in patients aged <16 years. Patients aged ≥16 years could not swallow the SBCEs mainly due to dysphagia (75.0%); those who retained it in the esophagus due to cardiac disease (28.6%), etc. and in the stomach due to diabetes mellitus (15.7%), etc. CONCLUSIONS: This large-scale study supports the safety and efficacy of ED in adult and pediatric patients. UMIN000042020.

Severe Liver Disorder Following Liver Transplantation in STING-Associated Vasculopathy with Onset in Infancy.

PURPOSE: STING-associated vasculopathy with onset in infancy (SAVI) is a type-I interferonopathy, characterized by systemic inflammation, peripheral vascular inflammation, and pulmonary manifestations. There are three reports of SAVI patients developing liver disease, but no report of a SAVI patient requiring liver transplantation. Therefore, the relevance of liver inflammation is unclear in SAVI. We report a SAVI patient who developed severe liver disorder following liver transplantation. METHODS: SAVI was diagnosed in a 4-year-old girl based on genetic analysis by whole-exome sequencing. We demonstrated clinical features, laboratory findings, and pathological examination of her original and transplanted livers. RESULTS: At 2 months of age, she developed bronchitis showing resistance to bronchodilators and antibiotics. At 10 months of age, she developed liver dysfunction with atypical cholangitis, which required liver transplantation at 1 year of age. At 2 years of age, multiple biliary cysts developed in the transplanted liver. At 3.9 years of age, SAVI was diagnosed by whole-exome sequencing. Inflammatory cells from the liver invaded the stomach wall directly, leading to fatal gastrointestinal bleeding unexpectedly at 4.6 years of age. In pathological findings, there were no typical findings of liver abscess, vasculitis, or graft rejection, but biliary cysts and infiltration of inflammatory cells, including plasmacytes around the bile duct area, in the transplanted liver were noted, which were findings similar to those of her original liver. CONCLUSION: Although further studies to clarify the mechanisms of the various liver disorders described in SAVI patients are needed, inflammatory liver manifestations may be amplified in the context of SAVI.

Stool preparation under anaerobic conditions contributes to retention of obligate anaerobes: potential improvement for fecal microbiota transplantation.

BACKGROUND: Fecal microbiota transplantation (FMT) in patients with ulcerative colitis has shown variable efficacy depending on the protocol used. A previous randomized controlled trial reported that anaerobic preparation of donor stool contributes to improved efficacy. Despite the suggestion that viable obligate anaerobes would be decreased through aerobic handling, there have been only a limited number of reports on how these aerobic or anaerobic procedures affect the composition of viable microbiota in the fecal slurries used for FMT. METHODS: We adopted 16S and 23S rRNA-targeted reverse transcription-quantitative polymerase chain reaction to quantify viable bacteria in fecal slurries. This study utilized specific primers designed to detect obligate anaerobes (including Clostridium coccoides group, C. leptum subgroup, Bacteroides fragilis group, Bifidobacterium, Atopobium cluster, and Prevotella) and facultative anaerobes (including total lactobacilli, Enterobacteriaceae, Enterococcus, Streptococcus, and Staphylococcus). We then calculated the ratio change (RC) between before and after mixing, and compared the resulting values between anaerobic-prep and aerobic-prep in samples fixed immediately after blending (RCAn0 vs. RCAe0) and in samples maintained (under anaerobic or aerobic conditions) for 1 h after blending (RCAn1 vs. RCAe1). RESULTS: For most obligate anaerobes, the median RC tended to be less than 1, indicating that the number of obligate anaerobes was decreased by the blending procedure. However, in samples maintained for 1 h after blending, anaerobic-prep counteracted the decrease otherwise seen for the C. coccoides group and B. fragilis groups (P < 0.01 for both). The C. leptum subgroup also tended to show higher RC by anaerobic-prep than by aerobic-prep, although this effect was not statistically significant. Among facultative anaerobes, Enterobacteriaceae, Enterococcus, and Staphylococcus showed median RC values of more than 1, indicating that these organisms survived and even grew after mixing. Moreover, oxygen exposure had no significant influence on the survival of the facultative anaerobes. CONCLUSIONS: The conditions under which the blending procedure was performed affected the proportion of live anaerobes in fecal slurries. The obligate anaerobes tended to be decreased by blending processes, but anaerobic-prep significantly mitigated this effect. Anaerobic-prep may improve the efficacy of FMT by permitting the efficient transfer of obligate anaerobes to patients with ulcerative colitis.

Ustekinumab for children and adolescents with inflammatory bowel disease at a tertiary children's hospital in Japan.

BACKGROUND AND AIM: Ustekinumab is a human monoclonal antibody targeting the p40 subunit of both interleukin-12 and interleukin-23 with reported efficacy to treat Crohn's disease. However, few studies have reported the use of ustekinumab for pediatric inflammatory bowel disease. This study aimed to assess the clinical efficacy and safety of ustekinumab in children and adolescents with inflammatory bowel disease. METHODS: Medical records of patients aged under 20 years with Crohn's disease or Crohn's disease-like inflammatory bowel disease who had received ustekinumab at a Japanese pediatric inflammatory bowel disease center were retrospectively reviewed for efficacy and safety. The primary outcome was the steroid-free clinical remission rate at weeks 26 and 52. The steroid-free remission rate beyond week 52 was also evaluated. Weighted pediatric Crohn's disease activity index and simple endoscopic score for Crohn's disease were used to assess disease activity. RESULTS: Seventeen patients were included (male : female = 8:9, A1a [diagnosed < 10 years old]:A1b [diagnosed ≥ 10 years old] = 8:9). All patients were on ustekinumab at week 26, and 9/10 continued treatment over 1 year. The steroid-free clinical remission rates were 59% at week 26, 50% at week 52, and 70% over 1 year. Three of eight children who underwent endoscopy after ustekinumab introduction achieved endoscopic remission. No serious adverse events were recorded during the study period. CONCLUSIONS: Ustekinumab may be an effective and safe treatment option for pediatric and adolescent Crohn's disease and Crohn's disease-like inflammatory bowel disease patients having nonresponse or adverse reactions to anti-tumor necrosis factor agents.

X-linked inhibitor of apoptosis protein deficiency complicated with Crohn's disease-like enterocolitis and Takayasu arteritis: A case report.

X-linked inhibitor of apoptosis protein (XIAP) deficiency results in monogenic inflammatory bowel disease. To date, no vasculitis associated with XIAP deficiency has been reported. A 10-year-old boy was diagnosed with Crohn's disease and he responded poorly to conventional treatment for Crohn's disease. He was dependent on corticosteroids and parenteral nutrition. To manage severe colitis, he underwent ileostomy followed by ileocolectomy for an ileo-sigmoid fistula. At the age of 15 years, he developed IgA vasculitis and at the age of 17 years, he developed refractory Takayasu arteritis (TAK), which was resistant to corticosteroid and immunosuppressive therapy. Whole-exome sequencing revealed a novel mutation of the splice acceptor site in XIAP (c.1057-1G > A) at the age of 19 years. Allogeneic hematopoietic stem cell transplantation was successful with subsequent withdrawal of intensive immunosuppressive therapy and clinical remission of both enterocolitis and TAK. This case suggests that patients with XIAP deficiency could develop intractable inflammatory disease involving the intestinal tract and blood vessels.

Infliximab for very early-onset inflammatory bowel disease: A tertiary center experience in Japan.

BACKGROUND AND AIM: Very early-onset inflammatory bowel disease (VEO-IBD), defined as IBD diagnosed before 6 years of age, tends to be refractory to conventional treatment for IBD. However, there have been a few reports about the usage of infliximab for VEO-IBD. This study aimed to evaluate the efficacy and safety of infliximab for VEO-IBD. METHODS: Medical records of a cohort of children with VEO-IBD who had received infliximab in a Japanese tertiary children's hospital were retrospectively reviewed for their disease characteristics and clinical course. Subjects were categorized into three groups for the descriptive comparison: ulcerative colitis type (UCT), non-UCT with perianal disease (NUC-PD), and non-UCT without perianal disease (NUC-NPD). RESULTS: Seventeen VEO-IBD patients (five UCT, five NUC-PD, and seven NUC-NPD) had received infliximab as their first biologic. In the UCT group, infliximab was continued over 54 weeks in two patients, and three eventually required surgery. In contrast, all patients in the NUC-PD and NUC-NPD groups followed up over 54 weeks remained on infliximab, and two of three patients and three of five patients were in remission at week 54, respectively. Infusion reactions occurred in all five UCT, three of five NUC-PD, and two of seven NUC-NPD patients; however, except for two patients with severe reactions, infliximab was continued with premedication and slow infusions. CONCLUSIONS: Infliximab appeared useful for children with VEO-IBD. Children with NUC-PD and NUC-NPD responded better with less infusion reaction compared with that with UCT.

Current role of colonoscopy in infants and young children: a multicenter study.

BACKGROUND: To evaluate the role of colonoscopy in infants and young children and clarify the distribution of colonoscopy-requiring diseases in this age group. METHODS: Cohorts of colonoscopies performed at three children's hospitals in Japan between April 2011 and March 2016 including infants and children younger than six years of age were retrospectively reviewed. RESULTS: In total, 453 colonoscopies were performed in 276 infants and young children. Of these 275 (60.8%) were for diagnostic purposes, 177 (39.2%) were performed as follow-up, and one case was performed for treatment. The median patient age at the time of diagnostic colonoscopy was 2.49 years, and there was a male-to-female ratio of 1.72:1. Abnormal macroscopic and/or histopathological findings were noted in 212 (77.1%) cases. Of these, definite diagnoses were established for the presence of eosinophilic gastrointestinal disorders (EGIDs), inflammatory bowel disease (IBD), and polyp/polyposis in 23, 18.5, and 14% of patients, respectively. Among 51 IBD cases, ulcerative colitis, Crohn's disease, and IBD-unclassified were identified in 47.1, 33.3, and 7.8%, retrospectively via endoscopic examination. Of these, 11 (22%) were eventually diagnosed with monogenic diseases via genetic testing. Of those with rectal bleeding, EGIDs, polyps/polyposis, and IBD were found in 27, 19, and 18%, retrospectively. There were significantly more cases of EGIDs and fewer ones of IBD and polyps/polyposis in patients with rectal bleeding younger than two years of age. Furthermore, 68% of all follow-up colonoscopies were performed in children with IBD. There were no serious complications in our study cohort. CONCLUSION: We determined the role of colonoscopy in infants and young children. Diseases diagnosed using colonoscopy in this age group included IBD, EGIDs, and polyps/polyposis. The increasing trend of patients with IBD and EGIDs worldwide means that the role of colonoscopy in infants and younger children will be more important in the future.

Rapid regulation of sialidase activity in response to neural activity and sialic acid removal during memory processing in rat hippocampus.

Sialidase cleaves sialic acids on the extracellular cell surface as well as inside the cell and is necessary for normal long-term potentiation (LTP) at mossy fiber-CA3 pyramidal cell synapses and for hippocampus-dependent spatial memory. Here, we investigated in detail the role of sialidase in memory processing. Sialidase activity measured with 4-methylumbelliferyl-α-d-N-acetylneuraminic acid (4MU-Neu5Ac) or 5-bromo-4-chloroindol-3-yl-α-d-N-acetylneuraminic acid (X-Neu5Ac) and Fast Red Violet LB was increased by high-K+-induced membrane depolarization. Sialidase activity was also increased by chemical LTP induction with forskolin and activation of BDNF signaling, non-NMDA receptors, or NMDA receptors. The increase in sialidase activity with neural excitation appears to be caused not by secreted sialidase or by an increase in sialidase expression but by a change in the subcellular localization of sialidase. Astrocytes as well as neurons are also involved in the neural activity-dependent increase in sialidase activity. Sialidase activity visualized with a benzothiazolylphenol-based sialic acid derivative (BTP3-Neu5Ac), a highly sensitive histochemical imaging probe for sialidase activity, at the CA3 stratum lucidum of rat acute hippocampal slices was immediately increased in response to LTP-inducible high-frequency stimulation on a time scale of seconds. To obtain direct evidence for sialic acid removal on the extracellular cell surface during neural excitation, the extracellular free sialic acid level in the hippocampus was monitored using in vivo microdialysis. The free sialic acid level was increased by high-K+-induced membrane depolarization. Desialylation also occurred during hippocampus-dependent memory formation in a contextual fear-conditioning paradigm. Our results show that neural activity-dependent desialylation by sialidase may be involved in hippocampal memory processing.

5-Aminosalicylate intolerance causing exacerbation in pediatric ulcerative colitis.

BACKGROUND: 5-Aminosalicylate (5-ASA) is widely used as the first-line drug for ulcerative colitis (UC). 5-ASA is mostly a safe and effective drug, but it can bring about exacerbation due to 5-ASA intolerance. 5-ASA intolerance can be confusing and it can mislead physicians into considering unnecessary treatment escalation, including corticosteroid (CS), biologics, or even surgery. In spite of the clinical importance of 5-ASA intolerance, there have been few studies on its incidence, clinical features, and diagnosis. METHODS: In order to evaluate the incidence, characteristic symptoms, disease course, and laboratory data of children with 5-ASA intolerance, we retrospectively reviewed the medical records of 80 children with UC. RESULTS: Eleven of 80 children (13.8%) with UC were diagnosed with 5-ASA intolerance. The median time between the initiation of 5-ASA and the onset of 5-ASA intolerance was 10 days (range, 4-20 days) in patients not receiving CS. Drug-induced lymphocyte stimulation test (DLST) was performed in 10 patients, and was positive in eight. C-reactive protein (CRP) increased significantly when exacerbation of colitis symptoms occurred. CONCLUSIONS: The incidence of 5-ASA intolerance was relatively high. Besides the challenge test, elevation of CRP and positive DLST appeared to support the diagnosis of 5-ASA intolerance.

Prolonged tacrolimus for pediatric gastrointestinal disorder: Double-edged sword?

BACKGROUND: Although tacrolimus (TAC) can induce remission in children with refractory inflammatory bowel disease (IBD) or autoimmune gastroenteropathy (AGE), its use in maintenance therapy remains controversial. The aim of this study was to investigate the potential nephrotoxic nature of prolonged TAC use. METHODS: This retrospective study reviewed children with gastrointestinal disorder who underwent kidney biopsy for the evaluation of renal damage during TAC therapy for >1 year. The clinical and histological features of renal damage were evaluated in this single-institution cohort. RESULTS: Eighteen of 121 children with IBD and two children with AGE followed at a national children hospital in Tokyo, Japan, received TAC between August 2006 and April 2013. Among them, five (Crohn's disease, n = 3; autoimmune gastropathy, n = 1; autoimmune enteropathy, n = 1) received TAC for >1 year, and underwent kidney biopsy. All five had achieved remission on TAC, but had histological evidence of chronic nephrotoxicity. Renal damage in one patient with relatively low TAC trough level remained mild. Estimated glomerular filtration rate (eGFR) at the time of kidney biopsy was lower than at the initiation of TAC in all four available patients. Among them, eGFR improved in one patient after the decrease or discontinuation of TAC. CONCLUSIONS: TAC appeared to be effective in children with refractory gastrointestinal disorder, but long-term use seems to cause irreversible renal damage. Rigorous monitoring of eGFR and kidney biopsy in selected cases should be considered for the proper adjustment of TAC.