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1.  Cyanophage Infection in the Bloom-Forming Cyanobacteria Microcystis aeruginosa in Surface Freshwater 
Microbes and Environments  2012;27(4):350-355.
Host-like genes are often found in viral genomes. To date, multiple host-like genes involved in photosynthesis and the pentose phosphate pathway have been found in phages of marine cyanobacteria Synechococcus and Prochlorococcus. These gene products are predicted to redirect host metabolism to deoxynucleotide biosynthesis for phage replication while maintaining photosynthesis. A cyanophage, Ma-LMM01, infecting the toxic cyanobacterium Microcystis aeruginosa, was isolated from a eutrophic freshwater lake and assigned as a member of a new lineage of the Myoviridae family. The genome encodes a host-like NblA. Cyanobacterial NblA is known to be involved in the degradation of the major light harvesting complex, the phycobilisomes. Ma-LMM01 nblA gene showed an early expression pattern and was highly transcribed during phage infection. We speculate that the co-option of nblA into Microcystis phages provides a significant fitness advantage to phages by preventing photoinhibition during infection and possibly represents an important part of the co-evolutionary interactions between cyanobacteria and their phages.
doi:10.1264/jsme2.ME12037
PMCID: PMC4103541  PMID: 23047146
cyanobacteria; cyanophage; non-bleaching gene (nblA); phycobilisome; Microcystis
2.  Lifestyle-Related Factors Contributing to Decline in Knee Extension Strength among Elderly Women: A Cross-Sectional and Longitudinal Cohort Study 
PLoS ONE  2015;10(7):e0132523.
This cross-sectional and 4-year longitudinal cohort study aimed to clarify how various lifestyle-related variables affect knee extension strength in elderly Japanese women. The participants were community-dwelling women (n = 575) living in the Itabashi Ward of Tokyo, Japan aged 75–85 years at baseline (in 2008) who returned for a follow-up examination 4 years later (in 2012). Maximum isometric knee extension strength in the dominant leg was measured during comprehensive medical check-ups at baseline and follow-up. Interviews with participants included questions on their history of 11 diseases and lifestyle-related factors such as physical activity as well as dietary, smoking, and drinking habits. Cross-sectional and longitudinal analyses yielded inconsistent results regarding the associations between lifestyle-related factors and knee extension strength. While going out more frequently and regular physical exercise positively affected baseline knee extension strength, they did not affect knee extension strength in the longitudinal analysis. The longitudinal analysis revealed that more frequent intake of soy products or green and yellow vegetables at baseline decreased age-related knee extension strength decline. The inconsistent results from the cross-sectional and longitudinal analyses indicate that conducting both types of analyses is crucial for researching this type of subject. The present study demonstrates that the age-related decline in muscle strength is lower in those who frequently eat soy products or green and yellow vegetables. Thus, recommending higher intake of soy products, and green and yellow vegetables for the elderly might help maintain their muscle health.
doi:10.1371/journal.pone.0132523
PMCID: PMC4503692  PMID: 26177292
3.  Changes in the Acetylome and Succinylome of Bacillus subtilis in Response to Carbon Source 
PLoS ONE  2015;10(6):e0131169.
Lysine residues can be post-translationally modified by various acyl modifications in bacteria and eukarya. Here, we showed that two major acyl modifications, acetylation and succinylation, were changed in response to the carbon source in the Gram-positive model bacterium Bacillus subtilis. Acetylation was more common when the cells were grown on glucose, glycerol, or pyruvate, whereas succinylation was upregulated when the cells were grown on citrate, reflecting the metabolic states that preferentially produce acetyl-CoA and succinyl-CoA, respectively. To identify and quantify changes in acetylation and succinylation in response to the carbon source, we performed a stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative proteomic analysis of cells grown on glucose or citrate. We identified 629 acetylated proteins with 1355 unique acetylation sites and 204 succinylated proteins with 327 unique succinylation sites. Acetylation targeted different metabolic pathways under the two growth conditions: branched-chain amino acid biosynthesis and purine metabolism in glucose and the citrate cycle in citrate. Succinylation preferentially targeted the citrate cycle in citrate. Acetylation and succinylation mostly targeted different lysine residues and showed a preference for different residues surrounding the modification sites, suggesting that the two modifications may depend on different factors such as characteristics of acyl-group donors, molecular environment of the lysine substrate, and/or the modifying enzymes. Changes in acetylation and succinylation were observed in proteins involved in central carbon metabolism and in components of the transcription and translation machineries, such as RNA polymerase and the ribosome. Mutations that modulate protein acylation affected B. subtilis growth. A mutation in acetate kinase (ackA) increased the global acetylation level, suggesting that acetyl phosphate-dependent acetylation is common in B. subtilis, just as it is in Escherichia coli. Our results suggest that acyl modifications play a role in the physiological adaptations to changes in carbon nutrient availability of B. subtilis.
doi:10.1371/journal.pone.0131169
PMCID: PMC4476798  PMID: 26098117
4.  A New Fractionation and Recovery Method of Viral Genomes Based on Nucleic Acid Composition and Structure Using Tandem Column Chromatography 
Microbes and Environments  2015;30(2):199-203.
Metagenomic studies have revealed the unexplored diversity of the environmental virosphere. However, most studies are biased towards specific types of viral genomes due to the absence of universal methods to access all viral genome types. In the present study, we established a novel system to efficiently separate single- and double-stranded DNA/RNA viral genomes using hydroxyapatite and cellulose chromatography. This method will allow us to quantitatively and simultaneously access four types of viral genomes and will provide important clues to further understand previously unexplored environmental viral populations and obtain potentially unbiased libraries from environmental viral communities.
doi:10.1264/jsme2.ME14174
PMCID: PMC4462933  PMID: 26004793
viral ecology; viral genome; column chromatography; nucleic acids
5.  Toddaculin, Isolated from of Toddalia asiatica (L.) Lam., Inhibited Osteoclastogenesis in RAW 264 Cells and Enhanced Osteoblastogenesis in MC3T3-E1 Cells 
PLoS ONE  2015;10(5):e0127158.
Osteoporosis with bone loss is widely recognized as a major health problem. Bone homeostasis is maintained by balancing bone formation and bone resorption. The imbalance caused by increased bone resorption over bone formation can lead to various bone-related diseases such as osteoporosis and rheumatoid arthritis. Osteoclasts are the principal cells responsible for bone resorption and the main targets of anti-resorptive therapies. However, excessive inhibition of osteoclast differentiation may lead to inhibition of osteoblast differentiation. Therefore, it is important to screen for new compounds capable of inhibiting bone resorption and enhancing bone formation. Toddalia asiatica (L.) Lam. has been utilized traditionally for medicinal purposes such as the treatment of rheumatism. Currently, the extract is considered to be a good source of pharmacological agents for the treatment of bone-related diseases, but the active compounds have yet to be identified. We investigated whether toddaculin, derived from Toddalia asiatica (L.) Lam., affects both processes by inhibiting bone resorption and enhancing bone formation. Towards this end, we used pre-osteoclastic RAW 264 cells and pre-osteoblastic MC3T3-E1 cells. We found that toddaculin not only inhibited the differentiation of osteoclasts via activation of the NF-κB, ERK 1/2, and p38 MAPK signaling pathways, but it also induced differentiation and mineralization of osteoblasts by regulating differentiation factors. Thus, toddaculin might be beneficial for the prevention and treatment of osteoporosis.
doi:10.1371/journal.pone.0127158
PMCID: PMC4436367  PMID: 25993011
6.  Effect of postconditioning on dynamic expression of tenascin-C and left ventricular remodeling after myocardial ischemia and reperfusion 
EJNMMI Research  2015;5:21.
Background
Tenascin-C (TNC), an extracellular matrix glycoprotein, is expressed transiently in distinct areas in association with active tissue remodeling. This study aimed to explore how ischemic postconditioning (PC) affects myocardial expression of TNC and ventricular remodeling using 125I-labeled anti-TNC antibody (125I-TNC-Ab) in a rat model of ischemia and reperfusion.
Methods
In control rats (n = 27), the left coronary artery (LCA) was occluded for 30 min followed by reperfusion for 1, 3, 7, and 14 days. PC (n = 27) was performed just after the reperfusion. At the time of the study, 125I-TNC-Ab (1.0 to 2.5 MBq) was injected. Six to 9 h later, to verify the area at risk, 99mTc-MIBI (100 to 200 MBq) was injected intravenously just after the LCA reocclusion, with the rats sacrificed 1 min later. Dual tracer autoradiography was performed to assess 125I-TNC-Ab uptake and area at risk. To examine the ventricular remodeling, echocardiography was performed 2 M after reperfusion in both groups.
Results
In control rats, 125I-TNC-Ab uptake ratio at 1 day after reperfusion was 3.73 ± 0.71 and increased at 3 days (4.65 ± 0.87), followed by a significant reduction at 7 days (2.91 ± 0.55, P < 0.005 vs 3 days) and14 days (2.01 ± 0.17, P < 0.005 vs 1 and 3 days). PC attenuated the 125I-TNC-Ab uptake throughout the reperfusion time from 1 to 14 days; 2.59 ± 0.59 at 1 day, P < 0.05: 3.10 ± 0.42 at 3 days, P < 0.005: 1.93 ± 0.37 at 7 days, P < 0.05: 1.40 ± 0.07 at 14 days, P < 0.001. In echocardiography, PC reduced the ventricular end-diastolic and systolic dimensions (1.00 ± 0.06 cm to 0.83 ± 0.14 cm (P < 0.05) and 0.90 ± 0.15 cm to 0.62 ± 0.19 cm (P < 0.05), respectively) and prevented a decline of ventricular percentage fractional shortening (10.5 ± 3.7 to 28.2 ± 10.7, P < 0.005).
Conclusions
These data indicate that 125I-TNC-Ab imaging may be a way to monitor myocardial injury, the subsequent repair process, and its response to novel therapeutic interventions like PC by visualizing TNC expression.
doi:10.1186/s13550-015-0100-8
PMCID: PMC4393400  PMID: 25883880
Tenascin-C; I-125-anti-tenascin-C antibody; Postconditioning; Ventricular remodeling; Myocardial ischemia and reperfusion
7.  Factors Affecting Cerebral Oxygenation in Hemodialysis Patients: Cerebral Oxygenation Associates with pH, Hemodialysis Duration, Serum Albumin Concentration, and Diabetes Mellitus 
PLoS ONE  2015;10(2):e0117474.
Background
Patients undergoing hemodialysis (HD) often develop cerebral disease complications. Furthermore, cerebral regional saturation of oxygen (rSO2) was previously reported to be significantly lower in HD patients than in healthy subjects. We aimed to identify the factors affecting the cerebral rSO2 in HD patients.
Methods
Fifty-four HD patients (38 men and 16 women; mean age, 67.7 ± 1.2 years, HD duration, 6.5 ± 1.9 years) were recruited. Cerebral rSO2 was monitored at the forehead before HD using an INVOS 5100C (Covidien Japan, Tokyo, Japan).
Results
The rSO2 levels were significantly lower in HD patients compared with healthy controls (49.5 ± 1.7% vs. 68.9 ± 1.6%, p <0.001). Multiple regression analysis showed that cerebral rSO2 independently associated with pH (standardized coefficient: -0.35), HD duration (standardized coefficient: -0.33), and serum albumin concentration (standardized coefficient: 0.28). Furthermore, the rSO2 was significantly lower in HD patients with diabetes mellitus (DM), compared with patients without DM (46.8 ± 1.7% vs. 52.1 ± 1.8%, p <0.05).
Conclusions
In HD patients, cerebral rSO2 was affected by multiple factors, including pH, HD duration, and serum albumin concentration. Furthermore, this is the first report describing significantly lower levels of rSO2 in HD patients with DM than in those without DM.
doi:10.1371/journal.pone.0117474
PMCID: PMC4338103  PMID: 25706868
8.  Hybrid video-assisted thoracoscopic surgery lobectomy of fissureless congenital cystic adenomatoid malformation: a case report 
Introduction
Thoracoscopic lobectomy for congenital pulmonary airway malformation has been indicated from the neonatal period to adolescence. However, it is difficult to approach the pulmonary artery for lobectomy in congenital lung malformations with incomplete or absent interlobar fissures. Multidetector computed tomographic images and computed tomography pulmonary angiography gave us helpful information before the operation. We performed thoracoscopic lobectomy for congenital pulmonary airway malformations with absent interlobar fissures and adhesions in accordance with information from multidetector computed tomographic images.
Case presentation
A 14-year-old Japanese girl received a diagnosis of congenital pulmonary airway malformation when she presented with pneumonia. Using multidetector computed tomography and three-dimensional reconstruction provides meticulous characterization of the anatomy in pediatric patients. We confirmed that her left A4+5 artery arose from her left pulmonary artery medial to A6. Her left pulmonary artery was divided just proximal to the A6 origin before the lobes were separated safely. We took advantage of using a stapler to divide the fissureless thick parenchyma. Perioperative diagnosis was congenital cystic adenomatoid malformation.
Conclusions
We used preoperative multidetector computed tomography to outline the bronchovascular anatomy and guide hybrid video-assisted thoracoscopic surgery for a congenital cystic adenomatoid malformation in a fissureless left lung.
doi:10.1186/1752-1947-9-23
PMCID: PMC4417292  PMID: 25652225
Congenital cystic adenomatoid malformation of lung; Hybrid VATS; Thoracic surgery
9.  PATIENTS’ LEVEL OF MEDICAL TERM RECOGNITION AS ESTIMATED BY HEALTHCARE WORKERS 
Nagoya Journal of Medical Science  2015;77(1-2):123-132.
ABSTRACT
To render risk communication between patients and healthcare workers more effective, gaps in the patients’ level of medical term recognition as estimated by healthcare workers was examined. This was a cross-sectional study conducted via an Internet survey. A total of 244 nurses and 211 medical doctors were surveyed. We examined 90 medical terms, including 57 medical terms examined by the National Institute for Japanese Language and 33 newly added medical terms. Differences between medical doctors and nurses with respect to the estimation of patients’ level of medical term recognition were assessed. The level of medical term recognition by patients was higher when estimated by nurses than when estimated by medical doctors. As members of team care, nurses must consider that patients find technical medical terms to be more difficult than anticipated and that patients are aware of these terms only to a certain extent while receiving healthcare information, such as drug information. Currently, nurses are expected to perform activities as clinical research coordinators and also are requested to work as home-visiting nurses. Therefore they also need ensure that patients understand the medical information provided to them.
PMCID: PMC4361514  PMID: 25797977
Risk communication; Perception gap; Shared decision-making; healthcare; Regulatory science
10.  Ingestion of hyaluronans (molecular weights 800 k and 300 k) improves dry skin conditions: a randomized, double blind, controlled study 
Hyaluronan (HA) has been increasingly used as a dietary supplement to improve the skin. However, the effect of ingested HA may depend on its molecular weight (MW) because its physiological activities in the body vary with its MW. In this study, we examined the effects of ingested HA with varying MW on the skin. In this randomized, double blind, placebo controlled study, 61 subjects with dry skin received oral HA (120 mg/day), of MWs 800 k and 300 k or placebo, for 6 weeks. The skin moisture contents of the first two groups increased more than those of the placebo group during the ingestion period. In addition, group HA 300 k exhibited significant improvements in skin moisture content 2 weeks after ingestion ended compared with the placebo group. A questionnaire survey about subjective facial aging symptoms showed that the HA treated groups exhibited significantly improved the skin condition compared with the placebo treated group. Furthermore, dermatologists objectively evaluated the clinical symptoms of the facial and whole body skin, showing that no adverse events were related to daily ingestion of HA. This study shows that both of ingesting HAs (MWs 800 k and 300 k) improved the skin condition by increasing the moisture content.
doi:10.3164/jcbn.14-81
PMCID: PMC4306664  PMID: 25834304
hyaluronan; molecular weight; ingestion; skin moisture content; dry skin
11.  Tenascin‐C Aggravates Autoimmune Myocarditis via Dendritic Cell Activation and Th17 Cell Differentiation 
Background
Tenascin‐C (TN‐C), an extracellular matrix glycoprotein, appears at several important steps of cardiac development in the embryo, but is sparse in the normal adult heart. TN‐C re‐expresses under pathological conditions including myocarditis, and is closely associated with tissue injury and inflammation in both experimental and clinical settings. However, the pathophysiological role of TN‐C in the development of myocarditis is not clear. We examined how TN‐C affects the initiation of experimental autoimmune myocarditis, immunologically.
Methods and Results
A model of experimental autoimmune myocarditis was established in BALB/c mice by immunization with murine α‐myosin heavy chains. We found that TN‐C knockout mice were protected from severe myocarditis compared to wild‐type mice. TN‐C induced synthesis of proinflammatory cytokines, including interleukin (IL)‐6, in dendritic cells via activation of a Toll‐like receptor 4, which led to T‐helper (Th)17 cell differentiation and exacerbated the myocardial inflammation. In the transfer experiment, dendritic cells loaded with cardiac myosin peptide acquired the functional capacity to induce myocarditis when stimulated with TN‐C; however, TN‐C‐stimulated dendritic cells generated from Toll‐like receptor 4 knockout mice did not induce myocarditis in recipients.
Conclusions
Our results demonstrated that TN‐C aggravates autoimmune myocarditis by driving the dendritic cell activation and Th17 differentiation via Toll‐like receptor 4. The blockade of Toll‐like receptor 4‐mediated signaling to inhibit the proinflammatory effects of TN‐C could be a promising therapeutic strategy against autoimmune myocarditis.
doi:10.1161/JAHA.114.001052
PMCID: PMC4338691  PMID: 25376187
dendritic cell; myocarditis; tenascin‐C; Th17; TLR4
12.  Aggravation of ovalbumin-induced murine asthma by co-exposure to desert-dust and organic chemicals: an animal model study 
Environmental Health  2014;13:83.
Background
The organic chemicals present in Asian sand dust (ASD) might contribute to the aggravation of lung eosinophila. Therefore, the aggravating effects of the Tar fraction from ASD on ovalbumin (OVA)-induced lung eosinophilia were investigated.
Methods
The Tar fraction was extracted from ASD collected from the atmosphere in Fukuoka, Japan. ASD collected from the Gobi desert was heated at 360°C to inactivate toxic organic substances (H-ASD). ICR mice were instilled intratracheally with 12 different test samples prepared with Tar (1 μg and 5 μg), H-ASD, and OVA in a normal saline solution containing 0.02% Tween 80. The lung pathology, cytological profiles in the bronchoalveolar lavage fluid (BALF), inflammatory cytokines/chemokines in BALF and OVA-specific immunoglobulin in serum were investigated.
Results
Several kinds of polycyclic aromatic hydrocarbons (PAHs) were detected in the Tar sample. H-ASD + Tar 5 μg induced slight neutrophilic lung inflammation. In the presence of OVA, Tar 5 μg increased the level of eosinophils slightly and induced trace levels of Th2 cytokines IL-5 and IL-13 in BALF. Also mild to moderate goblet cell proliferation and mild infiltration of eosinophils in the submucosa of airway were observed. These pathological changes caused by H-ASD + OVA were relatively small. However, in the presence of OVA and H-ASD, Tar, at as low a level as 1 μg, induced severe eosinophil infiltration and proliferation of goblet cells in the airways and significantly increased Th2 cytokines IL-5 and IL-13 in BALF. The mixture showed an adjuvant effect on OVA-specific IgG1 production.
Conclusions
These results indicate that H-ASD with even low levels of Tar exacerbates OVA-induced lung eosinophilia via increases of Th2-mediated cytokines. These results suggest that ASD-bound PAHs might contribute to the aggravation of lung eosinophila.
doi:10.1186/1476-069X-13-83
PMCID: PMC4216376  PMID: 25326908
Tar; Polycyclic aromatic hydrocarbons; Asian sand dust; Ovalbumin; Lung eosinophilia; Cytokine and chemokine
13.  Autoimmune pancreatitis with colonic stenosis: an unusual complication and atypical pancreatographic finding 
BMC Gastroenterology  2014;14:173.
Background
Type 1 autoimmune pancreatitis (AIP) often accompanies various systematic disorders such as sclerosing cholangitis, sialoadenitis, retroperitoneal fibrosis, interstitial pneumonitis and nephritis. Although rarely reported in acute pancreatitis, colonic stenosis is an uncommon complication in cases with AIP.
Case presentation
A 69-year-old Japanese man complained of abdominal pain and continuous diarrhea, resistant to intake of antimuscarinic and probiotic agents. A colonoscopy demonstrated a stenosis at the splenic flexure. Computed tomography revealed a focal enlargement of the pancreatic tail with a capsule-like rim, contacting with the descending colon. Endoscopic retrograde pancreatography (ERP) was unable to visualize the main pancreatic duct (MPD) at the pancreatic tail, despite a full contrast injection. A high serum IgG4 level (1060 mg/dL) and exclusion of pancreatic cancer by endoscopic ultrasound guided-fine needle aspiration suggested AIP, but did not fulfill the diagnostic criteria, and steroid therapy was initiated. One month after starting steroid intake, pancreatic swelling was minimized and the MPD was visualized by ERP, fulfilling the international consensus diagnostic criteria (ICDC) of AIP. Colonic stenosis was relieved and the patient’s symptoms disappeared.
Conclusion
The present case is the first report of AIP developing colonic stenosis by the inflammatory infiltration. In this case, steroid therapy was effective for the diagnosis and treatment of pancreatic mass involving the descending colon.
doi:10.1186/1471-230X-14-173
PMCID: PMC4192343  PMID: 25280867
Autoimmune pancreatitis; Colonic stenosis; Differential diagnosis; Steroid therapy
14.  The Relationship between Clinicopathological Features and Expression of Epithelial and Mesenchymal Markers in Spontaneous Canine Mammary Gland Tumors 
ABSTRACT
It is known that epithelial mesenchymal transition (EMT) contributes to the acquisition of malignant property in human cancers. However, the role of EMT in canine tumors remains to be elucidated. To evaluate the correlation between expression levels of protein markers involved in EMT and clinicopathological characteristics in canine mammary gland tumors, immunohistochemistry using antibodies against ZO-1, E-cadherin, vimentin, N-cadherin and fibronectin was performed on 119 clinical tissue samples. Consequently, loss of ZO-1 and E-cadherin, and gain of vimentin and N-cadherin were more frequently observed in malignant tumors than in benign tumors. However, there was no correlation among expression of these molecules. Univariate and multivariate analysis identified that loss of E-cadherin independently had a low one-year survival rate (adjusted odds ratio: 2.3, P=0.02). These results suggested that EMT might relate to acquisition of malignancy, and additionally, E-cadherin was strongly correlated with malignant behavior in canine mammary gland tumors.
doi:10.1292/jvms.14-0104
PMCID: PMC4221164  PMID: 24931646
canine mammary gland tumors; epithelial mesenchymal transition; immunohistochemistry; prognosis
15.  Molecular Characterization of a Novel N-Acetyltransferase from Chryseobacterium sp. 
N-Acetyltransferase from Chryseobacterium sp. strain 5-3B is an acetyl coenzyme A (acetyl-CoA)-dependent enzyme that catalyzes the enantioselective transfer of an acetyl group from acetyl-CoA to the amino group of l-2-phenylglycine to produce (2S)-2-acetylamino-2-phenylacetic acid. We purified the enzyme from strain 5-3B and deduced the N-terminal amino acid sequence. The gene, designated natA, was cloned with two other hypothetical protein genes; the three genes probably form a 2.5-kb operon. The deduced amino acid sequence of NatA showed high levels of identity to sequences of putative N-acetyltransferases of Chryseobacterium spp. but not to other known arylamine and arylalkylamine N-acetyltransferases. Phylogenetic analysis indicated that NatA forms a distinct lineage from known N-acetyltransferases. We heterologously expressed recombinant NatA (rNatA) in Escherichia coli and purified it. rNatA showed high activity for l-2-phenylglycine and its chloro- and hydroxyl-derivatives. The Km and Vmax values for l-2-phenylglycine were 0.145 ± 0.026 mM and 43.6 ± 2.39 μmol · min−1 · mg protein−1, respectively. The enzyme showed low activity for 5-aminosalicylic acid and 5-hydroxytryptamine, which are reported as good substrates of a known arylamine N-acetyltransferase and an arylalkylamine N-acetyltransferase. rNatA had a comparatively broad acyl donor specificity, transferring acyl groups to l-2-phenylglycine and producing the corresponding 2-acetylamino-2-phenylacetic acids (relative activity with acetyl donors acetyl-CoA, propanoyl-CoA, butanoyl-CoA, pentanoyl-CoA, and hexanoyl-CoA, 100:108:122:10:<1).
doi:10.1128/AEM.03449-13
PMCID: PMC3957623  PMID: 24375143
16.  Persistent Release of IL-1s from Skin Is Associated with Systemic Cardio-Vascular Disease, Emaciation and Systemic Amyloidosis: The Potential of Anti-IL-1 Therapy for Systemic Inflammatory Diseases 
PLoS ONE  2014;9(8):e104479.
The skin is an immune organ that contains innate and acquired immune systems and thus is able to respond to exogenous stimuli producing large amount of proinflammatory cytokines including IL-1 and IL-1 family members. The role of the epidermal IL-1 is not limited to initiation of local inflammatory responses, but also to induction of systemic inflammation. However, association of persistent release of IL-1 family members from severe skin inflammatory diseases such as psoriasis, epidermolysis bullosa, atopic dermatitis, blistering diseases and desmoglein-1 deficiency syndrome with diseases in systemic organs have not been so far assessed. Here, we showed the occurrence of severe systemic cardiovascular diseases and metabolic abnormalities including aberrant vascular wall remodeling with aortic stenosis, cardiomegaly, impaired limb and tail circulation, fatty tissue loss and systemic amyloid deposition in multiple organs with liver and kidney dysfunction in mouse models with severe dermatitis caused by persistent release of IL-1s from the skin. These morbid conditions were ameliorated by simultaneous administration of anti-IL-1α and IL-1β antibodies. These findings may explain the morbid association of arteriosclerosis, heart involvement, amyloidosis and cachexia in severe systemic skin diseases and systemic autoinflammatory diseases, and support the value of anti-IL-1 therapy for systemic inflammatory diseases.
doi:10.1371/journal.pone.0104479
PMCID: PMC4131904  PMID: 25119884
17.  Anatomical characterization of athetotic and spastic cerebral palsy using an atlas-based analysis 
Purpose
To analyze diffusion tensor imaging (DTI) in two types of cerebral palsy (CP): the athetotic-type and the spastic-type, using an atlas-based anatomical analysis of the entire brain, and to investigate whether these images have unique anatomical characteristics that can support functional diagnoses.
Methods
We retrospectively analyzed the DTI of seven children with athetotic-type, 11 children with spastic-type, and 20 healthy control children, all age-matched. The severity of motor dysfunction was evaluated with the Gross Motor Function Classification System (GMFCS). The images were normalized using a linear transformation, followed by large deformation diffeomorphic metric mapping. For 205 parcellated brain areas, the volume, fractional anisotropy, and mean diffusivity were measured. Principal component analysis (PCA) was performed for the Z scores of these parameters.
Result
The GMFCS scores in athetotic-type were significantly higher than those in spastic-type (p<0.001). PCA extracted anatomical components that comprised the two types of CP, as well as the severity of motor dysfunction. In the athetotic group, the abnormalities were more severe than in the spastic group. In the spastic group, significant changes were concentrated in the lateral ventricle and periventricular structures.
Conclusion
Our results quantitatively delineated anatomical characteristics that reflected the functional findings in two types of CP.
doi:10.1002/jmri.23931
PMCID: PMC3749241  PMID: 23737247
cerebral palsy; diffusion tensor imaging; atlas-based analysis; principal component analysis
18.  Ingested hyaluronan moisturizes dry skin 
Nutrition Journal  2014;13:70.
Hyaluronan (HA) is present in many tissues of the body and is essential to maintain moistness in the skin tissues, which contain approximately half the body’s HA mass. Due to its viscosity and moisturizing effect, HA is widely distributed as a medicine, cosmetic, food, and, recently marketed in Japan as a popular dietary supplement to promote skin moisture. In a randomized, double-blind, placebo-controlled clinical study it was found that ingested HA increased skin moisture and improved treatment outcomes for patients with dry skin. HA is also reported to be absorbed by the body distributed, in part, to the skin. Ingested HA contributes to the increased synthesis of HA and promotes cell proliferation in fibroblasts. These effects show that ingestion of HA moisturizes the skin and is expected to improve the quality of life for people who suffer from dry skin. This review examines the moisturizing effects of dry skin by ingested HA and summarizes the series of mechanisms from absorption to pharmacological action.
doi:10.1186/1475-2891-13-70
PMCID: PMC4110621  PMID: 25014997
Hyaluronan; Hyaluronic acid; Ingestion; Dry skin; Moisturizing
19.  Whole-genome sequencing of clarithromycin resistant Helicobacter pylori characterizes unidentified variants of multidrug resistant efflux pump genes 
Gut Pathogens  2014;6:27.
Background
Clarithromycin (CLR) is the key drug in eradication therapy of Helicobacter pylori (H. pylori) infection, and widespread use of CLR has led to an increase in primary CLR-resistant H. pylori. The known mechanism of CLR resistance has been established in A2146G and A2147G mutations in the 23S rRNA gene, but evidence of the involvement of other genetic mechanisms is lacking. Using the MiSeq platform, whole-genome sequencing of the 19 clinical strains and the reference strain ATCC26695 was performed to identify single nucleotide variants (SNVs) of multi-drug resistant efflux pump genes in the CLR-resistant phenotype.
Results
Based on sequencing data of ATCC26695, over one million sequencing reads with over 50-fold coverage were sufficient to detect SNVs, but not indels in the bacterial genome. Sequencing reads of the clinical isolates ranged from 1.82 to 10.8 million, and average coverage ranged from 90.9- to 686.3-fold, which were acceptable criteria for detecting SNVs. Utilizing the conventional approach of allele-specific PCR, point mutations in the 23S rRNA gene were detected in 12 clinical resistant isolates, but not in 7 clinical susceptible isolates. All sequencing reads of CLR-resistant strains had a G mutation in an identical position of the 23S rRNA gene. In addition, genetic variants of four gene clusters (hp0605-hp0607, hp0971-hp0969, hp1327-hp1329, and hp1489-hp1487) of TolC homologues, which have been implicated in multi-drug resistance, were examined. Specific SNVs were dominantly found in resistant strains.
Conclusions
Gene clusters of TolC homologues are involved in CLR susceptibility profiles in individual H. pylori strains. Whole-genome sequencing has yielded novel understanding of genotype-phenotype relationships.
doi:10.1186/1757-4749-6-27
PMCID: PMC4079918  PMID: 24995043
Whole-genome sequencing; Helicobacter pylori; Clarithromycin; Multidrug efflux; TolC homolog
20.  Enhancement of OVA-induced murine lung eosinophilia by co-exposure to contamination levels of LPS in Asian sand dust and heated dust 
Background
A previous study has shown that the aggravation of Asian sand dust (ASD) on ovalbumin (OVA)-induced lung eosinphilia was more severe in lipopolysaccharide (LPS)-rich ASD than in SiO2-rich ASD. Therefore, the effects of different LPS contamination levels in ASD on the aggravation of OVA-induced lung eosinophilia were investigated in the present study.
Methods
Before beginning the in vivo experiment, we investigated whether the ultra-pure LPS would act only on TLR4 or not using bone marrow-derived macrophages (BMDMs) of wild–type, TLR2-/-, TLR4-/- and MyD88-/- BALB/c mice. ASD collected from the desert was heated to remove toxic organic substances (H-ASD). BALB/c mice were instilled intratracheally with 12 different testing samples prepared with LPS (1 ng and 10 ng), H-ASD, and OVA in a normal saline solution. The lung pathology, cytological profiles in the bronchoalveolar lavage fluid (BALF), the levels of inflammatory cytokines/chemokines in BALF and OVA-specific immunoglobulin in serum were investigated.
Results
The LPS exhibited no response to the production of TNF-α and IL-6 in BMDMs from TLR4-/-, but did from TLR2-/-. H-ASD aggravated the LPS-induced neutrophilic lung inflammation. In the presence of OVA, LPS increased the level of eosinophils slightly and induced trace levels of Th2 cytokines IL-5 and IL-13 at the levels of 1 ng and 10 ng. In the presence of OVA and H-ASD, LPS induced severe eosinophil infiltration and proliferation of goblet cells in the airways as well as remarkable increases in Th2 cytokines IL-5 and IL-13 in BALF. The mixture containing LPS (1 ng) showed adjuvant activity on OVA-specific IgE and IgG1 production.
Conclusions
The results suggest that H-ASD with naturally-occurring levels of LPS enhances OVA-induced lung eosinophilia via increases in Th2-mediated cytokines and antigen-specific immunoglobulin. These results indicate that LPS is a strong candidate for being a major aggravating substance in ASD.
doi:10.1186/1710-1492-10-30
PMCID: PMC4058696  PMID: 24982682
Lipopolysaccharide; Asian sand dust; Ovalbumin; Lung eosinophilia; Cytokine and chemokine; Asthma
21.  Variation of the Virus-Related Elements within Syntenic Genomes of the Hyperthermophilic Archaeon Aeropyrum 
Applied and Environmental Microbiology  2013;79(19):5891-5898.
The increasing number of genome sequences of archaea and bacteria show their adaptation to different environmental conditions at the genomic level. Aeropyrum spp. are aerobic and hyperthermophilic archaea. Aeropyrum camini was isolated from a deep-sea hydrothermal vent, and Aeropyrum pernix was isolated from a coastal solfataric vent. To investigate the adaptation strategy in each habitat, we compared the genomes of the two species. Shared genome features were a small genome size, a high GC content, and a large portion of orthologous genes (86 to 88%). The genomes also showed high synteny. These shared features may have been derived from the small number of mobile genetic elements and the lack of a RecBCD system, a recombinational enzyme complex. In addition, the specialized physiology (aerobic and hyperthermophilic) of Aeropyrum spp. may also contribute to the entire-genome similarity. Despite having stable genomes, interference of synteny occurred with two proviruses, A. pernix spindle-shaped virus 1 (APSV1) and A. pernix ovoid virus 1 (APOV1), and clustered regularly interspaced short palindromic repeat (CRISPR) elements. Spacer sequences derived from the A. camini CRISPR showed significant matches with protospacers of the two proviruses infecting A. pernix, indicating that A. camini interacted with viruses closely related to APSV1 and APOV1. Furthermore, a significant fraction of the nonorthologous genes (41 to 45%) were proviral genes or ORFans probably originating from viruses. Although the genomes of A. camini and A. pernix were conserved, we observed nonsynteny that was attributed primarily to virus-related elements. Our findings indicated that the genomic diversification of Aeropyrum spp. is substantially caused by viruses.
doi:10.1128/AEM.01089-13
PMCID: PMC3811351  PMID: 23872576
22.  A novel, visible light-induced, rapidly cross-linkable gelatin scaffold for osteochondral tissue engineering 
Scientific Reports  2014;4:4457.
Osteochondral injuries remain difficult to repair. We developed a novel photo-cross-linkable furfurylamine-conjugated gelatin (gelatin-FA). Gelatin-FA was rapidly cross-linked by visible light with Rose Bengal, a light sensitizer, and was kept gelled for 3 weeks submerged in saline at 37°C. When bone marrow-derived stromal cells (BMSCs) were suspended in gelatin-FA with 0.05% Rose Bengal, approximately 87% of the cells were viable in the hydrogel at 24 h after photo-cross-linking, and the chondrogenic differentiation of BMSCs was maintained for up to 3 weeks. BMP4 fusion protein with a collagen binding domain (CBD) was retained in the hydrogels at higher levels than unmodified BMP4. Gelatin-FA was subsequently employed as a scaffold for BMSCs and CBD-BMP4 in a rabbit osteochondral defect model. In both cases, the defect was repaired with articular cartilage-like tissue and regenerated subchondral bone. This novel, photo-cross-linkable gelatin appears to be a promising scaffold for the treatment of osteochondral injury.
doi:10.1038/srep04457
PMCID: PMC3964514  PMID: 24662725
23.  Leveraging public health nurses for disaster risk communication in Fukushima City: a qualitative analysis of nurses' written records of parenting counseling and peer discussions 
Background
Local public health nurses (PHNs) have been recognized as the main health service providers in communities in Japan. The Fukushima nuclear disaster in 2011 has, however, created a major challenge for them in responding to mothers’ concerns. This was in part due to difficulties in assessing, understanding and communicating health risks on low-dose radiation exposure. In order to guide the development of risk communication plans, this study sought to investigate mothers’ primary concerns and possible solutions perceived by a core healthcare profession like the PHNs.
Methods
A total of 150 records from parenting counseling sessions conducted between PHNs and mothers who have attended mandatory 18-month health checkups for their children at the Fukushima City Health and Welfare Center in 2010, 2011 (year of disaster) and 2012 were examined. Discussion notes of three peer discussions among PHNs organized in response to the nuclear disaster in 2012 and 2013 were also analyzed. All transcribed data were first subjected to text mining to list the words according to their frequencies and inter-relationships. The Steps Coding and Theorization method was then undertaken as a framework for qualitative analysis.
Results
PHNs noted mothers to have considerable needs for information on radiation risks as they impact on decisions related to relocations, concerns for child safety, and experiences with interpersonal conflicts within the family owing to differing risk perceptions. PHNs identified themselves as the information channels in the community, recommended the building of their risk communication capacities to support residents in making well-informed decisions, and advocated for self-measurement of radiation levels to increase residents’ sense of control. PHNs also suggested a more standardized form of information dissemination and an expansion of community-based counseling services.
Conclusions
Inadequate risk communication on radiation in the Fukushima nuclear incident has resulted in multiple repercussions for mothers in the community. Empowerment of local residents to assume more active roles in the understanding of their environment, increasing PHNs’ capacity in communication, and an expansion of health services such as counseling will together better address risk communication challenges in post-disaster recovery efforts.
doi:10.1186/1472-6963-14-129
PMCID: PMC3995308  PMID: 24642079
Public health nurses; Risk communication; Parenting; Radiation; Health communication; Fukushima nuclear accident; Japan
24.  Primary cutaneous anaplastic large cell lymphoma occurring in an atopic dermatitis patient: a case report with review of the literature with emphasis on their association 
Although the risk of malignant lymphoma in patients with atopic dermatitis (AD) remains controversial, an increased risk of malignant T-cell lymphoma in patients with AD has been reported. Primary cutaneous anaplastic large cell lymphoma (C-ALCL) is a relatively common distinct clinicopathological entity. However, occurrence of C-ALCL in patients with AD has been rarely reported. Herein, we describe the 5th reported case of C-ALCL occurring in a patient with AD and review the clinicopathological features. A 30-year-old Japanese male with a long-standing history of AD presented with a gradually enlarged nodular lesion in the right abdominal wall, which had spontaneously regressed without therapy. Two years later, multiple nodular lesions appeared in his trunk, and swelling of multiple lymph nodes was also detected. Histopathological studies demonstrated diffuse proliferation of large-sized lymphocytes with large convoluted nuclei containing conspicuous nucleoli and relatively rich cytoplasm in the skin and lymph node. Immunohistochemically, these lymphocytes were positive for CD30, CD8, and MUM1, and negative for CD3, CD4, and ALK1. Accordingly, a diagnosis of primary C-ALCL was made. The patient died of disease after various courses of chemotherapy. Our clinicopathological review revealed that the prognosis of C-ALCL occurring in patients with AD is poor because two of 5 patients died of disease. Therefore, albeit extremely rare, AD patients with C-ALCL should be monitored closely, and additional clinicopathological studies are needed to clarify the pathogenesis of C-ALCL occurring in patients with AD.
PMCID: PMC4014256  PMID: 24817972
Primary cutaneous anaplastic large cell lymphoma; atopic dermatitis; lymph node
25.  Occurrence of Epstein-Barr virus-associated plasmacytic lymphoproliferative disorder after antithymocyte globulin therapy for aplastic anemia: a case report with review of the literature 
It is well established that patients with immunosuppression have a higher risk of development of lymphoproliferative disorders (LPDs), and Epstein-Barr virus (EBV) is associated with development of LPDs. Aplastic anemia (AA) is an immune-mediated hematological disorder, and immunosuppression therapy (IST), such as antithymocyte globulin (ATG), is widely used for treatment of AA. However, occurrence of LPD without bone marrow transplantation has been extremely rarely documented in patients with IST for AA. Herein, we report the 6th documented case of EBV-associated LPD after IST for AA and review the clinicopathological features of this extremely rare complication. A 46-year-old Japanese female was admitted for evaluation of progressive pancytopenia. Bone marrow biopsy revealed fatty marrow with marked decrease of trilineage cells, and bone marrow aspiration demonstrated no dysplastic changes. IST with rabbit ATG was administered, after which, she developed high fever. Bone marrow aspiration showed increase of atypical plasma cells with mildly enlarged nuclei and irregular nuclear contour. These atypical plasma cells were EBER-positive. Accordingly, a diagnosis of EBV-positive plasmacytic LPD was made. Most cases of LPDs are B-cell origin, and plasmacytic LPD is a rare subtype. The current report is the second case of plasmacytic LPD in patients with IST for AA. Therefore, detailed histopathological and immunohistochemical analyses are needed for correct diagnosis and treatment, and additional studies are needed to clarify the clinicopathological features of EBV-LPD after IST for AA.
PMCID: PMC4014258  PMID: 24817974
Epstein-Barr virus-associated lymphoproliferative disorder; antithymocyte globulin therapy; aplastic anemia

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