A nationwide survey of pediatric acquired demyelinating syndromes in Japan.

OBJECTIVE: To investigate the clinical and epidemiologic features of pediatric acquired demyelinating syndromes (ADS) of the CNS in Japan. METHODS: We conducted a nationwide survey and collected clinical data on children with ADS aged 15 years or younger, who visited hospitals between 2005 and 2007. RESULTS: Among 977 hospitals enrolled, 723 (74.0%) responded to our inquiries and reported a total of 439 patients as follows: 244 with acute disseminated encephalomyelitis (ADEM), 117 with multiple sclerosis (MS), 14 with neuromyelitis optica (NMO), and 64 with other ADS. We collected and analyzed detailed data from 204 cases, including those with ADEM (66), MS (58), and NMO (10). We observed the following: (1) the estimated annual incidence rate of pediatric ADEM in Japan was 0.40 per 100,000 children (95% confidence interval [CI], 0.34-0.46), with the lowest prevalence in the north; (2) the estimated prevalence rate of MS was 0.69 per 100,000 children (95% CI, 0.58-0.80), with the lowest prevalence in the south; (3) NMO in Japan was rare, with an estimated prevalence of 0.06 per 100,000 children (95% CI, 0.04-0.08); and (4) the sex ratio and mean age at onset varied by ADS type, and (5) male/female ratios correlated with ages at onset in each ADS group. CONCLUSIONS: Our results clarify the characteristic clinical features of pediatric ADS in the Japanese population.

Complex molecular genetic abnormalities involving three or more genetic mutations are important prognostic factors for acute myeloid leukemia.

We conducted a comprehensive analysis of 28 recurrently mutated genes in acute myeloid leukemia (AML) in 271 patients with de novo AML. Co-mutations were frequently detected in the intermediate cytogenetic risk group, at an average of 2.76 co-mutations per patient. When assessing the prognostic impact of these co-mutations in the intermediate cytogenetic risk group, overall survival (OS) was found to be significantly shorter (P=0.0006) and cumulative incidence of relapse (CIR) significantly higher (P=0.0052) in patients with complex molecular genetic abnormalities (CMGAs) involving three or more mutations. This trend was marked even among patients aged ⩽65 years who were also FLT3-ITD (FMS-like tyrosine kinase 3 internal tandem duplications)-negative (OS: P=0.0010; CIR: P=0.1800). Moreover, the multivariate analysis revealed that CMGA positivity was an independent prognostic factor associated with OS (P=0.0007). In stratification based on FLT3-ITD and CEBPA status and 'simplified analysis of co-mutations' using seven genes that featured frequently in CMGAs, CMGA positivity retained its prognostic value in transplantation-aged patients of the intermediate cytogenetic risk group (OS: P=0.0002. CIR: P<0.0001). In conclusion, CMGAs in AML were found to be strong independent adverse prognostic factors and simplified co-mutation analysis to have clinical usefulness and applicability.

Development of low-fluorescence thick photoresist for high-aspect-ratio microstructure in bio-application.

In this study, we propose and evaluate a novel low-auto-fluorescence photoresist (SJI photoresist) for bio-application, e.g., in gene analysis and cell assay. The spin-coated SJI photoresist has a wide thickness range of ten to several hundred micrometers, and photoresist microstructures with an aspect ratio of over 7 and micropatterns of less than 2 µm are successfully fabricated. The emission spectrum intensity of the SJI photoresist is found to be over 80% less than that of the widely used SU-8 photoresist. To evaluate the validity of using the proposed photoresist in bio-application for fluorescence observation, we demonstrate a chromosome extension device composed of the SJI photoresist. The normalized contrast ratio of the SJI photoresist exhibits a 50% improvement over that of the SU-8 photoresist; thus, the SJI photoresist is a versatile tool for bio-application.

Inhibition of S100A6 induces GVL effects in MLL/AF4-positive ALL in human PBMC-SCID mice.

Mixed-lineage leukemia (MLL)/AF4-positive ALL is associated with a poor prognosis even after allogeneic hematopoietic SCT (allo-HSCT). We reported previously that MLL/AF4-positive ALL shows resistance to TNF-α, which is the main factor in the GVL effect, by upregulation of S100A6 expression followed by interference with the p53-caspase 8-caspase 3 pathway in vitro. We examined whether inhibition of S100A6 can induce an effective GVL effect on MLL/AF4-positive ALL in a mouse model. MLL/AF4-positive ALL cell lines (SEM) transduced with lentiviral vectors expressing both S100A6 siRNA and luciferase (SEM-Luc-S100A6 siRNA) were produced. SEM-Luc-S100A6 siRNA cells and SEM-Luc-control siRNA cells were injected into groups of five SCID mice (1 × 10(7)/body). After confirmation of engraftment of SEM cells by in vivo imaging, the mice in each group were injected with 4.8 × 10(7) human PBMCs. SEM-Luc-S100A6 siRNA-injected mice showed significantly longer survival periods than SEM-Luc-control siRNA-injected mice (P=0.002). SEM-Luc-S100A6 siRNA-injected mice showed significantly slower tumor growth than those injected with SEM-Luc-control siRNA (P<0.0001). These results suggested that inhibition of S100A6 may be a promising therapeutic target for MLL/AF4-positive ALL in combination with allo-HSCT.

Faecal chitinase 3-like-1: a novel biomarker of disease activity in paediatric inflammatory bowel disease.

BACKGROUND: Chitinase 3-like-1 (CHI3L1) is up-regulated in the inflamed mucosa of inflammatory bowel disease (IBD). AIM: To evaluate the usefulness of a faecal CHI3L1 assay, as a reliable marker for predicting the severity of paediatric IBD. METHODS: Faecal samples were obtained from ulcerative colitis (UC, n = 94), Crohn's disease (CD, n = 87), and healthy individuals (n = 56). The faecal CHI3L1 and calprotectin levels were determined by ELISA. For endoscopic evaluation, the sum of the Matts' score for UC and the simple endoscopic score for CD (SES-CD) were used. Ileal lesions were evaluated by ultrasonography. RESULTS: Faecal CHI3L1 levels were significantly elevated in active UC (median 366.6 ng/g, n = 44) and active CD (median 632.7 ng/g, n = 48) patients, as compared with healthy individuals (median 2.2 ng/g, n = 56). In UC patients, the faecal CHI3L1 levels were positively correlated with the sum of the Matts' score (r = 0.73, P < 0.01, n = 42). In CD patients, there was a significant correlation between faecal CHI3L1 levels and endoscopic activity as determined by the SES-CD scoring system (r = 0.61, P < 0.01, n = 25). The faecal CHI3L1 levels of patients with wall thickening of their small intestine were significantly higher than those of healthy controls or patients without wall thickening. The cutoff value of 13.7 ng/g for fecal CHI3L1(the 95th percentile of the control value) predicted active lesions in IBD patients with a sensitivity of 84.7% and a specificity of 88.9%. CONCLUSION: Faecal CHI3L1 assays may be useful for predicting the severity and activity of mucosal inflammation in IBD.

Resistance of MLL-AFF1-positive acute lymphoblastic leukemia to tumor necrosis factor-alpha is mediated by S100A6 upregulation.

Mixed-lineage leukemia (MLL)-AFF1 (MLL-AF4)-positive acute lymphoblastic leukemia (ALL) is associated with poor prognosis, even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The resistance to graft-versus-leukemia (GVL) effects may be responsible for the poor effect of allo-HSCT on MLL-AFF1-positive ALL. Cytotoxic effector mechanisms mediated by tumor necrosis factor-alpha (TNF-α) was reported to contribute to the GVL effect. We showed that MLL-AFF1-positive ALL cell lines are resistant to TNF-α. To examine the mechanism of resistance to TNF-α of MLL-AFF1-positive leukemia, we focused on S100A6 as a possible factor. Upregulation of S100A6 expression and inhibition of the p53-caspase 8-caspase 3 pathway were observed only in MLL-AFF1-positive ALL cell lines in the presence of TNF-α. The effect of S100A6 on resistance to TNF-α by inhibition of the p53-caspase 8-caspase 3 pathway of MLL-AFF1-positive ALL cell lines were also confirmed by analysis using small interfering RNA against S100A6. This pathway was also confirmed in previously established MLL-AFF1 transgenic mice. These results suggest that MLL-AFF1-positive ALL escapes from TNF-α-mediated apoptosis by upregulation of S100A6 expression, followed by interfering with p53-caspase 8-caspase 3 pathway. These results suggest that S100A6 may be a promising therapeutic target for MLL-AFF1-positive ALL in combination with allo-HSCT.

Inhibitory effects of Japanese apricot (Prunus mume Siebold et Zucc.; Ume) on Helicobacter pylori-related chronic gastritis.

OBJECTIVES: We investigated the correlation between Japanese apricot (JA) intake and Helicobacter pylori-related chronic atrophic gastritis (CAG). METHODS: A questionnaire was administered and serum anti-H. pylori IgG antibodies measured in 1358 asymptomatic adults. The subjects were divided into high-intake and low-intake groups. Histological and serological evaluation of H. pylori-related CAG was performed in 68 non-elderly volunteers. RESULTS: The H. pylori-negative rate did not differ significantly between the high-intake and low-intake groups. Mean antibody titers were lower in the high-intake group, but the difference was not significant. There was no significant difference in the rate of H. pylori infection on the basis of JA intake when subjects were stratified by age. Among H. pylori-positive non-elderly subjects, antibody titers were significantly lower in the high-intake group (P=0.041). Endoscopic tissue biopsy from the 68 volunteers showed less H. pylori bacterial load and mononuclear infiltration irrespective of gastric site in the high-intake group. In the high-intake group, antral neutrophil infiltration was significantly less pronounced and corporal atrophy was less extensive. Serological evaluation using serum PG levels also confirmed these histopathological data. CONCLUSIONS: Our findings strongly indicate a preventive effect of JA intake on CAG by inhibiting H. pylori infection and reducing active mucosal inflammation.

Four cases of postrenal renal failure induced by renal stone associated with rotavirus infection.

Rotavirus (RV) is a common pathogen that causes acute gastroenteritis in childhood. Some cases with RV infection also have prerenal renal failure induced by dehydration associated with vomiting and diarrhea. Here, we report 4 patients with RV infection who developed postrenal renal failure induced by urinary tract obstruction with uroammoniac calculi or crystals. The patients did not have metabolic disorders or abnormalities of the urinary tract, and increased urinary excretion of uric acid was not recognized at discharge. In addition, no abnormalities in the uric acid transporter (URAT1) were found in any of the patients. Uric acid stone formation was considered to have originated from the low pH caused by dehydration and the increase of urinary uric acid excretion from damaged cells.

Association of gastric fluid microbes at birth with severe bronchopulmonary dysplasia.

OBJECTIVE: Gastric fluid microbes were examined in preterm infants at birth to assess their influence on the postnatal outcome. STUDY DESIGN: Prospective cohort study. SETTING: Level III neonatal intensive care unit. PATIENTS: A total of 103 premature neonates with a gestational age of less than 32 weeks. MAIN OUTCOME MEASURE: Gastric fluid microbes were identified by analysis of bacterial 16S ribosomal RNA gene. Additionally, the urease gene of Ureaplasma species was detected by polymerase chain reaction of gastric fluid obtained at birth and/or tracheal aspirate from ventilated preterm infants. The association between detection of microbes and bronchopulmonary dysplasia was investigated through assessment from clinical features and by a lung injury marker (KL-6). RESULTS: Forty-two of 103 gastric fluid specimens were positive for microbes. Ureaplasma species were detected in 23 of the 42 (55%) gastric fluid specimens. All infants with Ureaplasma species in tracheal aspirate fluid also had positive gastric fluid specimens. Compared to infants negative for gastric fluid microbes, infants positive for microbes had higher rates of maternal chorioamnionitis (18% vs 78%), premature rupture of membranes (11% vs 55%), severe bronchopulmonary dysplasia (1.6% vs 14%) and showed higher plasma KL-6 levels during the initial 4 weeks of life. CONCLUSION: Detection of gastric fluid microbes was correlated well with antenatal infection and severe bronchopulmonary dysplasia. Detection of Ureaplasma species in gastric fluid was associated with subsequent respiratory colonisation. These results suggest that antenatal exposure of the immature fetus to microbes may cause lung injury and promote the onset of bronchopulmonary dysplasia.

[Successful administration of nifekalant hydrochloride for postoperative junctional ectopic tachycardia in congenital cardiac surgery].

Two episode of junctional ectopic tachycardia (JET) caused hemodynamic deterioration early after tetralogy of Fallot repair in an 8-month-old infant. Sinus rhythm resumed in each of the episodes immediately after intravenous administration of nifekalant hydrochloride (NIF), a newly developed Vaughan-Williams class III antiarrhythmic drug in Japan. Although QT interval was modestly prolonged with NIF, no life-threatening ventricular arrhythmia (i.e., torsades de pointes) occurred. NIF might be an effective alternative in the treatment of postoperative JET in congenital cardiac surgery.

Protective effect of radical scavenger edaravone against puromycin nephrosis.

AIM: Recent studies have indicated that reactive oxygen species (ROS) play a role in the pathogenesis of glomerular injury leading to proteinuria in nephrotic syndrome. In the present investigation, we examined the effects of the radical scavenger edaravone administered at various time points to rats with puromycin nephrosis. MATERIALS AND METHODS: 35 Wistar rats were divided into five groups: treatment with puromycin aminonucleoside (PAN) alone, treatment with PAN followed by edaravone in the early period, treatment with PAN followed by edaravone administration in the late period, treatment with PAN and administration of edaravone for the whole experimental period, and untreated controls. On Days 3, 6 and 9, urinary protein excretion was measured. The levels of glomerular thiobarbituric acid-reactive substance (TBArs) were determined in all animals on Day 10. RESULTS: On Day 9, rats that had been administered edaravone showed reduced urinary protein excretion and reduced glomerular TBArs. In particular, edaravone administration in the late period, during which proteinuria was most acute, had the effect of reducing the severity of proteinuria. Glomerular TBArs were suppressed to the control level. Our results indicate that edaravone exerts a protective effect in the acute phase of PAN nephrosis when administered as antioxidant therapy at the onset of proteinuria. CONCLUSIONS: Edaravone can ameliorate urinary protein excretion after the onset of proteinuria in nephrotic syndrome.

Role of bremsstrahlung radiation in limiting the energy of runaway electrons in tokamaks.

Bremsstrahlung radiation of runaway electrons is found to be an energy limit for runaway electrons in tokamaks. The minimum and maximum energy of runaway electron beams is shown to be limited by collisions and bremsstrahlung radiation, respectively. It is also found that a massive injection of a high-Z gas such as xenon can terminate a disruption-generated runaway current before the runaway electrons hit the walls.

The effect of gamma-tocopherol administration on alpha-tocopherol levels and metabolism in humans.

BACKGROUND: The bioavailability of gamma-tocopherol and metabolites of vitamin E after gamma-tocopherol administration is not well understood. We investigated the effect of gamma-tocopherol administration on the levels and metabolism of alpha- and gamma-tocopherol in healthy volunteers. METHODS: We measured two metabolites of vitamin E (2,5,7,8-tetramethyl-2-(2'-carboxyethyl)-6-hydroxychroman (alpha-CEHC) and 2,7,8-trimethyl-2-(2'-carboxyethyl)-6-hydroxychroman (gamma-CEHC)) in plasma and urine by high-performance liquid chromatography with electrochemical detection (HPLC-ECD) during administration of gamma-tocopherol. Two groups of volunteers were enrolled. The gamma-tocopherol group received two gamma-tocopherol capsules (each containing 186.4 mg of gamma-tocopherol and 5 mg of alpha-tocopherol) for 28 days, while the control group received d-alpha-tocopherol at 5 mg/day, which was the same dose as that given to the gamma-tocopherol group. Blood and urine samples were obtained on days 0, 14, 28, 35, 42, and 56 after the initiation of gamma-tocopherol administration. RESULTS: The plasma gamma-tocopherol concentration increased markedly during administration of gamma-tocopherol and the plasma gamma-CEHC concentration increased along with that of gamma-tocopherol. The plasma alpha-tocopherol concentration decreased significantly during gamma-tocopherol administration. The plasma concentration of alpha-CEHC decreased significantly and urinary excretion of alpha-CEHC tended to increase in the gamma-tocopherol group. Urinary sodium secretion was significantly increased at 1 week after the cessation of gamma-tocopherol administration, but there was no significant difference of urine volume between the two groups. CONCLUSION: Metabolism of alpha-tocopherol is accelerated and the plasma alpha-tocopherol concentration is decreased during gamma-tocopherol administration.

Venepuncture is preferable to heel lance for blood sampling in term neonates.

BACKGROUND: The analgesic effect of oral sucrose in newborn infants undergoing painful procedures is generally accepted. For blood sampling, some studies have shown that venepuncture (VP) is less painful than heel lance (HL). OBJECTIVE: To determine the least painful and most effective method among blood sampling by VP or HL with or without sucrose. DESIGN: Randomised, double blind, placebo controlled trial. SUBJECTS: A total of 100 healthy, full term newborn infants being screened for inborn errors of metabolism were randomly allocated to one of four experimental groups (25 infants in each). Intervention and OUTCOME MEASURE: Seven specially trained nurses took turns to carry out blood sampling two minutes after administration of oral sucrose or water. Neonatal pain was assessed by the neonatal facial coding system (NFCS), as well as by crying. RESULTS: Without sucrose, the NFCS score was higher in the HL group than the VP group during blood sampling (median 58 v 23, p<0.001). Oral sucrose significantly reduced the score of the HL group (58 v 47, p<0.01) and also tended to reduce the score of the VP group (23 v 2, p<0.1). However, the HL with sucrose group still had a higher score than the VP without sucrose group (47 v 23, p<0.01). Crying and the total procedure time showed the same trends as the NFCS score. CONCLUSIONS: VP is less painful and more effective than HL for blood sampling in newborn infants. Although oral sucrose may have an additive analgesic effect, it is not necessarily required if VP is used for blood sampling.