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.

Immune Modulation Effects of Lactobacillus casei Variety rhamnosus on Enterocytes and Intestinal Stem Cells in a 5-FU-Induced Mucositis Mouse Model.

BACKGROUND: Intestinal mucositis remains one of the most deleterious side effects in cancer patients undergoing chemotherapy. We hypothesize that the probiotics could preserve gut ecology, ameliorate inflammation, and protect epithelia via immune modulations of enterocytes and intestinal stem cells. Our aim is to characterize these changes and the safety of probiotics via a 5-fluorouracil- (5-FU-) induced intestinal mucositis mouse model. METHODS: 5-FU-injected BALB/c mice were either orally administrated with saline or probiotic suspension of Lactobacillus casei variety rhamnosus (Lcr35). Diarrhea scores, serum proinflammatory cytokines, and T-cell subtypes were assessed. Immunostaining analyses for the proliferation of intestinal stem cells CD44 and Ki67 were processed. Samples of blood and internal organs were investigated for bacterial translocation. RESULTS: Diarrhea was attenuated after oral Lcr35 administration. Serum proinflammatory cytokines were significantly increased in the 5-FU group and were reversed by Lcr35. A tremendous rise of the CD3+/CD8+ count and a significant decrease of CD3+CD4+/CD3+CD8+ ratios were found in the 5-FU group and were both reversed by Lcr35. 5-FU significantly stimulated the expression of CD44 stem cells, and the expression was restored by Lcr35. 5-FU could increase the number of Ki67 proliferative cells. No bacterial translocation was found in this study. CONCLUSIONS: Our results showed that 5-FU caused intestinal inflammation mainly via Th1 and Th17 responses. 5-FU could stimulate stem cells and proliferation cells in a mouse model. We demonstrate chemotherapy could decrease immune competence. Probiotics were shown to modulate the immune response. This is the first study to analyze the immune modulation effects and safety of Lactobacillus strain on enterocytes and intestinal stem cells 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.

Serum vitamin D level is inversely associated with liver fibrosis in post Kasai's portoenterostomy biliary atresia patients living with native liver.

OBJECTIVE: This study aims to investigate the association of serum vitamin D (VD) levels with the severity of liver fibrosis (LF) in post Kasai's portoenterostomy biliary atresia (PKBA) patients living with their native liver. METHODS: In this cross-sectional study, carried out in a tertiary Children's Hospital in Taipei, Taiwan, PKBA patients living with their native liver were enrolled. Liver biochemistry data, serum 25-hydroxyvitamin D (25-OHVD), acoustic radiation force impulse (ARFI), and scores of Pediatric Quality of Life questionnaire (PedsQL) were collected. RESULTS: All the enrolled 33 PKBA patients (36.4% males), aged 1-23 years, possessed 25-OHVD less than 30ng/ml. An inverse correlation was detected between serum 25-OHVD and ARFI (r2 = 0.175; p = 0.024). We selected a cutoff value of 23ng/mL to divide PKBA patients into two groups, as the p-value was the most significant at this point when comparing the median ARFI of two groups (p = 0.003). Ten (30.3%) had 25-OHVD≥23ng/ml (HVD group), whereas 23(69.7%) had 25-OHVD<23ng/ml (LVD group). HVD group had lower ARFI (1.13m/s vs. 1.52m/s, p = 0.003), lower aspartate transaminase (AST) (29U/L vs. 64U/L, p = 0.033), and higher scores of self-reported health-related quality of life in psychosocial functioning (86.7 vs. 77.1, p = 0.047) than LVD group. CONCLUSION: VD levels are inversely associated with severity of LF in PKBA patients with native liver.

Vitamin D and health - The missing vitamin in humans.

Severe vitamin D deficiency may cause rickets in infants or children and osteomalacia in adults, though it is now uncommon in developed countries. However, subclinical vitamin D deficiency is more prevalent, and it is associated with osteoporosis and higher incidence of falls or fractures. It was reported that 96% children with rickets were breastfed, since breast milk contains inadequate vitamin D. The American Academy of Pediatrics 2008 recommended infants who were exclusively or partially breastfed required 400 international units vitamin D daily from the first few days of life. Furthermore, since vitamin D receptors are present all over the body, insufficient vitamin D status may correlate with several extra-skeletal effects, such as pregnancy-related complications and immune dysfunction. This paper discusses the researches regarding system-based vitamin D effects, the possible risk factors leading to vitamin D deficiency, and the recommendations of vitamin D requirements. It is well-known that vitamin D can be obtained by sun exposure or limited natural dietary sources. The American Academy of Dermatology declared ultraviolet radiation to be a known skin carcinogen, so it may not be safe or efficient to obtain vitamin D via sun exposure or other artificial sources. Therefore, many pediatricians and physicians recommend appropriate vitamin D supplementation to achieve optimal plasma concentration. Trials assessing the effects of vitamin D repletion and establishing its optimum serum level are ongoing. Medical advice for vitamin D supplementation should be individualized accordingly.

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.

Juvenile polyposis syndrome: An unusual case report of anemia and gastrointestinal bleeding in young infant.

BACKGROUND: Juvenile polyposis syndrome, a rare disorder in children, is characterized with multiple hamartomatous polyps in alimentary tract. A variety of manifestations include bleeding, intussusception, or polyp prolapse. In this study, we present an 8-month-old male infant of juvenile polyposis syndrome initially presenting with chronic anemia. To the best of our knowledge, this is the youngest case reported in the literature. METHODS: We report a rare case of an 8-month-old male infant who presented with chronic anemia and gastrointestinal bleeding initially. Panendoscopy and abdominal computed tomography showed multiple polyposis throughout the entire alimentary tract leading to intussusception. Technetium-99m-labeled red blood cell (RBC) bleeding scan revealed the possibility of gastrointestinal tract bleeding in the jejunum. Histopathological examination on biopsy samples showed Peutz-Jeghers syndrome was excluded, whereas the diagnosis of juvenile polyposis syndrome was established. RESULTS: Enteroscopic polypectomy is the mainstay of the treatment. However, polyps recurred and occupied the majority of the gastrointestinal tract in 6 months. Supportive management was given. The patient expired for severe sepsis at the age of 18 months. CONCLUSION: Juvenile polyposis syndrome is an inherited disease, so it is not possible to prevent it. Concerning of its poor outcome and high mortality rate, it is important that we should increase awareness and education of the parents at its earliest stages.

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.

Vertical transmission of hepatitis C virus: Current knowledge and perspectives.

Hepatitis C virus (HCV) infection is a major global health issue. Infection by the HCV can cause acute and chronic liver diseases and may lead to cirrhosis, hepatocellular carcinoma or liver failure. The World Health Organization estimates that approximately 3% of the world population have been infected with HCV and the worldwide prevalence is between 1% and 8% in pregnant women and between 0.05% and 5% in children. Following the introduction of blood product screening, vertical transmission becomes the leading cause of childhood HCV infection. The prevalence of pediatric HCV infection varies from 0.05% to 0.36% in developed countries and between 1.8% and 5% in the developing world. All children born to women with anti-HCV antibodies should be checked for HCV infection. Though universal screening is controversial, selective antenatal HCV screening on high-risk populations is highly recommended and should be tested probably. Multiple risk factors were shown to increase the possibility of HCV vertical transmission, including coinfections with human immunodeficiency virus, intravenous drug use and elevated maternal HCV viral load, while breastfeeding and HCV genotypes have been studied to have little impact. At present, no clinical intervention has been clearly studied and proved to reduce the HCV vertical transmission risk. Cesarean section should not be recommended as a procedure to prevent vertical transmission, however, breastfeeding is generally not forbidden. The high prevalence of global HCV infection necessitates renewed efforts in primary prevention, including vaccine development, as well as new approaches to reduce the burden of chronic liver disease. Future researches should focus on the interruption of vertical transmission, developments of HCV vaccine and direct-acting antivirals in infancy and early childhood.

A twenty-year review of early and late-presenting congenital Bochdalek diaphragmatic hernia: are they different clinical spectra?

BACKGROUND: Congenital Bochdalek diaphragmatic hernia (CDH) is easily recognized if it is present shortly after birth. However, cases of delayed CDH presentation are more subtle and therefore less easily diagnosed. METHODS: We retrospectively analyzed 85 patients who were under 18 and diagnosed with CDH between June 1987 and May 2007. Those diagnosed before 1 month of age were categorized as having early-presenting CDH and those diagnosed after 1 month were categorized as having late-presenting CDH. RESULTS: Of the 85 cases, 68 (80%) were early-presenting and 17 (20%) were late-presenting CDH. Respiratory symptoms were more common in early-presenting CDH, while gastrointestinal complaints were more dominant in the late-presenting group, particularly in patients with left diaphragmatic defects. Late-presenting CDH, which was more likely to be associated with chronic gastrointestinal symptoms, was associated with a lower mortality than acute early-presenting CDH with respiratory symptoms, despite the more prompt diagnosis of the latter. The small bowel was the organ most commonly herniated into the thorax. Congenital heart disease was the most commonly associated malformation, but the presence of associated anomalies did not increase mortality. CONCLUSION: Early-presenting CDH shows acute symptoms, is readily diagnosed, and requires prompt intervention to prevent death. In contrast, late-presenting CDH shows more subtle symptoms and is more difficult to diagnose. Although the late-presenting CHD has better prognosis, it still requires surgery intervention to alleviate the symptoms. Clinicians must maintain a high index of suspicion for CDH, regardless of its presentation.

Gastric volvulus in children.

Gastric volvulus (GV) is a rare disease in children that may not be recognized early in its course. We retrospectively analyzed 15 patients under 18 years of age who presented to our medical center with GV between January 1995 and June 2005. Patients with complete volvulus and acute obstruction requiring immediate intervention were defined as acute GV. Chronic GV was diagnosed in the presence of partial volvulus with chronic, nonspecific symptoms and signs. Chronic GV (12/ 15) was more common than acute GV (3/15). Organoaxial GV was the most common type (9/15), and there was a high incidence (6/15) of associated anomalies that predisposed to the condition. None of our patients had Borchardt's triad (acute localized epigastric distension, unproductive retching, and the inability to pass a nasogastric tube) which is described in adults with acute GV. Acute GV was immediately treated surgically, but conservative management was successful in patients with chronic idiopathic GV. When acute GV in children fails to exhibit the full gamut of Borchardt's triad, the diagnosis may be delayed. Immediate surgical reduction is recommended for acute GV. For chronic idiopathic GV, the treatment may be based on the age at diagnosis, the severity of symptoms, and how patients are expected to comply with conservative measures.