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1.  Comparative effectiveness of inhaled corticosteroids for paediatric asthma: protocol for a systematic review and Bayesian network meta-analysis 
BMJ Open  2015;5(10):e008501.
Use of inhaled corticosteroid (ICS) is the mainstream maintenance therapy for paediatric asthma. Several forms of ICS are available, but the relative effectiveness among ICS has not been well investigated in published, randomised, controlled trials. The paucity of direct comparisons between ICS may have resulted in insufficient estimation in former systematic reviews/meta-analyses. To supplement the information on the comparative effectiveness of ICS for paediatric asthma, we plan to conduct a network meta-analysis that will enable summary of direct and indirect evidence.
Methods and analysis
We will retrieve randomised, controlled trials that examined the effectiveness of ICS for paediatric asthma from the PubMed and Cochrane Central Register of Controlled Trials. After one author scans the title and abstract for eligible studies, two authors will independently review study data and assess the quality of the study. Studies of children (≤18 years old) with chronic asthma or recurrent wheezing episodes will be included if they used ICS for ≥4 weeks. We will define a priori core outcomes and supplemental outcomes of paediatric asthma, including exacerbation, healthcare use and pulmonary function. Studies reporting a minimum of one core outcome will be entered into the systematic review. After the systematic review is performed, extracted data of relevant studies will be synthesised in the Bayesian framework using a random-effects model.
Ethics and dissemination
The results will be disseminated through peer-reviewed publications and conference presentations.
Protocol registration number
UMIN (000016724) and PROSPERO (CRD42015025889).
PMCID: PMC4620167  PMID: 26493456
2.  FFA1-selective agonistic activity based on docking simulation using FFA1 and GPR120 homology models 
British Journal of Pharmacology  2013;168(7):1570-1583.
The free fatty acid FFA1 receptor and GPR120 are GPCRs whose endogenous ligands are medium- and long-chain FFAs, and they are important in regulating insulin and GLP-1 secretion respectively. Given that the ligands of FFA1 receptor and GPR120 have similar properties, selective pharmacological tools are required to study their functions further.
We used a docking simulation approach using homology models for each receptor. Biological activity was assessed by phosphorylation of ERK and elevation of intracellular calcium ([Ca2+]i) in cells transfected with FFA1 receptor or GPR120. Insulin secretion from murine pancreatic beta cells (MIN6) was also measured.
Calculated hydrogen bonding energies between a series of synthetic carboxylic acid compounds and the homology models of the FFA1 receptor and GPR120, using docking simulations, correlated well with the effects of the compounds on ERK phosphorylation in transfected cells (R2= 0.65 for FFA1 receptor and 0.76 for GPR120). NCG75, the compound with the highest predicted selectivity for FFA1 receptors from this structure-activity relationship analysis, activated ERK and increased [Ca2+]i as potently as the known FFA1 receptor-selective agonist, Compound 1. Site-directed mutagenesis analysis based on the docking simulation showed that different amino acid residues were important for the recognition and activation by FFA1 receptor agonists. Moreover, NCG75 strongly induced ERK and [Ca2+]i responses, and promoted insulin secretion from MIN6 cells, which express endogenous FFA1 receptors.
A docking simulation approach using FFA1 receptor and GPR120 homology models could be useful in predicting FFA1 receptor-selective agonists.
PMCID: PMC3605867  PMID: 22639973
G-protein coupled receptor; FFA1; GPR120; agonist; homology modelling
3.  Cephalhematoma and petechial rashes associated with acute parvovirus B19 infection: a case report 
BMC Infectious Diseases  2013;13:465.
Parvovirus B19 can cause petechial rashes in the acute phase of illness as well as erythema infectiosum (fifth disease) during convalescence. This petechial rash is often called “gloves and socks” syndrome because of the typical distribution of the eruption. However, involvement of other sites (e.g., intertriginous area) and generalized involvement have been recently recognized. We report here a patient with parvovirus-associated petechiae and cephalhematoma.
Case presentation
The patient was a previously healthy 10-year-old boy. There was a family history of fatal bleeding; his sister died of intracranial bleeding with an uncertain cause at the age of 5 months. The patient was admitted to our hospital because of sudden onset of cephalhematoma associated with fever. He reported that he had no recent head trauma but that he massaged his scalp on the day before admission. On admission, his temperature was 38.8°C; otherwise, he was in a stable condition. Besides cephalhematoma, petechial rashes were present on his trunk and limbs. The initial laboratory tests were essentially normal, including platelet count and coagulation tests. Expanded laboratory tests were repeated to explore the etiology of his skin hemorrhage, all of which indicated that hematological disorders were unlikely. His symptoms subsided spontaneously over the next few days and he was discharged uneventfully. Anti-parvovirus IgM titer was elevated during hospitalization and typical erythema infectiosum was seen approximately 1 week after discharge. During 6 months follow-up, he remained stable without recurrence of a hemorrhagic episode. Finally, we concluded that his cephalhematoma was responsible for acute parvoviral infection.
This is believed to be the first report describing a possible association between parvovirus B19 infection and cephalhematoma. Parvovirus B19 infection should be considered in the differential diagnosis of children who present with unexplained hemorrhage such as cephalhematoma or petechiae.
PMCID: PMC3851625  PMID: 24093148
Parvovirus B19 infection; Erythema infectiosum; Fifth disease; Papular–purpuric gloves and socks syndrome; Cephalhematoma
4.  Intussusception among Japanese children: an epidemiologic study using an administrative database 
BMC Pediatrics  2012;12:36.
The epidemiology of intussusception, including its incidence, can vary between different countries. The aim of this study was to describe the epidemiology of childhood intussusception in Japan using data from a nationwide inpatient database.
We screened the database for eligible cases ≤ 18 years of age, who were coded with a discharge diagnosis of intussusception (International Classification of Diseases, 10th revision: K-561) between July to December in 2007 and 2008. We then selected cases according to Level 1 of the diagnostic certainty criteria developed by the Brighton Collaboration Intussusception Working Group. We examined the demographics, management, and outcomes of cases, and estimated the incidence of intussusception.
We identified 2,427 cases of intussusception. There were an estimated 2,000 cases of infantile intussusception annually in Japan, an incidence of 180-190 cases per 100,000 infants. The median age at diagnosis was 17 months, and two-thirds of the patients were male. Treatment with an enema was successful in 93.0% of cases (2255/2427). The remainder required surgery. Secondary cases accounted for 3.1% (76/2427). Median length of hospital stay was 3 days. Of the 2,427 cases, we found 2 fatal cases associated with intussusception.
This is currently the largest survey of childhood intussusception in Asia using a standardized case definition. Our results provide an estimate of the baseline risk of intussusception in Japan, and it is higher than the risk observed in other countries.
PMCID: PMC3350444  PMID: 22439793
5.  Saccharomyces cerevisiae Rot1 Is an Essential Molecular Chaperone in the Endoplasmic Reticulum 
Molecular Biology of the Cell  2008;19(8):3514-3525.
Molecular chaperones prevent aggregation of denatured proteins in vitro and are thought to support folding of diverse proteins in vivo. Chaperones may have some selectivity for their substrate proteins, but knowledge of particular in vivo substrates is still poor. We here show that yeast Rot1, an essential, type-I ER membrane protein functions as a chaperone. Recombinant Rot1 exhibited antiaggregation activity in vitro, which was partly impaired by a temperature-sensitive rot1-2 mutation. In vivo, the rot1-2 mutation caused accelerated degradation of five proteins in the secretory pathway via ER-associated degradation, resulting in a decrease in their cellular levels. Furthermore, we demonstrate a physical and probably transient interaction of Rot1 with four of these proteins. Collectively, these results indicate that Rot1 functions as a chaperone in vivo supporting the folding of those proteins. Their folding also requires BiP, and one of these proteins was simultaneously associated with both Rot1 and BiP, suggesting that they can cooperate to facilitate protein folding. The Rot1-dependent proteins include a soluble, type I and II, and polytopic membrane proteins, and they do not share structural similarities. In addition, their dependency on Rot1 appeared different. We therefore propose that Rot1 is a general chaperone with some substrate specificity.
PMCID: PMC2488298  PMID: 18508919
6.  Two regulatory steps of ER-stress sensor Ire1 involving its cluster formation and interaction with unfolded proteins 
The Journal of Cell Biology  2007;179(1):75-86.
Chaperone protein BiP binds to Ire1 and dissociates in response to endoplasmic reticulum (ER) stress. However, it remains unclear how the signal transducer Ire1 senses ER stress and is subsequently activated. The crystal structure of the core stress-sensing region (CSSR) of yeast Ire1 luminal domain led to the controversial suggestion that the molecule can bind to unfolded proteins. We demonstrate that, upon ER stress, Ire1 clusters and actually interacts with unfolded proteins. Ire1 mutations that affect these phenomena reveal that Ire1 is activated via two steps, both of which are ER stress regulated, albeit in different ways. In the first step, BiP dissociation from Ire1 leads to its cluster formation. In the second step, direct interaction of unfolded proteins with the CSSR orients the cytosolic effector domains of clustered Ire1 molecules.
PMCID: PMC2064738  PMID: 17923530
7.  Genetic Evidence for a Role of BiP/Kar2 That Regulates Ire1 in Response to Accumulation of Unfolded Proteins 
Molecular Biology of the Cell  2003;14(6):2559-2569.
In the unfolded protein response (UPR) signaling pathway, accumulation of unfolded proteins in the endoplasmic reticulum (ER) activates a transmembrane kinase/ribonuclease Ire1, which causes the transcriptional induction of ER-resident chaperones, including BiP/Kar2. It was previously hypothesized that BiP/Kar2 plays a direct role in the signaling mechanism. In this model, association of BiP/Kar2 with Ire1 represses the UPR pathway while under conditions of ER stress, BiP/Kar2 dissociation leads to activation. To test this model, we analyzed five temperature-sensitive alleles of the yeast KAR2 gene. When cells carrying a mutation in the Kar2 substrate-binding domain were incubated at the restrictive temperature, association of Kar2 to Ire1 was disrupted, and the UPR pathway was activated even in the absence of extrinsic ER stress. Conversely, cells carrying a mutation in the Kar2 ATPase domain, in which Kar2 poorly dissociated from Ire1 even in the presence of tunicamycin, a potent inducer of ER stress, were unable to activate the pathway. Our findings provide strong evidence in support of BiP/Kar2-dependent Ire1 regulation model and suggest that Ire1 associates with Kar2 as a chaperone substrate. We speculate that recognition of unfolded proteins is based on their competition with Ire1 for binding with BiP/Kar2.
PMCID: PMC194903  PMID: 12808051

Results 1-7 (7)