Blue Rubber Bleb Nevus Syndrome (BRBNS): A Rare Cause of Refractory Anemia in Children.

Refractory anemia is not uncommon in pediatric patients, and anemia caused by gastrointestinal tract bleeding should always be kept in mind. Aside from infection or intestinal malrotation related bleeding, vascular malformation should also be considered. Blue rubber bleb nevus syndrome (BRBNS) is a rare vascular disorder consisting of multiple venous malformations. Lack of experience in pediatric BRBNS might lead to delayed diagnosis or misdiagnosis. Herein, we report a case of an eleven-year-old boy with recurrent pallor appearance and weakness diagnosed with BRBNS. After a thorough examination, he was treated with endoscopic polypectomy, and further iron supplements and folic acid. He is now under regular follow-up at our outpatient department. No complication is noted for six months. BRBNS is a rare venous malformation syndrome that mostly involves skin and the gastrointestinal tract. Multidisciplinary approach should be arranged for diagnosis and management. Up to date, no consensus for BRBNS treatment has been reached. Management usually depends on clinical symptoms and severity of damage of involved organs. The options of treatment include conservative, medical, endoscopic, and surgical management.

Effects of Vitamin D-Deficient Diet on Intestinal Epithelial Integrity and Zonulin Expression in a C57BL/6 Mouse Model.

Background and Aims: Vitamin D (VD) plays an important role not only in mineral balance and skeletal maintenance but also in immune modulation. VD status was found correlated with the pathophysiology and severity of inflammatory bowel diseases and other autoimmune disorders. Epithelial barrier function is primarily regulated by the tight-junction (TJ) proteins. In this study, we try to establish an animal model by raising mice fed VD-deficient diet and to investigate the effects of VD-deficient diet on gut integrity and zonulin expression. Methods: Male C57BL/6 mice were administered either VD-deficient [VDD group, 25(OH)2D3 0 IU/per mouse] or VD-sufficient [VDS group, 25(OH)2D3 37.8 IU/per mouse] special diets for 7 weeks. Body weight and diet intake were recorded weekly. Serum VD levels were detected. After sacrifice, jejunum and colon specimens were collected. The villus length and crypt depth of the jejunum as well as mucosa thickness of the colon were measured. Various serum pro-inflammatory cytokines and intestinal TJ proteins were assessed. The serum level of zonulin and the mRNA expression of jejunum zonulin were also investigated. Results: We found that mice fed a VDD diet had a lower serum level of VD after 7 weeks (p < 0.001). VDD mice gained significant less weight (p = 0.022) and took a similar amount of diet (p = 0.398) when compared to mice raised on a VDS diet. Significantly decreased colon mucosa thickness was found in VDD mice compared with the VDS group (p = 0.022). A marked increase in serum pro-inflammatory cytokine levels was demonstrated in VDD mice. All relative levels of claudin (CLD)-1 (p = 0.007), CLD-3 (p < 0.001), CLD-7 (p < 0.001), and zonulin-1 (ZO-1, p = 0.038) protein expressions were significantly decreased in the VDD group when compared to the VDS group. A significant upregulation of mRNA expression of jejunum zonulin (p = 0.043) and elevated serum zonulin (p = 0.001) were found in the VDD group. Conclusions: We successfully demonstrated that VDD could lead to impaired barrier properties. We assume that sufficient VD could maintain intestinal epithelial integrity and prevent mucosal barrier dysfunction. VD supplementation may serve as part of a therapeutic strategy for human autoimmune and infectious diseases with intestinal barrier dysfunction (leaky gut) in the future. To our knowledge, this is the first study to demonstrate that VDD could lead to a significant upregulation in mRNA expression of the jejunum zonulin level and also a marked elevation of serum zonulin in a mouse model.

Modulations of probiotics on gut microbiota in a 5-fluorouracil-induced mouse model of mucositis.

BACKGROUND AND AIM: Intestinal mucositis remained one of the most deleterious complications in cancer patients undergoing chemotherapy. 5-FU treatment was reported to affect the abundance of gut microbiota and cause mucositis, which might be ameliorated by probiotics. We investigate the potential changes of 5-FU treatment and the modulations of probiotics on gut microbiota in a mouse model. METHODS: Male BALB/c mice received either 5-FU or saline (S). They were separated and fed saline, Lactobacillus casei variety rhamnosus (Lcr) and Lactobacillus reuteri DSM 17938 (BG). Lcr and BG were simultaneously administered with 5-FU for 5 days. Stool specimens were collected for DNA extraction and pyrosequenced for bioinformatic analysis. RESULTS: Fecal microbial communities were obviously diverse. Bacteroides and Bacteroidaceae were the most abundant microbiota in FU.BG group while S24_7 was the most in S.S group. At phylum and class levels, abundances of Betaproteobacteria, Erysipelotrichi, Gammaproteobacteria, and Verrucomicrobia were significantly increased in the FU groups. Probiotics supplementation did increase the abundances of Enterobacteriales and Turicibacterales. We demonstrated that probiotics did modulate the abundance and diversity of gut microbiota. Bacterial motility proteins were found enriched and upregulated in the S.BG group. No mortality was noted. No bacterial translocation was found in spleen and blood among the six groups. CONCLUSION: Gut microbiota of mice undergoing chemotherapy exhibited a distinct disruption in bacterial composition. Probiotic did modulate the abundance and diversity of gut microbiota. This is the first study to analyze the effects and safety of Lactobacillus strains on 5-FU-induced mucositis systematically and assess changes in the intestinal microbiota after probiotic intervention.

SCID/NOD mice model for 5-FU induced intestinal mucositis: Safety and effects of probiotics as therapy.

BACKGROUND: For chemotherapy patients, intestinal mucositis is a frequent complication. Previously, we evaluated the beneficial effect of oral probiotics in 5-Fluorouracil (5-FU) induced mucositis in BALB/c mice. Here, we used SCID/NOD mice instead to simulate the immunodeficiency of chemotherapy patients: first, to evaluate the safety of probiotic supplementation and second, to determine the probiotic effect in response to 5-FU intestinal mucositis. METHODS: Thirty-six SCID/NOD mice were injected with saline (three control groups) or 5-FU (three experimental groups) intraperitoneally daily for five days. Mice were given either oral saline daily, probiotic suspension of Lactobacillus casei variety rhamnosus (Lcr35, Antibiophilus™, France) or Lactobacillus acidophilus and Bifidobacterium bifidum (LaBi, Infloran™, Italy). Blood, liver, spleen, and lymph node tissue samples were evaluated for probiotic translocation via culture and Q-PCR. Weight change, diarrhea score, jejunal villus height (VH) and crypt depth (CD), and serum cytokine levels of TNF-α, IFNγ, IL-1ß, IL-6, IL-4, IL-10, IL-13, and IL-17 were also assessed. RESULTS: No weight loss was found in the SCID control group. Mean weight loss of 10.63 ± 0.87% was noted by day five in 5-FU group without probiotics but it was only 6.2 ± 0.43% if mice were given Lcr35 (p < 0.01) and 7.1 ± 1.80% (p < 0.01) if they were given LaBi. Diarrhea score of 5-FU group without probiotics was 2.0 ± 0.0 by day five, which dropped to 1.33 ± 0.17 (p < 0.05) and 1.42 ± 0.24 (p < 0.05) with Lcr35 and LaBi, respectively. Average VH significantly decreased and CD significantly increased in SCID mice given 5-FU. With probiotics, average CD improved (p < 0.05) while VH lengthened as well. Besides IL-13, all cytokine levels increased in 5-FU SCID mice. Both Lcr35 and LaBi significantly inhibited serum cytokines (p < 0.05). No probiotic strains were detected in blood cultures of any mice. CONCLUSION: Using SCID/NOD mice as a novel model for 5-FU induced intestinal mucositis, we find that probiotics Lcr35 and LaBi do not lead to bacteremia, can improve diarrhea and body weight, can restore jejunal crypt depth, and significantly inhibit cytokines TNF-α, IL-1ß, IFNγ, IL-6, IL-4, IL-10, and IL-17.

Does Vitamin D Deficiency Affect the Immunogenic Responses to Influenza Vaccination? A Systematic Review and Meta-Analysis.

Influenza virus infection is a major global public health problem, and the efficacy of influenza vaccination is not satisfactory. Vitamin D is involved in many immune-mediated inflammatory processes. The impact of vitamin D levels on the immunogenic response to influenza vaccination is not clear. We performed a comprehensive literature search and systematic review of studies that investigated vitamin D and influenza vaccination. Data pertaining to study population, vaccine components, vitamin D levels, and immunogenic response were analyzed. Nine studies, with a combined study population of 2367 patients, were included in the systematic review. Four studies were included in the meta-analysis to investigate the influence of vitamin D deficiency (VDD) on the seroprotection (SP) rates and seroconversion (SC) rates following influenza vaccination. We found no significant association between vitamin D level and the immunogenic response to influenza vaccination. However, strain-specific differences may exist. We observed lower SP rates of influenza A virus subtype H3N2 (A/H3N2) and B strain in VDD patients than patients with normal vitamin D levels (A/H3N2: 71.8% vs. 80.1%, odds ratio (OR): 0.63, 95% confidence interval (CI): 0.43-0.91, p = 0.01; B strain: 69.6% vs. 76.4%, OR: 0.68, 95% CI: 0.5-0.93, p = 0.01). However, the SP rates of A/H1N1 and SC rates of all three strains were not significantly different in VDD and control groups. In conclusion, no association was observed between VDD and immunogenic response to influenza vaccination.

Amelioration of Chemotherapy-Induced Intestinal Mucositis by Orally Administered Probiotics in a Mouse Model.

BACKGROUND AND AIMS: Intestinal mucositis is a frequently encountered side effect in oncology patients undergoing chemotherapy. No well-established or up to date therapeutic strategies are available. To study a novel way to alleviate mucositis, we investigate the effects and safety of probiotic supplementation in ameliorating 5-FU-induced intestinal mucositis in a mouse model. METHODS: Seventy-two mice were injected saline or 5-Fluorouracil (5-FU) intraperitoneally daily. Mice were either orally administrated daily saline, probiotic suspension of Lactobacillus casei variety rhamnosus (Lcr35) or Lactobacillus acidophilus and Bifidobacterium bifidum (LaBi). Diarrhea score, pro-inflammatory cytokines serum levels, intestinal villus height and crypt depth and total RNA from tissue were assessed. Samples of blood, liver and spleen tissues were assessed for translocation. RESULTS: Marked diarrhea developed in the 5-FU groups but was attenuated after oral Lcr35 and LaBi administrations. Diarrhea scores decreased significantly from 2.64 to 1.45 and 0.80, respectively (P<0.001). Those mice in 5-FU groups had significantly higher proinflammatory cytokine levels (TNF-α: 234.80 vs. 29.10, P<0.001, IL-6: 25.13 vs. 7.43, P<0.001, IFN-γ: 22.07 vs. 17.06, P = 0.137). A repairing of damage in jejunal villi was observed following probiotics administration. We also found TNF-α, IL-1ß and IL-6 mRNA expressions were up-regulated in intestinal mucositis tissues following 5-FU treatment (TNF-α: 4.35 vs. 1.18, IL-1ß: 2.29 vs. 1.07, IL-6: 1.49 vs. 1.02) and that probiotics treatment suppressed this up-regulation (P<0.05). No bacterial translocation was found in this study. CONCLUSIONS: In conclusion, our results show that oral administration of probiotics Lcr35 and LaBi can ameliorate chemotherapy-induced intestinal mucositis in a mouse model. This suggests probiotics may serve as an alternative therapeutic strategy for the prevention or management of chemotherapy-induced mucositis in the future.

Recurrent Intussusception: when Should Surgical Intervention be performed?

OBJECTIVE: To determine the optimal timing of surgery for recurrent intussusception. METHODS: We retrospectively reviewed medical records of patients aged from 0 to 18 years old with diagnosis of intussusception in the Pediatric Department at Mackay Memorial Hospital between January 1995 and May 2010. RESULTS: During the study period, there were 686 children (divided into three age groups: 367 < 2 years, 289 aged 2 to 5 years, 30 > 5 years) with diagnoses of intussusception. Eighty-five of the 686 patients had recurrent intussusception, of whom 56 had two, 16 had three, 11 had four, and 2 had five episodes. The recurrence rate after the first, second, third, and fourth barium enema reductions were 15.7%, 37.7%, 68.4%, and 100.0%, respectively. The incidence of recurrence and failure rate of barium enema reduction did not differ significantly among these three age groups. Surgery was performed in 177 children (146 during the first episode and 31 in recurrent cases). The probability of eventual surgery after first enema reduction was 21.8%, after the second 35.7%, and after the third 70.0%. Lead points were found in 15 children, and all of them were found during surgery for the first episode of intussusception. CONCLUSION: The probability of recurrence was 100% after the fourth episode of intussusception in our study. After the third episode of intussusception, the probability of recurrence and eventual surgery were 68% and 70%, respectively. From this study, surgical intervention should be considered at the third episode of intussusception.

Free amino acids in full-term and pre-term human milk and infant formula.

OBJECTIVE: Although the nutritional value of human milk has been thoroughly studied, few reports describing its free amino acid (FAA) content have been published. Although infant formulas are designed to approximate the nutrient composition of human milk, the content and concentration of free amino acids are unknown. We compared the FAA concentrations of milk from mothers of preterm and full-term infants with those in several infant formulas. METHOD: Human milk was obtained during three different stages of lactation (colostral, transitional and mature milk). Sixty-seven samples were collected from 44 healthy mothers of term infants and 23 mothers of premature infants 29 to 36 weeks gestation (mean 33 weeks). Two brands of powdered term formula (TF-A and TF-B) and two brands designed for preterm infants (PTF-A and PTF-B )were also studied. Ion exchange chromatography was used for free amino acid analysis. RESULTS: The mean concentration of total FAA in human milk was significantly higher than any of the infant formulas (8139 micromol/L for pre-term human milk; 3462 micromol/L for full term human milk; TF-A, 720 micromol/L; TF-B, 697 micromol/L; PTF-A, 820 micromol/L; PTF-B, 789 micromol/L) (P <0.01). FAA concentration in term and premature human colostral milk was significantly higher than in human transitional and mature milks (P <0.01). In comparing individual FAAs, there were significant differences in concentrations between term human milk and preterm milk except for phosphoethanolamine, hydroxyproline, asparagine, and alpha-amino-eta-butyric acid. There were significant differences in all FAA concentrations between all human milks and infant formulas (P <0.05), but no significant differences were found among the study formulas. CONCLUSION: The concentration of FAA is high in human colostral milk and decreases through the transitional and mature milk stages. FAA is higher in all human milks than in infant formulas.