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1.  The dynamic genome of Hydra 
Chapman, Jarrod A. | Kirkness, Ewen F. | Simakov, Oleg | Hampson, Steven E. | Mitros, Therese | Weinmaier, Therese | Rattei, Thomas | Balasubramanian, Prakash G. | Borman, Jon | Busam, Dana | Disbennett, Kathryn | Pfannkoch, Cynthia | Sumin, Nadezhda | Sutton, Granger G. | Viswanathan, Lakshmi Devi | Walenz, Brian | Goodstein, David M. | Hellsten, Uffe | Kawashima, Takeshi | Prochnik, Simon E. | Putnam, Nicholas H. | Shu, Shengquiang | Blumberg, Bruce | Dana, Catherine E. | Gee, Lydia | Kibler, Dennis F. | Law, Lee | Lindgens, Dirk | Martinez, Daniel E. | Peng, Jisong | Wigge, Philip A. | Bertulat, Bianca | Guder, Corina | Nakamura, Yukio | Ozbek, Suat | Watanabe, Hiroshi | Khalturin, Konstantin | Hemmrich, Georg | Franke, André | Augustin, René | Fraune, Sebastian | Hayakawa, Eisuke | Hayakawa, Shiho | Hirose, Mamiko | Hwang, Jung Shan | Ikeo, Kazuho | Nishimiya-Fujisawa, Chiemi | Ogura, Atshushi | Takahashi, Toshio | Steinmetz, Patrick R. H. | Zhang, Xiaoming | Aufschnaiter, Roland | Eder, Marie-Kristin | Gorny, Anne-Kathrin | Salvenmoser, Willi | Heimberg, Alysha M. | Wheeler, Benjamin M. | Peterson, Kevin J. | Böttger, Angelika | Tischler, Patrick | Wolf, Alexander | Gojobori, Takashi | Remington, Karin A. | Strausberg, Robert L. | Venter, J. Craig | Technau, Ulrich | Hobmayer, Bert | Bosch, Thomas C. G. | Holstein, Thomas W. | Fujisawa, Toshitaka | Bode, Hans R. | David, Charles N. | Rokhsar, Daniel S. | Steele, Robert E.
Nature  2010;464(7288):592-596.
The freshwater cnidarian Hydra was first described in 17021 and has been the object of study for 300 years. Experimental studies of Hydra between 1736 and 1744 culminated in the discovery of asexual reproduction of an animal by budding, the first description of regeneration in an animal, and successful transplantation of tissue between animals2. Today, Hydra is an important model for studies of axial patterning3, stem cell biology4 and regeneration5. Here we report the genome of Hydra magnipapillata and compare it to the genomes of the anthozoan Nematostella vectensis6 and other animals. The Hydra genome has been shaped by bursts of transposable element expansion, horizontal gene transfer, trans-splicing, and simplification of gene structure and gene content that parallel simplification of the Hydra life cycle. We also report the sequence of the genome of a novel bacterium stably associated with H. magnipapillata. Comparisons of the Hydra genome to the genomes of other animals shed light on the evolution of epithelia, contractile tissues, developmentally regulated transcription factors, the Spemann–Mangold organizer, pluripotency genes and the neuromuscular junction.
PMCID: PMC4479502  PMID: 20228792
2.  Accuracy and Reproducibility of Automated, Standardized Coronary Transluminal Attenuation Gradient Measurements 
Coronary Computed Tomography Angiography (CCTA) contrast opacification gradients, or Transluminal Attenuation Gradients (TAG) offer incremental value to predict functionally significant lesions. This study introduces and evaluates an automated gradients software package that can potentially supplant current, labor-intensive manual TAG calculation methods.
All 60 major coronary arteries in 20 patients who underwent a clinically indicated single heart beat 320×0.5 mm detector row CCTA were retrospectively evaluated by two readers using a previously validated manual measurement approach and two additional readers who used the new automated gradient software. Accuracy of the automated method against the manual measurements, considered the reference standard, was assessed via linear regression and Bland-Altman analyses. Inter- and intra-observer reproducibility and factors that can affect accuracy or reproducibility of both manual and automated TAG measurements, including CAD severity and iterative reconstruction, were also assessed.
Analysis time was reduced by 68% when compared to manual TAG measurement. There was excellent correlation between automated TAG and the reference standard manual TAG. Bland-Altman analyses indicated low mean differences (1 HU/cm) and narrower inter- and intra-observer limits of agreement for automated compared to manual measurements (25% and 36% reduction with automated software, respectively). Among patient and technical factors assessed, none affected agreement of manual and automated TAG measurement.
Automated 320×0.5 mm detector row gradient software reduces computation time by 68% with high accuracy and reproducibility.
PMCID: PMC4104747  PMID: 24839136
Coronary CT Angiography; Cardiac Imaging; Hounsfield units; Contrast Opacification Gradients; Transluminal attenuation gradient
3.  Class Switch Recombination and Somatic Hypermutation of Virus-Neutralizing Antibodies Are Not Essential for Control of Friend Retrovirus Infection 
Journal of Virology  2014;89(2):1468-1473.
Toll-like receptor 7 and Myd88 are required for antiretroviral antibody and germinal center responses, but whether somatic hypermutation and class-switch recombination are required for antiretroviral immunity has not been examined. Mice deficient in activation-induced cytidine deaminase (AID) resisted Friend virus infection, produced virus-neutralizing antibodies, and controlled viremia. Passive transfer demonstrated that immune IgM from AID-deficient mice contributes to Friend virus control in the presence of virus-specific CD4+ T cells.
PMCID: PMC4300674  PMID: 25378499
4.  Imaging of reactive oxygen species using [3H]hydromethidine in mice with cisplatin-induced nephrotoxicity 
EJNMMI Research  2015;5:38.
Reactive oxygen species (ROS) have been implicated in cisplatin-induced nephrotoxicity. The aim of this study was to investigate the potential of using [3H]-labeled N-methyl-2,3-diamino-6-phenyl-dihydrophenanthridine ([3H]hydromethidine) for ex vivo imaging of regional ROS overproduction in mouse kidney induced by cisplatin.
Male C57BL/6 J mice were intraperitoneally administered with a single dose of cisplatin (30 mg/kg). Renal function was assessed by measuring serum creatinine and blood urea nitrogen (BUN) levels and morphology by histological examination. Renal malondialdehyde levels were measured as a lipid peroxidation marker. Autoradiographic studies were performed with kidney sections from mice at 60 min after [3H]hydromethidine injection.
Radioactivity accumulation after [3H]hydromethidine injection was observed in the renal corticomedullary area of cisplatin-treated mice and was attenuated by pretreatment with dimethylthiourea (DMTU), a hydroxyl radical scavenger. Cisplatin administration significantly elevated serum creatinine and BUN levels, caused renal tissue damage, and promoted renal lipid peroxidation. These changes were significantly suppressed by DMTU pretreatment.
The present study showed that [3H]hydromethidine was rapidly distributed to the kidney after its injection and trapped there in the presence of ROS such as hydroxyl radicals, suggesting that [3H]hydromethidine is useful for assessment of the renal ROS amount in cisplatin-induced nephrotoxicity.
PMCID: PMC4497996  PMID: 26160497
Cisplatin; Hydroxyl radical; Nephrotoxicity; Reactive oxygen species
5.  Ex Vivo Prefabricated Rat Skin Flap Using Cell Sheets and an Arteriovenous Vascular Bundle 
Supplemental Digital Content is available in the text.
Recently, research on tissue-engineered skin substitutes have been active in plastic surgery, and significant development has been made in this area over the past several decades. However, a regenerative skin flap has not been developed that could provide immediate blood flow after transplantation. Here, we make a regenerative skin flap ex vivo that is potentially suitable for microsurgical transplantation in future clinical applications.
In rats, for preparing a stable vascular carrier, a femoral vascular pedicle was sandwiched between collagen sponges and inserted into a porous chamber in the abdomen. The vascular bed was harvested 3 weeks later, and extracorporeal perfusion was performed. A green fluorescent protein positive epidermal cell sheet was placed on the vascular bed. After perfusion culture, the whole construct was harvested and fixed for morphological analyses.
After approximately 10 days perfusion, the epidermal cell sheet cornified sufficiently. The desquamated corneum was positive for filaggrin. The basement membrane protein laminin 332 and type 4 collagen were deposited on the interface area between the vascular bed and the epidermal cell sheet. Moreover, an electron microscopic image showed anchoring junctions and keratohyalin granules. These results show that we were able to produce native-like skin.
We have succeeded in creating regenerative skin flap ex vivo that is similar to native skin, and this technique could be applied to create various tissues in the future.
PMCID: PMC4494494  PMID: 26180725
6.  Extracapsular Invasion of Sentinel Lymph Nodes Is Not Associated With Disease Recurrence in Breast Cancer 
International Surgery  2014;99(4):305-308.
The purpose of this study was to evaluate the presence of extracapsular invasion (ECI) in positive sentinel lymph nodes (SLNs) as a predictor of disease recurrence in breast cancer. SLN biopsy was performed on 318 breasts of 316 breast cancer patients, of which 50 (15.7%) had positive SLNs. Six (12.0%) of these 50 cases had disease recurrence. The clinicopathologic features of these cases were reviewed. The ECI at SLNs was not significantly associated with disease recurrence. The recurrence-free interval by Kaplan-Meier curves did not differ significantly among patients with and without ECI at SLNs. On the other hand, metastasis at non-SLNs was observed in 12 cases (24.0%) among the 50 cases with positive SLNs, and in the non-SLN metastasis group there were 7 patients with ECI at non-SLNs. Three of 7 cases with ECI at non-SLNs had disease recurrence and none of those 5 without ECI at non-SLNs had disease recurrence. Our current study suggests that the presence of ECI at metastatic SLNs is not associated with recurrent disease in breast cancer. Our results also imply that patients with ECI at positive non-SLNs have a high risk of disease recurrence.
PMCID: PMC4114353  PMID: 25058757
Sentinel lymph node; Breast cancer; Extracapsular invasion; Prognosis
7.  Evidence for a Role of the Transcriptional Regulator Maid in Tumorigenesis and Aging 
PLoS ONE  2015;10(6):e0129950.
Maid is a helix-loop-helix protein that is involved in cell proliferation. In order to further elucidate its physiological functions, we studied Maid activity in two small fish model systems. We found that Maid expression was greatest in zebrafish liver and that it increased following partial hepatectomy. Maid levels were also high in hepatic preneoplastic foci induced by treatment of zebrafish with diethylnitrosamine (DEN), but low in hepatocellular carcinomas (HCC), mixed tumors, and cholangiocarcinomas developing in these animals. In DEN-treated transgenic medaka overexpressing Maid, hepatic BrdU uptake and proliferation were reduced. After successive breedings, Maid transgenic medaka exhibited decreased movement and a higher incidence of abnormal spine curvature, possibly due to the senescence of spinal cord cells. Taken together, our results suggest that Maid levels can influence the progression of liver cancer. In conclusion, we found that Maid is important regulator of hepatocarconogenesis and aging.
PMCID: PMC4479567  PMID: 26107180
8.  Mest but Not MiR-335 Affects Skeletal Muscle Growth and Regeneration 
PLoS ONE  2015;10(6):e0130436.
When skeletal muscle fibers are injured, they regenerate and grow until their sizes are adjusted to surrounding muscle fibers and other relevant organs. In this study, we examined whether Mest, one of paternally expressed imprinted genes that regulates body size during development, and miR-335 located in the second intron of the Mest gene play roles in muscle regeneration. We generated miR-335-deficient mice, and found that miR-335 is a paternally expressed imprinted microRNA. Although both Mest and miR-335 are highly expressed during muscle development and regeneration, only Mest+/- (maternal/paternal) mice show retardation of body growth. In addition to reduced body weight in Mest+/-; DMD-null mice, decreased muscle growth was observed in Mest+/- mice during cardiotoxin-induced regeneration, suggesting roles of Mest in muscle regeneration. Moreover, expressions of H19 and Igf2r, maternally expressed imprinted genes were affected in tibialis anterior muscle of Mest+/-; DMD-null mice compared to DMD-null mice. Thus, Mest likely mediates muscle regeneration through regulation of imprinted gene networks in skeletal muscle.
PMCID: PMC4476715  PMID: 26098312
9.  Effects of indacaterol versus tiotropium on respiratory mechanics assessed by the forced oscillation technique in patients with chronic obstructive pulmonary disease 
The forced oscillation technique (FOT) can measure respiratory mechanics and has attracted attention in chronic obstructive pulmonary disease (COPD). We aimed to evaluate the effects of only indacaterol and tiotropium monotherapies on airflow limitation and respiratory impedance. Pulmonary function tests, COPD assessment test (CAT), and multifrequency FOT with MostGraph-01 were performed at the beginning and after 8 weeks of treatment with indacaterol or tiotropium. The resistance index, resistance at 5 Hz (R5), resistance at 20 Hz (R20), reactance index, reactance at 5 Hz (X5), resonant frequency (Fres), and low-frequency reactance area (ALX) were determined at whole-breath, inspiratory, and expiratory phases. Eighty-two patients (mean age: 73 years; mean forced expiratory volume in 1 second (FEV1): 61.6%±19.0% predicted) were randomized to indacaterol or tiotropium treatment. Both bronchodilators improved airflow limitation, with mean trough improvements in FEV1 of 165 mL and 80 mL in the indacaterol and tiotropium groups, respectively. The CAT score decreased in the indacaterol group (P<0.001; 11.2±6.6 to 7.5±5.6). Compared with tiotropium, indacaterol significantly improved FEV1, percent predicted FEV1, and CAT score (P=0.042, P=0.008, and P=0.027, respectively). For respiratory impedance, indacaterol and tiotropium changed R5, X5, Fres, and ALX at whole-breath, inspiratory, and expiratory phases. In the indacaterol group, the changes in R5, R5–R20, X5, Fres, and ALX were significantly correlated with the changes in FEV1. The use of the FOT may enable the evaluation of the effects of bronchodilators in addition to FEV1-indicated therapeutic effects in COPD.
PMCID: PMC4476438  PMID: 26124653
chronic obstructive pulmonary disease; forced oscillation technique; indacaterol; monotherapy; MostGraph-01; reactance; resistance; tiotropium
10.  Anorexia Nervosa during Adolescence Is Associated with Decreased Gray Matter Volume in the Inferior Frontal Gyrus 
PLoS ONE  2015;10(6):e0128548.
Anorexia nervosa (AN) is an eating disorder characterized by the relentless pursuit to lose weight, mostly through self-starvation, and a distorted body image. AN tends to begin during adolescence among women. However, the underlying neural mechanisms related to AN remain unclear. Using voxel-based morphometry based on magnetic resonance imaging scans, we investigated whether the presence of AN was associated with discernible changes in brain morphology. Participants were 20 un-medicated, right-handed patients with early-onset AN and 14 healthy control subjects. Group differences in gray matter volume (GMV) were assessed using high-resolution, T1-weighted, volumetric magnetic resonance imaging datasets (3T Trio scanner; Siemens AG) and analyzed after controlling for age and total GMV, which was decreased in the bilateral inferior frontal gyrus (IFG) (left IFG: FWE corrected, p < 0.05; right IFG: uncorrected, p < 0.05) of patients with AN. The GMV in the bilateral IFG correlated significantly with current age (left IFG: r = -.481, p < .05; right IFG: r = -.601, p < .01) and was limited to the AN group. We speculate that decreased IFG volume might lead to deficits in executive functioning or inhibitory control within neural reward systems. Precocious or unbalanced neurological trimming within this particular region might be an important factor for the pathogenesis of AN onset.
PMCID: PMC4465897  PMID: 26067825
11.  Acute Angle-Closure Glaucoma After General Anesthesia for Bone Grafting 
Anesthesia Progress  2014;61(4):162-164.
Acute angle-closure glaucoma (AACG) is a rare complication of general anesthesia. The coexistence of individual risk factors for postoperative AACG and factors associated with intraocular hypertension are considered to be required for postoperative AACG to develop. We present a case of AACG after general anesthesia for oral bone grafting in a patient with no preoperative eye symptoms. In this case, several factors such as postoperative care in a darkened room, psychological stress, and postoperative hypertension may have precipitated the event in this patient, who may have had preexisting undiagnosed elevated intraocular pressure. The interval between the earliest appearance of symptoms at 9 hours and the ultimate diagnosis was 36 hours. In the postoperative period following general anesthesia, any patient is at risk for AACG. It is important that a postoperative diagnosis of AACG should be considered and a timely consultation with an ophthalmologist be considered if a postoperative patient complains of red eyes, visual disorder, eye pain, headache, and nausea.
PMCID: PMC4269356  PMID: 25517552
Acute angle-closure glaucoma; General anesthesia; Postoperative ophthalmological emergency
12.  High-resolution live imaging reveals axon-glia interactions during peripheral nerve injury and repair in zebrafish 
Disease Models & Mechanisms  2015;8(6):553-564.
Neural damage is a devastating outcome of physical trauma. The glia are one of the main effectors of neuronal repair in the nervous system, but the dynamic interactions between peripheral neurons and Schwann cells during injury and regeneration remain incompletely characterized. Here, we combine laser microsurgery, genetic analysis, high-resolution intravital imaging and lattice light-sheet microscopy to study the interaction between Schwann cells and sensory neurons in a zebrafish model of neurotrauma. We found that chronic denervation by neuronal ablation leads to Schwann-cell death, whereas acute denervation by axonal severing does not affect the overall complexity and architecture of the glia. Neuronal-circuit regeneration begins when Schwann cells extend bridging processes to close the injury gap. Regenerating axons grow faster and directionally after the physiological clearing of distal debris by the Schwann cells. This might facilitate circuit repair by ensuring that axons are guided through unoccupied spaces within bands of Büngner towards their original peripheral target. Accordingly, in the absence of Schwann cells, regenerating axons are misrouted, impairing the re-innervation of sensory organs. Our results indicate that regenerating axons use haptotaxis as a directional cue during the reconstitution of a neural circuit. These findings have implications for therapies aimed at neurorepair, which will benefit from preserving the architecture of the peripheral glia during periods of denervation.
Summary: Schwann cells are important components of the peripheral glia. We use microsurgery and high-resolution live imaging to show how Schwann cells control the regeneration of a sensorineural circuit.
PMCID: PMC4457030  PMID: 26035865
High-resolution imaging; Neurotrauma; Regeneration; Schwann cells; Haptotaxis
13.  Neuregulin 1 Type II-ErbB Signaling Promotes Cell Divisions Generating Neurons from Neural Progenitor Cells in the Developing Zebrafish Brain 
PLoS ONE  2015;10(5):e0127360.
Post-mitotic neurons are generated from neural progenitor cells (NPCs) at the expense of their proliferation. Molecular and cellular mechanisms that regulate neuron production temporally and spatially should impact on the size and shape of the brain. While transcription factors such as neurogenin1 (neurog1) and neurod govern progression of neurogenesis as cell-intrinsic mechanisms, recent studies show regulatory roles of several cell-extrinsic or intercellular signaling molecules including Notch, FGF and Wnt in production of neurons/neural progenitor cells from neural stem cells/radial glial cells (NSCs/RGCs) in the ventricular zone (VZ). However, it remains elusive how production of post-mitotic neurons from neural progenitor cells is regulated in the sub-ventricular zone (SVZ). Here we show that newborn neurons accumulate in the basal-to-apical direction in the optic tectum (OT) of zebrafish embryos. While neural progenitor cells are amplified by mitoses in the apical ventricular zone, neurons are exclusively produced through mitoses of neural progenitor cells in the sub-basal zone, later in the sub-ventricular zone, and accumulate apically onto older neurons. This neurogenesis depends on Neuregulin 1 type II (NRG1-II)–ErbB signaling. Treatment with an ErbB inhibitor, AG1478 impairs mitoses in the sub-ventricular zone of the optic tectum. Removal of AG1478 resumes sub-ventricular mitoses without precedent mitoses in the apical ventricular zone prior to basal-to-apical accumulation of neurons, suggesting critical roles of ErbB signaling in mitoses for post-mitotic neuron production. Knockdown of NRG1-II impairs both mitoses in the sub-basal/sub-ventricular zone and the ventricular zone. Injection of soluble human NRG1 into the developing brain ameliorates neurogenesis of NRG1-II-knockdown embryos, suggesting a conserved role of NRG1 as a cell-extrinsic signal. From these results, we propose that NRG1-ErbB signaling stimulates cell divisions generating neurons from neural progenitor cells in the developing vertebrate brain.
PMCID: PMC4441363  PMID: 26001123
14.  Hemichorea-hemiballismus caused by postoperative hyperperfusion after clipping of a giant unruptured middle cerebral artery aneurysm 
Movement disorders after the clipping for an unruptured giant aneurysm are rare. The information on the pathogenesis and treatment options for this condition is largely unknown.
Case Description:
An 82-year-old female with no neurological deficits underwent a clipping for a giant middle cerebral artery (MCA) aneurysm. Immediately after surgery, she presented with hemichorea–hemiballismus (HC–HB) on the left side. Postoperative angiograms and single-photon emission computed tomography demonstrated the hyperperfusion in the right frontal cortex and the decreased perfusion in the basal ganglia, indicating that the abrupt hemodynamic changes due to the obliteration of the giant aneurysm caused the dysfunction of the frontal cortical and subcortical pathway and the basal ganglia. Administration of tiapride hydrochloride was dramatically effective in controlling the HC–HB until the hyperperfusion resolved. Single-photon emission computed tomography obtained 8 weeks after surgery revealed that the cerebral blood flow had been normalized in the right frontal cortex. The relative hypoperfusion of the right basal ganglia was also resolved. Then tiapride hydrochloride was discontinued without a relapse of HC–HB.
This case appears consistent with the theory that the connecting fibers responsible for the development of HC–HB are also located in the frontal lobe. The treatment of giant aneurysms involving the M1 portion can cause abrupt hemodynamic changes in both frontal cortex and the basal ganglia, which can potentially induce postoperative movement disorders.
PMCID: PMC4443400  PMID: 26015872
Aneurysm; chorea; clipping; giant aneurysm; hyperperfusion; single-photon emission computed tomography
15.  Usefulness of repetitive intraoperative indocyanine green-based videoangiography to confirm complete obliteration of micro-arteriovenous malformations 
It is difficult to intraoperatively confirm the total disappearance of arteriovenous (AV) shunts during surgery for microarteriovenous malformations (micro-AVMs), especially when the nidus is extremely small or diffuse on preoperative angiography. Although intraoperative angiography is effective for evaluating residual shunts, procedure-related risks raise important concerns. The purpose of this study was to assess the usefulness of intraoperative indocyanine green-based videoangiography (ICG–VA) to determine complete disappearance of micro-AVMs during surgery.
We retrospectively analyzed eight patients with ruptured micro-AVMs who were treated using craniotomy with ICG–VA at our institution.
Two patients underwent emergency partial evacuation of hematoma and external decompression before the diagnostic angiography. While three patients had a nidus smaller than 1 cm, five patients had only early draining veins without an appreciable nidus. The draining veins were superficial in six cases and deep in two cases. The average interval from onset to surgery was 33 days (range, 2–57). ICG–VA was repetitively conducted until disappearance of the AV shunt was confirmed. No residual AV shunt was observed on postoperative radiological examinations. In all cases, the diagnosis of AVM was confirmed from the results of postoperative pathological examination.
ICG–VA could detect early draining veins more clearly in situ than diagnostic angiography. Although it is not as effective for visualizing lesions with deep draining veins, repetitive ICG–VA was safe and effective for confirming the disappearance of AV shunts with superficial drainage.
PMCID: PMC4443402  PMID: 26015873
Arteriovenous malformation; hematoma; indocyanine green-based videoangiography; microarteriovenous malformation
16.  Severe respiratory failure associated with influenza B virus infection 
Respirology Case Reports  2015;3(2):61-63.
A 72-year-old man who had been diagnosed with type B influenza infection and high fever 4 days previously was admitted to our hospital. He presented with severe respiratory insufficiency; chest computed tomography (CT) revealed extensive ground-glass opacity in lung fields on both sides. Although peramivir and antibiotics were administered, reticular shadows on chest CT worsened and respiratory insufficiency deteriorated. The patient fulfilled the criteria for severe acute respiratory distress syndrome. Despite multimodal therapy, including noninvasive positive pressure ventilation, polymyxin B-immobilized fiber column hemoperfusion, and methylprednisolone infusion, his general condition gradually deteriorated. He died of respiratory failure on day 129. Pathology findings of the lungs during autopsy showed diffuse alveolar damage. To our knowledge, this is the first report of severe respiratory failure after type B influenza infection. Clinicians should be aware of the potential for fatal respiratory failure in cases of type B as well as type A influenza infections.
PMCID: PMC4469142  PMID: 26090113
ARDS; diffuse alveolar damage; influenza; pneumonia; respiratory failure
17.  Comparison of ankle plantar flexor activity between double-leg heel raise and walking 
Journal of Physical Therapy Science  2015;27(5):1523-1526.
[Purpose] We aimed to evaluate the difference in the muscle activity between the double-leg heel raise (DHR) and treadmill walking. [Subjects] Thirty healthy males aged 21.5 ± 1.6 years (body mass 63.6 ± 9.3 kg, height 171.0 ± 4.5 cm) participated in the study. [Methods] Electromyograms were simultaneously recorded from both heads of the gastrocnemius and the soleus of the right side during the DHR and treadmill walking. The DHR conditions were maximum plantar flexion (MPF), 3/4 MPF, 2/4 MPF, and 1/4 MPF, and the walking speeds were 20, 40, 60, 80, and 100 m/min. [Results] The muscle activity during the DHR and walking significantly increased with increments in the height of the heel raise and walking speed, respectively. Comparison of the muscle activity at MPF with that at each walking speed revealed that the muscle activity in the soleus and gastrocnemius medial head during walking exceeded that during the DHR in less than 3.3% of cases. [Conclusion] The DHR test is useful for evaluating the ankle plantar flexor activity necessary for walking.
PMCID: PMC4483433  PMID: 26157255
Double-leg heel raise; Walking; Plantar flexor
18.  Differentiation of malignant tumours from granulomas by using dynamic [18F]-fluoro-L-α-methyltyrosine positron emission tomography 
EJNMMI Research  2015;5:29.
Previous clinical studies have revealed the potential of [18F]-fluoro-L-α-methyltyrosine (18F-FAMT) for the differential diagnosis of malignant tumours from sarcoidosis. However, one concern regarding the differential diagnosis with 18F-FAMT is the possibility of false negatives given the small absolute uptake of 18F-FAMT that has been observed in some malignant tumours. The aim of this study was to evaluate a usefulness of dynamic 18F-FAMT positron emission tomography (PET) for differentiating malignant tumours from granulomas.
Rats bearing both granulomas (Mycobacterium bovis bacillus Calmette-Guérin (BCG)-induced) and tumours (C6 glioma cell-induced) underwent dynamic 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG) PET and 18F-FAMT PET for 120 min on consecutive days. Time-activity curves, static images, mean standardized uptake values (SUVs) and the SUV ratios (SUVRs; calculated by dividing SUV at each time point by that of 2 min after injection) were assessed.
In tumours, 18F-FAMT showed a shoulder peak immediately after the initial distribution followed by gradual clearance compared with granulomas. Although the mean SUV in the tumours (1.00 ± 0.10) was significantly higher than that in the granulomas (0.88 ± 0.12), a large overlap was observed. In contrast, the SUVR was markedly higher in tumours than in granulomas (50 min/2 min, 0.72 ± 0.06 and 0.56 ± 0.05, respectively) with no overlap. The dynamic patterns, SUVR, and mean SUV of 18F-FDG in the granulomas were comparable to those in the tumours.
Dynamic 18F-FAMT and SUVR analysis might compensate for the current limitations and help in improving the diagnostic accuracy of 18F-FAMT.
PMCID: PMC4420762  PMID: 25977883
3-[18F]-Fluoro-α-methyl-L-tyrosine; Granuloma; Inflammation; Tumour; Dynamic positron emission tomography
19.  The BioMart community portal: an innovative alternative to large, centralized data repositories 
Smedley, Damian | Haider, Syed | Durinck, Steffen | Pandini, Luca | Provero, Paolo | Allen, James | Arnaiz, Olivier | Awedh, Mohammad Hamza | Baldock, Richard | Barbiera, Giulia | Bardou, Philippe | Beck, Tim | Blake, Andrew | Bonierbale, Merideth | Brookes, Anthony J. | Bucci, Gabriele | Buetti, Iwan | Burge, Sarah | Cabau, Cédric | Carlson, Joseph W. | Chelala, Claude | Chrysostomou, Charalambos | Cittaro, Davide | Collin, Olivier | Cordova, Raul | Cutts, Rosalind J. | Dassi, Erik | Genova, Alex Di | Djari, Anis | Esposito, Anthony | Estrella, Heather | Eyras, Eduardo | Fernandez-Banet, Julio | Forbes, Simon | Free, Robert C. | Fujisawa, Takatomo | Gadaleta, Emanuela | Garcia-Manteiga, Jose M. | Goodstein, David | Gray, Kristian | Guerra-Assunção, José Afonso | Haggarty, Bernard | Han, Dong-Jin | Han, Byung Woo | Harris, Todd | Harshbarger, Jayson | Hastings, Robert K. | Hayes, Richard D. | Hoede, Claire | Hu, Shen | Hu, Zhi-Liang | Hutchins, Lucie | Kan, Zhengyan | Kawaji, Hideya | Keliet, Aminah | Kerhornou, Arnaud | Kim, Sunghoon | Kinsella, Rhoda | Klopp, Christophe | Kong, Lei | Lawson, Daniel | Lazarevic, Dejan | Lee, Ji-Hyun | Letellier, Thomas | Li, Chuan-Yun | Lio, Pietro | Liu, Chu-Jun | Luo, Jie | Maass, Alejandro | Mariette, Jerome | Maurel, Thomas | Merella, Stefania | Mohamed, Azza Mostafa | Moreews, Francois | Nabihoudine, Ibounyamine | Ndegwa, Nelson | Noirot, Céline | Perez-Llamas, Cristian | Primig, Michael | Quattrone, Alessandro | Quesneville, Hadi | Rambaldi, Davide | Reecy, James | Riba, Michela | Rosanoff, Steven | Saddiq, Amna Ali | Salas, Elisa | Sallou, Olivier | Shepherd, Rebecca | Simon, Reinhard | Sperling, Linda | Spooner, William | Staines, Daniel M. | Steinbach, Delphine | Stone, Kevin | Stupka, Elia | Teague, Jon W. | Dayem Ullah, Abu Z. | Wang, Jun | Ware, Doreen | Wong-Erasmus, Marie | Youens-Clark, Ken | Zadissa, Amonida | Zhang, Shi-Jian | Kasprzyk, Arek
Nucleic Acids Research  2015;43(Web Server issue):W589-W598.
The BioMart Community Portal ( is a community-driven effort to provide a unified interface to biomedical databases that are distributed worldwide. The portal provides access to numerous database projects supported by 30 scientific organizations. It includes over 800 different biological datasets spanning genomics, proteomics, model organisms, cancer data, ontology information and more. All resources available through the portal are independently administered and funded by their host organizations. The BioMart data federation technology provides a unified interface to all the available data. The latest version of the portal comes with many new databases that have been created by our ever-growing community. It also comes with better support and extensibility for data analysis and visualization tools. A new addition to our toolbox, the enrichment analysis tool is now accessible through graphical and web service interface. The BioMart community portal averages over one million requests per day. Building on this level of service and the wealth of information that has become available, the BioMart Community Portal has introduced a new, more scalable and cheaper alternative to the large data stores maintained by specialized organizations.
PMCID: PMC4489294  PMID: 25897122
20.  Tumor Exosomes Induce Tunneling Nanotubes in Lipid Raft-Enriched Regions of Human Mesothelioma Cells 
Experimental cell research  2014;323(1):178-188.
Tunneling nanotubes (TnTs) are long, non-adherent, actin-based cellular extensions that act as conduits for transport of cellular cargo between connected cells. The mechanisms of nanotube formation and the effects of the tumor microenvironment and cellular signals on TnT formation are unknown. In the present study, we explored exosomes as potential mediators of TnT formation in mesothelioma and the potential relationship of lipid rafts to TnT formation. Mesothelioma cells co-cultured with exogenous mesothelioma-derived exosomes formed more TnTs than cells cultured without exosomes within 24-48 hours; and this effect was most prominent in media conditions (low-serum, hyperglycemic medium) that support TnT formation (1.3-1.9-fold difference). Fluorescence and electron microscopy confirmed the purity of isolated exosomes and revealed that they localized predominantly at the base of and within TnTs, in addition to the extracellular environment. Time-lapse microscopic imaging demonstrated uptake of tumor exosomes by TnTs, which facilitated intercellular transfer of these exosomes between connected cells. Mesothelioma cells connected via TnTs were also significantly enriched for lipid rafts at nearly a 2-fold higher number compared with cells not connected by TnTs. Our findings provide supportive evidence of exosomes as potential chemotactic stimuli for TnT formation, and also lipid raft formation as a potential biomarker for TnT-forming cells.
PMCID: PMC4159162  PMID: 24468420
Tunneling nanotubes; exosomes; lipid rafts; intercellular transfer; intercellular communication; mesothelioma
21.  Effect of dipeptidyl peptidase-4 inhibition on circadian blood pressure during the development of salt-dependent hypertension in rats 
A growing body of evidence has indicated that dipeptidyl peptidase-4 (DPP-4) inhibitors have antihypertensive effects. Here, we aim to examine the effect of vildagliptin, a DPP-4-specific inhibitor, on blood pressure and its circadian-dipping pattern during the development of salt-dependent hypertension in Dahl salt-sensitive (DSS) rats. DSS rats were treated with a high-salt diet (8% NaCl) plus vehicle or vildagliptin (3 or 10 mg kg−1 twice daily by oral gavage) for 7 days. Blood pressure was measured by the telemetry system. High-salt diet for 7 days significantly increased the mean arterial pressure (MAP), systolic blood pressure (SBP) and were also associated with an extreme dipping pattern of blood pressure in DSS rats. Treatment with vildagliptin dose-dependently decreased plasma DPP-4 activity, increased plasma glucagon-like peptide 1 (GLP-1) levels and attenuated the development of salt-induced hypertension. Furthermore, vildagliptin significantly increased urine sodium excretion and normalized the dipping pattern of blood pressure. In contrast, intracerebroventricular infusion of vildagliptin (50, 500 or 2500 μg) did not alter MAP and heart rate in DSS rats. These data suggest that salt-dependent hypertension initially develops with an extreme blood pressure dipping pattern. The DPP-4 inhibitor, vildagliptin, may elicit beneficial antihypertensive effects, including the improvement of abnormal circadian blood pressure pattern, by enhancing urinary sodium excretion.
PMCID: PMC4390453  PMID: 25588850
blood pressure; Dahl salt-sensitive rats; dipeptidyl peptidase-4 (DPP-4) inhibitors; dipping pattern
22.  Patient-reported outcomes after discontinuation of long-term topical corticosteroid treatment for atopic dermatitis: a targeted cross-sectional survey 
Topical corticosteroid (TCS) treatment is widely prescribed for atopic dermatitis (AD). However, TCS treatment is associated with tachyphylaxis, and discontinuation after long-term use may cause exacerbation of symptoms. Some AD patients are reluctant to use TCS.
To evaluate patient-reported short- and long-term outcomes after discontinuation of TCS treatment for AD.
Questionnaires were distributed to adult AD patients (n=1,812) of doctors who did not recommend TCS as first-line therapy for patients who preferred to avoid TCS. Data collected included current TCS use, duration of TCS use, past discontinuation of TCS use, exacerbation of symptoms after discontinuation of TCS use, and limitations to daily activities because of AD.
Of 918 respondents, 97.7% had used TCS, of whom 92.3% had experienced discontinuation of TCS use. After discontinuation, 63.9% experienced their most severe AD symptoms ever. The severity of exacerbation of symptoms was significantly correlated with the length of TCS use (P<0.001). Although most respondents who experienced severe exacerbation after TCS discontinuation were not current TCS users, they generally had fewer current limitations to activities than when AD symptoms were at their worst.
Adult Japanese AD patients who experience severe exacerbation of symptoms immediately after discontinuation of TCS use generally improve over time. We suggest caution regarding long-term TCS treatment in AD patients.
PMCID: PMC4396455  PMID: 25897263
adverse effects of corticosteroids; symptom exacerbation; rosacea-like dermatitis
23.  What Drives Farmers to Make Top-Down or Bottom-Up Adaptation to Climate Change and Fluctuations? A Comparative Study on 3 Cases of Apple Farming in Japan and South Africa 
PLoS ONE  2015;10(3):e0120563.
Agriculture is one of the most vulnerable sectors to climate change. Farmers have been exposed to multiple stressors including climate change, and they have managed to adapt to those risks. The adaptation actions undertaken by farmers and their decision making are, however, only poorly understood. By studying adaptation practices undertaken by apple farmers in three regions: Nagano and Kazuno in Japan and Elgin in South Africa, we categorize the adaptation actions into two types: farmer initiated bottom-up adaptation and institution led top-down adaptation. We found that the driver which differentiates the type of adaptation likely adopted was strongly related to the farmers’ characteristics, particularly their dependence on the institutions, e.g. the farmers’ cooperative, in selling their products. The farmers who rely on the farmers’ cooperative for their sales are likely to adopt the institution-led adaptation, whereas the farmers who have established their own sales channels tend to start innovative actions by bottom-up. We further argue that even though the two types have contrasting features, the combinations of the both types of adaptations could lead to more successful adaptation particularly in agriculture. This study also emphasizes that more farm-level studies for various crops and regions are warranted to provide substantial feedbacks to adaptation policy.
PMCID: PMC4378992  PMID: 25822534
24.  Tuning the photoluminescence of condensed-phase cyclic trinuclear Au(I) complexes through control of their aggregated structures by external stimuli 
Scientific Reports  2015;5:7934.
A series of new cyclic trinuclear Au(I) complexes with alkoxy side chains of various lengths were synthesized as photoluminescence materials. None of the complexes emitted luminescence in solution; however, some showed photoluminescence in the crystalline phase. Single crystal X-ray structural analyses revealed that an intermolecular interaction between two Au atoms (aurophilic interaction) existed only in the emissive complexes, which formed molecular aggregates in the crystal. Because isolated molecules show no luminescence in the present system, we conclude that only molecules aggregated via aurophilic interactions can luminesce. We demonstrated that luminescence properties, such as colour and intensity, were very sensitive to the aggregated structure of the molecules. We also found that such luminescence properties can be controlled by a change in the aggregated structure induced by external stimuli, such as heat, solvent, and mechanical stress.
PMCID: PMC4399505  PMID: 25879782
25.  Prognostic Significance of Anti-Aminoacyl-tRNA Synthetase Antibodies in Polymyositis/Dermatomyositis-Associated Interstitial Lung Disease: A Retrospective Case Control Study 
PLoS ONE  2015;10(3):e0120313.
In polymyositis/dermatomyositis (PM/DM), anti-aminoacyl-tRNA synthetase (ARS) antibodies are closely associated with interstitial lung disease (ILD), a frequent pulmonary complication. However, the clinical significance of anti-ARS antibodies is not well established.
We aimed to evaluate the clinical significance of anti-ARS antibodies in PM/DM-ILD patients.
Forty-eight consecutive PM/DM-ILD patients were studied retrospectively. Anti-ARS antibodies were screened by ELISA and confirmed by RNA immunoprecipitation test. Medical records, high-resolution computed tomography images, and surgical lung biopsy specimens were compared between ARS-positive (ARS group) and ARS-negative patients (non-ARS group).
Anti-ARS antibodies were detected in 23 of 48 patients (48%). Radiologically, nonspecific interstitial pneumonia (NSIP) pattern was observed more frequently in the ARS group than in the non-ARS group (73.9% vs. 40%, P = 0.02). Pathologically, NSIP was the most frequent in both groups. Ten-year survival rate was also significantly higher in the ARS group than in the non-ARS group (91.6% vs. 58.7%, P = 0.02). Univariate Cox hazards analysis revealed that the presence of anti-ARS antibodies was associated with better prognosis (HR = 0.34, 95% CI 0.08–0.80; P = 0.01).
The presence of anti-ARS antibodies is a possible prognostic marker in patients with PM/DM-ILD.
PMCID: PMC4366175  PMID: 25789468

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