Publications by authors named "Naoki Yokoyama"

65 Publications

Suppression of Allograft Fibrosis by Regulation of Mammalian Target of Rapamycin-Related Protein Expression in Kidney-Transplanted Recipients Treated with Everolimus and Reduced Tacrolimus.

Ann Transplant 2021 Jan 12;26:e926476. Epub 2021 Jan 12.

Division of Urology, Department of Surgery, Faculty of Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.

BACKGROUND Although renoprotective effects of everolimus (EVR) in kidney transplantation (KTx) have been widely reported, its pathophysiological mechanism remains unclear. MATERIAL AND METHODS We compared changes in eGFR (ΔGFR, ml/min/1.73 m²) and the ratio of the fibrotic area in biopsy specimens (ΔFI,%) from 3 months to 3 years after KTx between the EVR+ group (EVR addition and Tac reduction early after KTx, n=32), and the EVR- group (normal Tac without EVR, n=28). We also immunohistochemically evaluated mTOR-related protein expression. RESULTS ΔGFR and ΔFI in the EVR+ vs. EVR- groups were -0.27±6.8 vs. -9.8±12.8 (p<0.001) and 2.4±4.9 vs. 9.5±10.5 (p<0.001), respectively. Phosphorylated mTOR and phosphorylated 4EBP1 expression at 3 years in the EVR+ group was significantly lower than that in the EVR- group. Moreover, in the subgroup analysis comparing ΔGFR and ΔFI among groups stratified by immunosuppressive regimen and mTOR signal enhancement, the ΔFI in patients with EVR+ with decreased mTOR signal enhancement was significantly milder than that in other patients. In addition, in the multivariate analysis, EVR addition was the only independent predictor for allograft fibrosis, whereas the Tac C₀ concentration at neither 1 nor 3 years proved to be a risk factor. CONCLUSIONS These results suggested that EVR addition and Tac reduction may attenuate kidney allograft fibrosis, and that the suppression of mTOR signaling process may be involved in the anti-fibrotic effect of this immunosuppressive regimen. These results provide suggestions of how to utilize EVR for patients with KTx and improve graft function.
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http://dx.doi.org/10.12659/AOT.926476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812696PMC
January 2021

Syntheses and Properties of (Nitronyl nitroxide)-substituted Tri-phenylamine ortho-Bridged by Two Oxygen and Sulfur Atoms.

Chem Asian J 2021 Jan 1;16(1):72-79. Epub 2020 Dec 1.

Graduate School of Science, Osaka City University, Sumiyoshi-ku, Osaka, 558-8585, Japan.

A nitronyl nitroxide unit (NN) was linked with a triphenylamine-based condensed polycyclic skeleton DOTT to form a radical substituted donor NN-DOTT. X-ray crystal structure analysis demonstrated a flat bowl shape of the DOTT unit. EPR spectra showed the localization of electron spin on the NN unit. Chemical oxidation of the DOTT unit produced radical-substituted radical cation salts NN-DOTT  ⋅ SbF and NN-DOTT  ⋅ FeBr that are stable under ambient conditions. The magnetic behavior of NN-DOTT  ⋅ SbF is characterized by the strong intramolecular ferromagnetic interaction between NN and DOTT . The X-ray structural analysis of NN-DOTT  ⋅ FeBr shows planar structure of DOTT and 1D mixed-stack column of NN-DOTT and FeBr . Magnetic measurements established that NN-DOTT  ⋅ FeBr undergoes magnetic phase transition into a weak ferromagnet at 7 K.
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http://dx.doi.org/10.1002/asia.202001227DOI Listing
January 2021

Spontaneous differentiation of periodontal ligament stem cells into myofibroblast during ex vivo expansion.

J Cell Physiol 2019 11 8;234(11):20377-20391. Epub 2019 Apr 8.

Ochanomizu University, Tokyo, Japan.

Periodontitis is characterized by the chronic inflammation and destruction of tooth-supporting tissues. Periodontal ligament stem cell (PDLSC) is the mesenchymal stem cell (MSC) population isolated from periodontal ligament, which is the key tissue for regeneration of periodontal tissues. Although transplantation of PDLSCs is proposed as novel regenerative therapy, limited information is available, regarding the characteristic change of PDLSCs during ex vivo expansion. In this study, we encountered morphological change of PDLSCs during standard cell culture and aimed to investigate the change of PDLSCs in stem cell characteristics and to search for the culture condition to maintain stem cell properties. Characteristics of PDLSCs were examined using in vitro osteoblast and adipocyte differentiation. Myofibroblast differentiation was confirmed using immunohistochemistry and collagen gel contraction assay. Replicative senescence was examined by β-gal staining. PDLSCs changed their morphology from spindle to flat and wide during ex vivo expansion. After the morphological change, PDLSCs showed several features of myofibroblast including extensive stress fiber formation, contraction activity, and myofibroblast marker expression. Upon the morphological change, osteoblastic and adipocyte differentiation capacity were reduced and expression of stem cell-related genes were decreased. β-Gal staining was not always correlated with the morphological change of PDLSCs. Moreover, exogenous addition of bFGF and PDGF-BB served to maintain spindle shape and osteoblastic differentiation potential of PDLSCs. This study demonstrates that spontaneous differentiation of PDLSCs during ex vivo expansion and may provide the important information of cell culture condition of PDLSCs for clinical use.
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http://dx.doi.org/10.1002/jcp.28639DOI Listing
November 2019

The Fate of Transplanted Periodontal Ligament Stem Cells in Surgically Created Periodontal Defects in Rats.

Int J Mol Sci 2019 Jan 7;20(1). Epub 2019 Jan 7.

Ochanomizu University, 2-1-1, Otsuka, Bunkyo-Ku, Tokyo 112-8610, Japan.

Periodontal disease is chronic inflammation that leads to the destruction of tooth-supporting periodontal tissues. We devised a novel method ("cell transfer technology") to transfer cells onto a scaffold surface and reported the potential of the technique for regenerative medicine. The aim of this study is to examine the efficacy of this technique in periodontal regeneration and the fate of transplanted cells. Human periodontal ligament stem cells (PDLSCs) were transferred to decellularized amniotic membrane and transplanted into periodontal defects in rats. Regeneration of tissues was examined by microcomputed tomography and histological observation. The fate of transplanted PDLSCs was traced using PKH26 and human Alu sequence detection by PCR. Imaging showed more bone in PDLSC-transplanted defects than those in control (amnion only). Histological examination confirmed the enhanced periodontal tissue formation in PDLSC defects. New formation of cementum, periodontal ligament, and bone were prominently observed in PDLSC defects. PKH26-labeled PDLSCs were found at limited areas in regenerated periodontal tissues. Human Alu sequence detection revealed that the level of Alu sequence was not increased, but rather decreased. This study describes a novel stem cell transplantation strategy for periodontal disease using the cell transfer technology and offers new insight for cell-based periodontal regeneration.
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http://dx.doi.org/10.3390/ijms20010192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337301PMC
January 2019

Cell transfer technology for tissue engineering.

Inflamm Regen 2017 16;37:21. Epub 2017 Oct 16.

Department of Cellular Physiological Chemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510 Japan.

We recently developed novel cell transplantation method "cell transfer technology" utilizing photolithography. Using this method, we can transfer ex vivo expanded cells onto scaffold material in desired patterns, like printing of pictures and letters on a paper. We have investigated the possibility of this novel method for cell-based therapy using several disease models. We first transferred endothelial cells in capillary-like patterns on amnion. The transplantation of the endothelial cell-transferred amnion enhanced the reperfusion in mouse ischemic limb model. The fusion of transplanted capillary with host vessel networks was also observed. The osteoblast- and periodontal ligament stem cell-transferred amnion were next transplanted in bone and periodontal defects models. After healing period, both transplantations improved the regeneration of bone and periodontal tissues, respectively. This method was further applicable to transfer of multiple cell types and the transplantation of osteoblasts and periodontal ligament stem cell-transferred amnion resulted in the improved bone regeneration compared with single cell type transplantation. These data suggested the therapeutic potential of the technology in cell-based therapies for reperfusion of ischemic limb and regeneration of bone and periodontal tissues. Cell transfer technology is applicable to wide range of regenerative medicine in the future.
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http://dx.doi.org/10.1186/s41232-017-0052-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725820PMC
October 2017

Neuroprotective effects of human umbilical cord-derived mesenchymal stem cells on periventricular leukomalacia-like brain injury in neonatal rats.

Inflamm Regen 2017 16;37. Epub 2017 Jan 16.

Department of Cellular Physiological Chemistry, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-Ku, Tokyo, 113-8510 Japan.

Background: Periventricular leukomalacia (PVL) is a type of multifactorial brain injury that causes cerebral palsy in premature infants. To date, effective therapies for PVL have not been available. In this study, we examined whether mesenchymal stem cells (MSCs) possess neuroprotective property in a lipopolysaccharide (LPS)-induced neonatal rat PVL-like brain injury.

Methods: Human umbilical cord-derived MSCs (UCMSCs) were used in this study. Four-day-old rats were intraperitoneally injected with LPS (15 mg/kg) to cause the PVL-like brain injury and were treated immediately after the LPS-injection with UCMSCs, conditioned medium prepared from MSCs (UCMSC-CM) or interferon-gamma (IFN-γ)-pretreated MSC (IFN-γ-UCMSC-CM). To assess systemic reaction to LPS-infusion, IFN-γ in sera was measured by ELISA. The brain injury was evaluated by immunostaining of myelin basic protein (MBP) and caspase-3. RT-PCR was used to quantitate pro-inflammatory cytokine levels in the brain injury, and the expression of tumor necrosis factor-stimulated gene-6 (TSG-6) or indoleamine 2,3-dioxygenase (IDO) to evaluate anti-inflammatory or immunomodulatory molecules in UCMSCs, respectively. A cytokine and growth factor array was employed to investigate the cytokine secretion profiles of UCMSCs.

Results: Elevated serum IFN-γ was observed in LPS-infused rats. The expression of IL-6, tumor necrosis factor-alpha (TNF-α), IL-1ß, and monocyte chemoattractant protein-1 (MCP-1) were increased in the brain by LPS-infusion in comparison to saline-infused control. LPS-infusion increased caspase-3-positive cells and decreased MBP-positive area in neonatal rat brains. A cytokine and growth factor array demonstrated that UCMSCs secreted various cytokines and growth factors. UCMSCs significantly suppressed IL-1ß expression in the brains and reversed LPS-caused decrease in MBP-positive area. UCMSC-CM did not reverse MBP-positive area in the injured brain, while IFN-γ-UCMSC-CM significantly increased MBP-positive area compared to control (no treatment). IFN-γ-pretreatment increased TSG-6 and IDO expression in UCMSCs.

Conclusion: We demonstrated that bolus intraperitoneal infusion of LPS caused PVL-like brain injury in neonatal rats and UCMSCs infusion ameliorated dysmyelination in LPS-induced neonatal rat brain injury. Conditioned medium prepared from IFN-γ-pretreated UCMSCs significantly reversed the brain damage in comparison with UCMSC-CM, suggesting that the preconditioning of UCMSCs would improve their neuroprotective effects. The mechanisms underline the therapeutic effects of MSCs on PVL need continued investigation to develop a more effective treatment.
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http://dx.doi.org/10.1186/s41232-016-0032-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725779PMC
January 2017

Exosomes of human placenta-derived mesenchymal stem cells stimulate angiogenesis.

Stem Cell Res Ther 2017 10 3;8(1):219. Epub 2017 Oct 3.

Department of Nanomedicine (DNP), Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, 113-8510, Tokyo, Japan.

Background: The therapeutic potential of mesenchymal stem cells (MSCs) may be attributed partly to humoral factors such as growth factors, cytokines, and chemokines. Human term placental tissue-derived MSCs (PlaMSCs), or conditioned medium left over from cultures of these cells, have been reported to enhance angiogenesis. Recently, the exosome, which can transport a diverse suite of macromolecules, has gained attention as a novel intercellular communication tool. However, the potential role of the exosome in PlaMSC therapeutic action is not well understood. The purpose of this study was to evaluate PlaMSC-derived exosome angiogenesis promotion in vitro and in vivo.

Methods: MSCs were isolated from human term placental tissue by enzymatic digestion. Conditioned medium was collected after 48-h incubation in serum-free medium (PlaMSC-CM). Angiogenic factors present in PlaMSC-CM were screened by a growth factor array. Exosomes were prepared by ultracentrifugation of PlaMSC-CM, and confirmed by transmission electron microscopy, dynamic light scattering, and western blot analyses. The proangiogenic activity of PlaMSC-derived exosomes (PlaMSC-exo) was assessed using an endothelial tube formation assay, a cell migration assay, and reverse transcription-PCR analysis. The in-vivo angiogenic activity of PlaMSC-exo was evaluated using a murine auricle ischemic injury model.

Results: PlaMSC-CM contained both angiogenic and angiostatic factors, which enhanced endothelial tube formation. PlaMSC-exo were incorporated into endothelial cells; these exosomes stimulated both endothelial tube formation and migration, and enhanced angiogenesis-related gene expression. Laser Doppler blood flow analysis showed that PlaMSC-exo infusion also enhanced angiogenesis in an in-vivo murine auricle ischemic injury model.

Conclusions: PlaMSC-exo enhanced angiogenesis in vitro and in vivo, suggesting that exosomes play a role in the proangiogenic activity of PlaMSCs. PlaMSC-exo may be a novel therapeutic approach for treating ischemic diseases.
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http://dx.doi.org/10.1186/s13287-017-0660-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5627451PMC
October 2017

Crescentic IgA nephropathy in a child: Effect of a new combination therapy.

Pediatr Int 2017 Apr 28;59(4):501-503. Epub 2017 Feb 28.

Department of Pediatrics, Akashi Medical Center, Akashi, Japan.

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http://dx.doi.org/10.1111/ped.13225DOI Listing
April 2017

Conditioned Medium from Periodontal Ligament Stem Cells Enhances Periodontal Regeneration.

Tissue Eng Part A 2017 05 27;23(9-10):367-377. Epub 2017 Jan 27.

4 Department of Cellular Physiological Chemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University , Tokyo, Japan .

Periodontal disease is one of the most common infectious diseases in adults and is characterized by the destruction of tooth-supporting tissues. Mesenchymal stem cells (MSCs) comprise the mesoderm-originating stem cell population, which has been studied and used for cell therapy. However, because of the lower rate of cell survival after MSC transplantation in various disease models, paracrine functions of MSCs have been receiving increased attention as a regenerative mechanism. The aim of this study was to investigate the regenerative potential of transplanted conditioned medium (CM) obtained from cultured periodontal ligament stem cells (PDLSCs), the adult stem cell population in tooth-supporting tissues, using a rat periodontal defect model. Cell-free CM was collected from PDLSCs and fibroblasts, using ultrafiltration and transplanted into surgically created periodontal defects. Protein content of CM was examined by antibody arrays. Formation of new periodontal tissues was analyzed using microcomputed tomography and histological sections. PDLSC-CM transplantation enhanced periodontal tissue regeneration in a concentration-dependent manner, whereas fibroblast-CM did not show any regenerative function. Proteomic analysis revealed that extracellular matrix proteins, enzymes, angiogenic factors, growth factors and cytokines were contained in PDLSC-CM. Furthermore, PDLSC-CM transplantation resulted in the decreased mRNA level of tumor necrosis factor-α (TNF-α) in healing periodontal tissues. In addition, we found that PDLSC-CM suppressed the mRNA level of TNF-α in the monocyte/macrophage cell line, RAW cells, stimulated with IFN-γ. Our findings suggested that PDLSC-CM enhanced periodontal regeneration by suppressing the inflammatory response through TNF-α production, and transplantation of PDLSC-CM could be a novel approach for periodontal regenerative therapy.
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http://dx.doi.org/10.1089/ten.TEA.2016.0274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444511PMC
May 2017

Double-layered cell transfer technology for bone regeneration.

Sci Rep 2016 09 14;6:33286. Epub 2016 Sep 14.

Department of Cellular Physiological Chemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.

For cell-based medicine, to mimic in vivo cellular localization, various tissue engineering approaches have been studied to obtain a desirable arrangement of cells on scaffold materials. We have developed a novel method of cell manipulation called "cell transfer technology", enabling the transfer of cultured cells onto scaffold materials, and controlling cell topology. Here we show that using this technique, two different cell types can be transferred onto a scaffold surface as stable double layers or in patterned arrangements. Various combinations of adherent cells were transferred to a scaffold, amniotic membrane, in overlapping bilayers (double-layered cell transfer), and transferred cells showed stability upon deformations of the material including folding and trimming. Transplantation of mesenchymal stem cells from periodontal ligaments (PDLSC) and osteoblasts, using double-layered cell transfer significantly enhanced bone formation, when compared to single cell type transplantation. Our findings suggest that this double-layer cell transfer is useful to produce a cell transplantation material that can bear two cell layers. Moreover, the transplantation of an amniotic membrane with PDLSCs/osteoblasts by cell transfer technology has therapeutic potential for bone defects. We conclude that cell transfer technology provides a novel and unique cell transplantation method for bone regeneration.
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http://dx.doi.org/10.1038/srep33286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021950PMC
September 2016

Mitochondrial respiratory chain complex IV deficiency complicated with chronic intestinal pseudo-obstruction in a neonate.

Pediatr Int 2016 Jul 6;58(7):651-5. Epub 2016 Jun 6.

Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.

A female infant born at 36 weeks gestational age with birthweight 2135 g, and who developed respiratory disorder, hyperlactacidemia and hypertrophic cardiomyopathy after birth, was admitted to hospital at 3 days of age. After admission, bilious emesis, abdominal distention, and passage disorder of the gastrointestinal tract were resistant to various drugs. Exploratory laparotomy was performed at 93 days of age, but no organic lesions were identified and normal Meissner/Auerbach nerve plexus was confirmed, which led to a clinical diagnosis of chronic intestinal pseudo-obstruction (CIPO). She was diagnosed with mitochondrial respiratory chain complex IV deficiency on histopathology of the abdominal rectus muscle and enzyme activity measurement. This is the first report of a neonate with mitochondrial respiratory chain complex deficiency with intractable CIPO. CIPO can occur in neonates with mitochondrial respiratory chain disorder, necessitating differential diagnosis from Hirschsprung disease.
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http://dx.doi.org/10.1111/ped.12907DOI Listing
July 2016

Placenta Mesenchymal Stem Cell Derived Exosomes Confer Plasticity on Fibroblasts.

J Cell Biochem 2016 07 5;117(7):1658-70. Epub 2016 Feb 5.

Department of Cellular Physiological Chemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.

Mesenchymal stem cell (MSC)-conditioned medium (MSC-CM) has been reported to enhance wound healing. Exosomes contain nucleic acids, proteins, and lipids, and function as an intercellular communication vehicle for mediating some paracrine effects. However, the function of MSC-derived exosomes (MSC-exo) remains elusive. In this study, we isolated human placenta MSC (PlaMSC)-derived exosomes (PlaMSC-exo) and examined their function in vitro. PlaMSCs were isolated from human term placenta using enzymatic digestion. PlaMSC-exo were prepared from the conditioned medium of PlaMSC (PlaMSC-CM) by ultracentrifugation. The expression of stemness-related genes, such as OCT4 and NANOG, in normal adult human dermal fibroblasts (NHDF) after incubation with PlaMSC-exo was measured by real-time reverse transcriptase PCR analysis (real-time PCR). The effect of PlaMSC-exo on OCT4 transcription activity was assessed using Oct4-EGFP reporter mice-derived dermal fibroblasts. The stimulating effects of PlaMSC-exo on osteoblastic and adipocyte-differentiation of NHDF were evaluated by alkaline phosphatase (ALP), and Alizarin red S- and oil red O-staining, respectively. The expression of osteoblast- and adipocyte-related genes was also assessed by real-time PCR. The treatment of NHDF with PlaMSC-exo significantly upregulated OCT4 and NANOG mRNA expression. PlaMSC-exo also enhanced OCT4 transcription. The NHDF treated with PlaMSC-exo exhibited osteoblastic and adipocyte-differentiation in osteogenic and adipogenic induction media. PlaMSC-exo increase the expression of OCT4 and NANOG mRNA in fibroblasts. As a result, PlaMSC-exo influence the differentiation competence of fibroblasts to both osteoblastic and adipocyte-differentiation. It shows a new feature of MSCs and the possibility of clinical application of MSC-exo. J. Cell. Biochem. 117: 1658-1670, 2016. © 2015 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jcb.25459DOI Listing
July 2016

Current incidence of clinical kernicterus in preterm infants in Japan.

Pediatr Int 2015 Jun;57(3):494-7

Department of Pediatrics, Kakogawa West Municipal Hospital, Kakogawa.

Clinical kernicterus in preterm infants has recently been reported in Japan, diagnosed on the basis of clinical findings during the neonatal and infancy periods. We investigated the incidence of clinical kernicterus in preterm infants <30 weeks gestational age (GA) based on a nationwide survey conducted in 233 certified educational facilities for neonatologists. The numbers of infants admitted and infants who died within 14 days after birth during 2011, and the number of infants who subsequently developed clinical kernicterus, were recorded. A total of 2720 infants were analyzed, representing 59% (2720/4623) of all preterm live births <30 weeks GA in Japan in 2011. Of these, 159 (5.8%) died within 14 days after birth, similar to the national rate. Five infants developed clinical kernicterus in infancy (5/2720, 0.18%). The current incidence of clinical kernicterus in Japan is therefore estimated at 1.8 per 1000 live births <30 weeks GA.
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http://dx.doi.org/10.1111/ped.12651DOI Listing
June 2015

Low-temperature catalyst activator: mechanism of dense carbon nanotube forest growth studied using synchrotron radiation.

IUCrJ 2014 Jul 22;1(Pt 4):221-7. Epub 2014 May 22.

Collaborative Research Team Green Nanoelectronics Center (GNC), National Institute of Advanced Industrial Science and Technology (AIST) , 16-1 Onogawa, Tsukuba, Ibaraki 305-8569, Japan.

The mechanism of the one-order-of-magnitude increase in the density of vertically aligned carbon nanotubes (CNTs) achieved by a recently developed thermal chemical vapor deposition process was studied using synchrotron radiation spectroscopic techniques. In the developed process, a Ti film is used as the underlayer for an Fe catalyst film. A characteristic point of this process is that C2H2 feeding for the catalyst starts at a low temperature of 450°C, whereas conventional feeding temperatures are ∼800°C. Photoemission spectroscopy using soft and hard X-rays revealed that the Ti underlayer reduced the initially oxidized Fe layer at 450°C. A photoemission intensity analysis also suggested that the oxidized Ti layer at 450°C behaved as a support for nanoparticle formation of the reduced Fe, which is required for dense CNT growth. In fact, a CNT growth experiment, where the catalyst chemical state was monitored in situ by X-ray absorption spectroscopy, showed that the reduced Fe yielded a CNT forest at 450°C. Contrarily, an Fe layer without the Ti underlayer did not yield such a CNT forest at 450°C. Photoemission electron microscopy showed that catalyst annealing at the conventional feeding temperature of 800°C caused excess catalyst agglomeration, which should lead to sparse CNTs. In conclusion, in the developed growth process, the low-temperature catalyst activation by the Ti underlayer before the excess Fe agglomeration realised the CNT densification.
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http://dx.doi.org/10.1107/S2052252514009907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4107922PMC
July 2014

Clinical outcome of paclitaxel and carboplatin as second-line chemotherapy for advanced urothelial carcinoma resistant to first-line therapy with gemcitabine and cisplatin.

Urol Int 2014 13;92(2):180-5. Epub 2013 Nov 13.

Division of Urology, Hyogo Cancer Center, Akashi, Japan.

Objective: The objective was to investigate the efficacy and tolerability of combined therapy with paclitaxel and carboplatin (TC) in patients with advanced urothelial carcinoma after the failure of first-line chemotherapy with gemcitabine and cisplatin (GC).

Patients And Methods: This was a retrospective study including a total of 16 patients with advanced urothelial carcinoma who showed evidence of progressive and/or recurrent disease after first-line therapy with GC and subsequently received second-line chemotherapy consisting of paclitaxel (175 mg/m(2)) and carboplatin (area under the curve 5). TC therapy was repeated every 3 weeks and was continued until disease progression or intolerable toxicity was observed.

Results: The baseline patient characteristics were rather favorable; only 3 of 16 patients had liver metastases and 7 patients had an Eastern Cooperative Oncology Group performance status of 0. Of these, response to TC therapy was achieved in 5 (31.3%), including 2 with complete and 3 with partial response. The median progression-free and overall survival times in the 16 patients were 7.9 and 17.3 months, respectively.

Conclusions: TC therapy appeared to show modest activity with acceptable tolerability in patients refractory to GC therapy; therefore, TC chemotherapy might be considered as an alternative option as a second-line regimen for advanced urothelial carcinoma following GC therapy.
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http://dx.doi.org/10.1159/000354149DOI Listing
December 2014

Periodontal regeneration using periodontal ligament stem cell-transferred amnion.

Tissue Eng Part A 2014 Feb 9;20(3-4):693-704. Epub 2013 Dec 9.

1 Department of Nanomedicine (DNP), Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University , Tokyo, Japan .

Periodontal disease is characterized by the destruction of tooth supporting tissues. Regeneration of periodontal tissues using ex vivo expanded cells has been introduced and studied, although appropriate methodology has not yet been established. We developed a novel cell transplant method for periodontal regeneration using periodontal ligament stem cell (PDLSC)-transferred amniotic membrane (PDLSC-amnion). The aim of this study was to investigate the regenerative potential of PDLSC-amnion in a rat periodontal defect model. Cultured PDLSCs were transferred onto amniotic membranes using a glass substrate treated with polyethylene glycol and photolithography. The properties of PDLSCs were investigated by flow cytometry and in vitro differentiation. PDLSC-amnion was transplanted into surgically created periodontal defects in rat maxillary molars. Periodontal regeneration was evaluated by microcomputed tomography (micro-CT) and histological analysis. PDLSCs showed mesenchymal stem cell-like characteristics such as cell surface marker expression (CD90, CD44, CD73, CD105, CD146, and STRO-1) and trilineage differentiation ability (i.e., into osteoblasts, adipocytes, and chondrocytes). PDLSC-amnion exhibited a single layer of PDLSCs on the amniotic membrane and stability of the sheet even with movement and deformation caused by surgical instruments. We observed that the PDLSC-amnion enhanced periodontal tissue regeneration as determined by micro-CT and histology by 4 weeks after transplantation. These data suggest that PDLSC-amnion has therapeutic potential as a novel cell-based regenerative periodontal therapy.
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http://dx.doi.org/10.1089/ten.TEA.2013.0017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3926144PMC
February 2014

Microfluidic biosensor for the detection of DNA by fluorescence enhancement and the following streptavidin detection by fluorescence quenching.

Biosens Bioelectron 2014 Jan 6;51:280-5. Epub 2013 Aug 6.

Department of Applied Chemistry, Graduate School of Engineering, Nagoya University, Nagoya, Japan; MEXT Innovative Research Center for Preventive Medical Engineering, Nagoya University, Nagoya, Japan; Department of Chemical and Biological Engineering, Chalmers University of Technology, Göteborg, Sweden. Electronic address:

We reported an optical DNA/protein microfluidic sensor which consists of single stranded (ss) DNA-Cy3 probes on gold surface and simple line-shape microfluidic channel. These ssDNA-Cy3 probes with random sequence in bulk solution or on gold surface exhibits fluorescence enhancement after binding with complementary ssDNA (cssDNA) targets. Particularly it did not require complicated design or hairpin-like stem-loop conformation, which made it easier to be made and applied in analytes detection by fluorescence switching techniques. Using ssDNA-cy3 probes attached on gold surface in a microfluidic channel, strong fluorescence enhancement was measured by ssDNA with cssDNA binding or ssDNA with cssDNA-biotin binding. The following introduction of streptavidin resulted in fluorescence quenching (fluorescence decrease) because of the binding of hybridized DNA-biotin with streptavidin. This sensor showed strong affinity and high sensitivity toward the streptavidin, the minimum detectable concentration for streptavidin was 1 pM, equating to an absolute detection limit of 60 amol in this microfluidic channel. Microfluidic channel height and flow rate is optimized to increase surface reaction efficiency and fluorescence switching efficiency. In contrast to previously reported optical molecular beacon approach, this sensor can be used not only for the detection of cssDNA target, but also for the detection of streptavidin. This microfluidic sensor offers the promise of analyzing kinds of molecular targets or immunoreactions.
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http://dx.doi.org/10.1016/j.bios.2013.07.058DOI Listing
January 2014

Conduction tuning of graphene based on defect-induced localization.

ACS Nano 2013 Jul 26;7(7):5694-700. Epub 2013 Jun 26.

Green Nanoelectronics Center (GNC), National Institute of Advanced Industrial Science and Technology (AIST), 16-1 Onogawa, Tsukuba 305-8569, Japan.

The conduction properties of graphene were tuned by tailoring the lattice by using an accelerated helium ion beam to embed low-density defects in the lattice. The density of the embedded defects was estimated to be 2-3 orders of magnitude lower than that of carbon atoms, and they functionalized a graphene sheet in a more stable manner than chemical surface modifications can do. Current modulation through back gate biasing was demonstrated at room temperature with a current on-off ratio of 2 orders of magnitude, and the activation energy of the thermally activated transport regime was evaluated. The exponential dependence of the current on the length of the functionalized region in graphene suggested that conduction tuning is possible through strong localization of carriers at sites induced by a sparsely distributed random potential modulation.
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http://dx.doi.org/10.1021/nn401992qDOI Listing
July 2013

Severe retinopathy of prematurity with retinal detachment in monozygotic twins.

Pediatr Int 2013 Jun;55(3):366-8

Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.

We report a monochorionic diamniotic twin pair born at 29 weeks of gestation in which both twins developed severe retinopathy of prematurity (ROP) with retinal detachment. The pregnancy was terminated due to reversal of donor-recipient phenotypes in possible TTTS. Both twins had unstable cardiopulmonary status during the first week, and developed chronic lung disease. The larger twin, born at 1372 g, developed stage 4a ROP in both eyes, and the smaller twin, born at 1168 g, developed stage 4a ROP in the left eye. Genetic analysis of NDP, FZD4, LRP5, TSPAN12 genes revealed no mutations; however, VEGF gene polymorphism analysis showed heterozygous carrier state of the VEGF 936T allele in both twins, which is a risk factor for threshold ROP in Japanese newborn infants. We speculate the synergistic effects of unstable perinatal cardiopulmonary status and genetic predisposition due to VEGF 936C>T polymorphism caused the development of severe ROP with retinal detachment.
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http://dx.doi.org/10.1111/j.1442-200X.2012.03690.xDOI Listing
June 2013

The effect of granulocyte and monocyte adsorptive apheresis on serum cytokine levels in patients with ulcerative colitis.

Cytokine 2013 Apr 5;62(1):146-50. Epub 2013 Mar 5.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Iwate 020-8505, Japan.

Background: Granulocyte and monocyte adsorptive apheresis (GMA) with an Adacolumn has been reported to be effective as induction therapy in ulcerative colitis (UC). However, the effects of GMA on serial changes in cytokine levels have not been well characterized. We therefore, investigated cytokine levels in UC patients before and after treatment with GMA. A total of 16 patients with active UC, 10 men, and six women, mean age, 42.6 years were included. Fourteen patients had total colitis and two patients had left-sided colitis. The study included nine patients with a chronic intermittent course, six with a chronic continuous course and one with a single episode. The duration of each GMA session was 60 min at a flow rate of 30 mL/min as per study protocol. Serum levels of 17 cytokines were determined simultaneously using a Bio-Plex suspension array system before and after treatment with GMA. Serum interleukin (IL)-10 and macrophage inflammatory protein-1β levels were increased significantly in UC patients after GMA treatment compared to pre-treatment levels (P < 0.05). In particular, GMA treatment caused a significant increase in serum IL-10 levels compared to pre-treatment in patients with total colitis or with a chronic intermittent UC course. In conclusion, this investigation showed that GMA was associated with a marked increase in serum level of the anti-inflammatory cytokine, IL-10. The rise in circulating IL-10 is interesting, and potentially a significant factor in the efficacy of GMA in patients with inflammatory bowel diseases.
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http://dx.doi.org/10.1016/j.cyto.2013.01.019DOI Listing
April 2013

Innate sexuality determines the mechanisms of telomere maintenance.

Int J Dev Biol 2013 ;57(1):69-72

Department of Biological Sciences and Informatics, Keio University, Hiyoshi, Kouhoku-ku, Yokohama, Japan.

Recently, telomere length has been shown to be differentially regulated in asexually and sexually reproducing planarians. In addition, it was found that asexual worms maintain telomere length somatically during reproduction by fission or when regeneration is induced by amputation, whereas sexual worms only achieve telomere elongation through sexual reproduction. We have established an experimental bioassay system to induce switching from asexual to sexual reproduction in planarians, that is, sexualization. In this study, the relationship between the reproductive mode and telomere maintenance was investigated using innate asexually reproducing worms, innate sexually reproducing worms, and experimentally sexualized worms. Here, we show that innate asexual planarians maintain telomere length during cell division and that innate sexual planarians exhibit telomere shortening. However, experimental sexualized worms maintain telomere length during cell division. These results indicate that innate sexuality is linked to the mechanism of telomere maintenance.
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http://dx.doi.org/10.1387/ijdb.120114mmDOI Listing
November 2013

Periodontal ligament stem cells possess the characteristics of pericytes.

J Periodontol 2013 Oct 14;84(10):1425-33. Epub 2012 Dec 14.

Department of Nanomedicine, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo, Japan.

Background: Periodontal ligament (PDL) contributes to maintaining homeostasis in periodontal tissues by supplying stem/progenitor cells. It has long been suggested that PDL stem cells/progenitors are located around blood vessels. Recently mesenchymal stem cells (MSCs) have been isolated and cultured from PDL in vitro, although the location of the stem cells in PDL is unclear. The purpose of this study is to test the characteristics of human PDL stem cells (PDLSCs) and examine their similarity to related vascular cell types, such as pericytes and endothelial cells.

Methods: PDLSCs were obtained from healthy extracted teeth using the collagenase/dispase enzyme digestion method. MSC and pericyte characteristics of PDLSCs were examined by cell surface marker expression using flow cytometry. The expression of pericyte markers was tested using immunohistochemistry. Pericyte-like functions of PDLSCs were examined in co-culture of PDLSCs and umbilical vein endothelial cells on a gel matrix.

Results: Cultured PDLSCs were positive for both MSC markers and pericyte markers, including cluster of differentiation 146 (CD146), neural/glial antigen 2 (NG2), and CD140b. When pericyte marker expression was explored in rat periodontal tissue sections, CD146- and NG2-positive signals were observed in the perivascular area of the PDL. Further, when the cells were cultured with human umbilical cord endothelial cells under conditions for forming capillary-like structures in vitro, PDLSCs localized adjacent to endothelial cells and contributed to the stability of the capillary-like structure.

Conclusions: PDLSCs possess pericyte-like characteristics and may localize as pericytes in the PDL. These data provide useful information for stem cell biology in periodontal research and stem cell-based periodontal therapy.
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http://dx.doi.org/10.1902/jop.2012.120547DOI Listing
October 2013

Anisotropic graphene growth accompanied by step bunching on a dynamic copper surface.

Nanotechnology 2013 Jan 10;24(2):025603. Epub 2012 Dec 10.

Collaborative Research Team Green Nanoelectronics Center, National Institute of Advanced Industrial Science and Technology, 16-1 Onogawa, Tsukuba, Ibaraki 305-8569, Japan.

We investigated the initial stage of chemical vapor deposition graphene growth on Cu film at low pressure, where Cu evaporation intensively occurs. Surface steps on the Cu surface were found to be the nucleation sites of graphene islands and to affect the subsequent growth. For the first time, we observed anisotropic graphene growth on the Cu surface accompanied by morphological changes, resulting in an arrayed graphene ribbon formation. The resultant surface morphology is attributed to step bunching during growth. Detailed analyses suggest that the graphene arrays, which were preferentially formed along the steps, served as partial shields of the Cu surface, preventing step-flow-like Cu atom diffusion and evaporation at the growth site. As a result, the growth locations acted as a pinning site of the step motion, leading to step bunching. Such selective growth by using surface morphology has the potential to control not only the nucleation site but also the geometry of graphene for tailoring graphene-based nanomaterials such as nanoribbons and quantum dots.
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http://dx.doi.org/10.1088/0957-4484/24/2/025603DOI Listing
January 2013

Colonic mucosa-associated lymphoid tissue lymphoma.

Case Rep Gastroenterol 2012 May 29;6(2):569-75. Epub 2012 Aug 29.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan.

Colonic mucosa-associated lymphoid tissue (MALT) lymphomas are rare and a definitive treatment has not been established. Solitary or multiple, elevated or polypoid lesions are the usual appearances of MALT lymphoma in the colon and sometimes the surface may reveal abnormal vascularity. In this paper we report our experience with four cases of colonic MALT lymphoma and review the relevant literature. The first patient had a smooth elevated lesion in the rectum and histopathologic examination of the biopsy from the lesion showed centrocyte-like cells infiltrating the lamina propria. Endoscopic ultrasonography (EUS) revealed thickening of the submucosa and muscularis propria. The patient underwent radiation therapy, and 9 months later a repeat colonoscopy showed complete resolution of the lesion. In case 2, colonoscopy showed a polyp in the cecum; the biopsy was diagnostic of MALT lymphoma. EUS detected a hypoechoic lesion confined to the mucosal layer of the colonic wall. The patient underwent endoscopic mucosal resection of the lesion and after 6 years of follow-up there was no evidence of recurrence. The third patient had a sessile elevated lesion in the sigmoid colon for which she underwent sigmoidectomy. Pathological examination of the surgical specimen was suggestive of MALT lymphoma. The last patient had a smooth elevated lesion in the rectum and magnification endoscopy showed irregular vascular pattern. The patient underwent endoscopic submucosal dissection, and biopsy examination showed the tumor to be MALT lymphoma. Although rare, awareness of MALT lymphoma of the colon is important to evaluate the patient appropriately and to plan further management.
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http://dx.doi.org/10.1159/000342726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3457043PMC
May 2012

Novel treatment strategy for Japanese newborns with high serum unbound bilirubin.

Pediatr Int 2013 Feb 11;55(1):54-9. Epub 2012 Dec 11.

Department of Pediatrics, Kobe University Hospital, Kobe.

Background: Serum unbound bilirubin (UB) is a measure of bilirubin not bound to albumin, and has been reported to be better than total bilirubin level at identifying infants at risk of developing bilirubin-induced neurotoxicity, including auditory abnormalities. A detailed treatment strategy for newborns with high serum UB has not been established. The aim of this study was to assess auditory outcomes in newborns with serum UB ≥1.00 μg/dL who were treated according to a novel treatment protocol.

Methods: A prospective clinical study was conducted in newborns weighing >1500 g with serum UB ≥1.00 μg/dL who were admitted to Kobe University Hospital and Kakogawa Municipal Hospital, Japan from 2006 to 2011. Enrolled newborns were treated as follows: (i) if serum UB was 1.00-1.50 μg/dL, phototherapy and infusion were given with or without albumin or immunoglobulin therapy; and (ii) if serum UB was >1.50 μg/dL, exchange transfusion was performed immediately. Auditory brainstem responses were evaluated at the time of discharge.

Results: A total of 89 Japanese newborns with UB ≥1.00 μg/dL were enrolled at a median age of 4 days. Of these, 85 had UB 1.00-1.50 μg/dL and four had UB >1.50 μg/dL. After being treated according to the protocol, no newborns were diagnosed with auditory brainstem response abnormalities.

Conclusions: The present treatment protocol for Japanese newborns with serum UB ≥1.00 μg/dL may be useful for the prevention of bilirubin-induced auditory abnormalities.
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http://dx.doi.org/10.1111/j.1442-200X.2012.03726.xDOI Listing
February 2013

Unusual Manifestation of Gastric Helicobacter pylori Infection.

Case Rep Gastroenterol 2012 May 12;6(2):465-71. Epub 2012 Jul 12.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan.

Infection with Helicobacter pylori (HP) is common in many parts of the world. While most patients are asymptomatic, it causes peptic ulcer disease and malignancy in some of them. Other rare conditions have occasionally been reported in association with this infection. We report a case of hypertrophic gastropathy caused by HP in a 52-year-old asymptomatic patient. He was found to have marked enlargement of the gastric mucosal folds on radiological imaging and endoscopy. A gastric mucosal biopsy showed HP colonization associated with neutrophilic inflammation. After exclusion of neoplasia, other infections and infiltrative disorders, HP was thought to be the cause of the gastric fold hypertrophy. The patient responded well to HP eradication therapy, with normalization of the gastric mucosal folds. HP infection should be considered in the differential diagnosis of hypertrophic gastropathy and treated accordingly.
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http://dx.doi.org/10.1159/000341511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398096PMC
May 2012

Correlation and precision of serum free bilirubin concentrations determined by single and two peroxidase concentration methods in term or late-preterm newborn infants using a FDA-approved analyzer.

Clin Lab 2012 ;58(5-6):507-14

Department of Pediatrics, Kobe University Graduate School of Medicine, Japan.

Background: Free bilirubin concentration (B(f)) is an index for identifying newborns at risk for developing bilirubin-induced neurotoxicity. It has been suggested that B(f) measured by a single peroxidase concentration (B(f-single)) does not equal the equilibrium concentration of B(f), which is confirmed by B(f) at two different peroxidase concentrations (B(f-two)). However, the differences between B(f-single) and B(f-two) are unknown in the serum of term or late-preterm newborn infants. Furthermore, to apply B(f-single) with savings on time and cost to the clinical setting, it is very important for us to clarify the differences between B(f-single) and B(f-two).

Methods: Forty serum samples were obtained from 21 term or late-preterm newborns who were admitted at Kobe University Hospital. Using a peroxidase method, B(f-single) was measured at one peroxidase concentration, and B(f-two) was determined at two different peroxidase concentrations (the manufacturer's recommended peroxidase concentration and half the manufacturer's recommended peroxidase concentration). To clarify the relationship between B(f-single) and peroxidase concentrations, B(f-single) was measured at five different concentrations of peroxidase reagent. Intra-day and inter-day analyses were performed to assess the precision of B(f-single) and B(f-two).

Results: 1/B(f-single) increased as peroxidase concentration increased. B(f-single) was significantly lower than B(f-two) (B(f-single): 0.50 microg/dL [0.13 - 1.22 microg/dL] versus B(f-two): 0.59 microg/dL [0.15 - 1.76 microg/dL], p < 0.001), but B(f-single) was significantly correlated with B(f-two) (r = 0.953, p < 0.0001). Intra-day analysis showed that the CV was 9.7% for B(f-two) and 3.3% for B(f-single), and the inter-day CV was 12.4% for B(f-two) and 3.2% for B(f-single).

Conclusions: Although B(f-single) and B(f-two) are not identical, B(f-single) is significantly correlated with B(f-two) and it is more precise than B(f-two) in term or late-preterm newborns.
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July 2012

Selective graphene formation on copper twin crystals.

J Am Chem Soc 2012 Aug 18;134(30):12492-8. Epub 2012 Jul 18.

Green Nanoelectronics Center (GNC), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan.

Selective graphene growth on copper twin crystals by chemical vapor deposition has been achieved. Graphene ribbons can be formed only on narrow twin crystal regions with a (001) or high-index surface sandwiched between Cu crystals having (111) surfaces by tuning the growth conditions, especially by controlling the partial pressure of CH(4) in Ar/H(2) carrier gas. At a relatively low CH(4) pressure, graphene nucleation at steps on Cu (111) surfaces is suppressed, and graphene is preferentially nucleated and formed on twin crystal regions. Graphene ribbons as narrow as ~100 nm have been obtained in experiments. The preferential graphene nucleation and formation seem to be caused primarily by a difference in surface-dependent adsorption energies of reactants, which has been estimated by first principles calculations. Concentrations of reactants on a Cu surface have also been analyzed by solving a diffusion equation that qualitatively explains our experimental observations of the preferential graphene nucleation. Our findings may lead to self-organizing formation of graphene nanoribbons without reliance on top-down approaches in the future.
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http://dx.doi.org/10.1021/ja300811pDOI Listing
August 2012

Culture-proven neonatal sepsis in Japanese neonatal care units in 2006-2008.

Neonatology 2012 16;102(1):75-80. Epub 2012 May 16.

Department of Pediatrics, Kobe University Hospital, Chuo-ku, Kobe, Japan.

Background: Recent Japanese epidemiology of neonatal sepsis and its predominant pathogens has not been reported. It is also unknown whether there are center differences in the incidence of neonatal sepsis, including early-onset sepsis (EOS) and late-onset sepsis (LOS) in Japan.

Objectives: To investigate the morbidity and characteristics of neonatal sepsis in recent years and the differences in the incidence of sepsis among Japanese neonatal care units.

Methods: We retrospectively collected the data of newborn infants with culture-proven sepsis that occurred in five Japanese centers of perinatal care from 2006 to 2008. The incidence of sepsis was calculated, including EOS and LOS, and compared among centers.

Results: Morbidity from sepsis occurred in 51/6,894 (0.74%) infants. The incidence of EOS and LOS was 0.13 and 0.61%, respectively. The incidence of total sepsis and LOS in infants <1,000 g of birth weight was significantly higher than that in infants who weighed >1,000 g at birth, whereas there were no significant differences in the incidence of EOS between the different birth weights. Methicillin-resistant Staphylococcus aureus was the most common pathogen involved in morbidity and mortality of neonatal sepsis. Significant center differences were observed in the incidence of LOS, but not EOS.

Conclusions: The majority of culture-proven neonatal sepsis is LOS, which differs among centers, especially in infants who weigh <1,000 g at birth in Japan. We consider that it is important to control nosocomial infection in newborn care units to further reduce the morbidity of neonatal sepsis in Japan.
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http://dx.doi.org/10.1159/000337833DOI Listing
December 2012

A p.D116G mutation in CREB1 leads to novel multiple malformation syndrome resembling CrebA knockout mouse.

Hum Mutat 2012 Apr 14;33(4):651-4. Epub 2012 Feb 14.

Division of Diagnostic Molecular Pathology, Kobe University Graduate School of Medicine, Kobe, Japan.

We evaluated an autopsy case with severe neonatal respiratory distress, hypoplasia of thymus, thyroid gland and cerebellum, and agenesis of the corpus callosum displaying striking phenotypic similarity to the CrebA knockout mouse. On the assumption that comparable genetic alterations must be present, we checked the whole genomic DNA sequence of cyclic adenosine monophosphate (cAMP) response element binding protein 1 (CREB1), the human counterpart of mouse CrebA, and found a missense c.347A>G mutation corresponding to p.D116G within the kinase-inducible domain (KID) of CREB1. When transcribed in vitro, while Ser-133 phosphorylation of KID was maintained upon forskolin treatment, mutated CREB1 protein failed to associate with the KIX domain of co-activator CREBBP/EP300, and thereby, interrupted cAMP-dependent protein kinase A signal transduction as the dominant-negative form. This is the first report of a sporadic CREB1-related multiple malformation syndrome that, in light of accumulated knowledge of phenotypic features in gene-targeted animals, clearly emphasizes the importance of cross-species translational research.
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http://dx.doi.org/10.1002/humu.22027DOI Listing
April 2012