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1.  Brain structural changes and neuropsychological impairments in male polydipsic schizophrenia 
BMC Psychiatry  2012;12:210.
Background
Polydipsia frequently occurs in schizophrenia patients. The excessive water loading in polydipsia occasionally induces a hyponatremic state and leads to water intoxication. Whether polydipsia in schizophrenic patients correlates with neuropsychological impairments or structural brain changes is not clear and remains controversial.
Methods
Eight polydipsic schizophrenia patients, eight nonpolydipsic schizophrenia patients, and eight healthy controls were recruited. All subjects underwent magnetic resonance imaging (MRI) and neuropsychological testing. Structural abnormalities were analyzed using a voxel-based morphometry (VBM) approach, and patients’ neuropsychological function was assessed using the Brief Assessment of Cognition in Schizophrenia, Japanese version (BACS-J).
Results
No significant differences were found between the two patient groups with respect to the clinical characteristics. Compared with healthy controls, polydipsic patients showed widespread brain volume reduction and neuropsychological impairment. Furthermore, the left insula was significantly reduced in polydipsic patients compared with nonpolydipsic patients. These nonpolydipsic patients performed intermediate to the other two groups in the neuropsychological function test.
Conclusions
It is possible that polydipsia or the secondary hyponatremia might induce left insula volume reduction. Furthermore, this structural brain change may indirectly induce more severe neuropsychological impairments in polydipsic patients. Thus, we suggest that insula abnormalities might contribute to the pathophysiology of polydipsic patients.
doi:10.1186/1471-244X-12-210
PMCID: PMC3532364  PMID: 23181904
Schizophrenia; Polydipsia; Volumetry; MRI; Neuropsychological impairment; Brief assessment of cognition in schizophrenia
2.  Inhibition of MAO-A and stimulation of behavioural activities in mice by the inactive prodrug form of the anti-influenza agent oseltamivir 
British Journal of Pharmacology  2013;169(1):115-129.
Background and Purpose
Oseltamivir is the most widely prescribed anti-influenza medication. However, in rare instances, it has been reported to stimulate behavioural activities in adolescents. The goal of this study was to determine the molecular mechanism responsible for these behavioural activities.
Experimental Approach
We performed an in vitro assay of MAO-A, the enzyme responsible for neurotransmitter degradation, using either the active form – oseltamivir carboxylate (OC) or the inactive prodrug – oseltamivir ethyl ester (OEE). We also analysed the docking of MAO-A with OEE or OC in silico. Mouse behaviours after OEE or OC administration were monitored using automated video and computer analysis.
Key Results
OEE, but not OC, competitively and selectively inhibited human MAO-A. The estimated Ki value was comparable with the Km values of native substrates of MAO-A. Docking simulations in silico based on the tertiary structure of MAO-A suggested that OEE could fit into the inner pocket of the enzyme. Behavioural monitoring using automated video analysis further revealed that OEE, not OC, significantly enhanced spontaneous behavioural activities in mice, such as jumping, rearing, sniffing, turning and walking.
Conclusions and Implications
Our multilevel analyses suggested OEE to be the cause of the side effects associated with oseltamivir and revealed the molecular mechanism underlying the stimulated behaviours induced by oseltamivir in some circumstances.
doi:10.1111/bph.12102
PMCID: PMC3632243  PMID: 23320399
oseltamivir; monoamine oxidase; stimulated behaviour; prodrug
3.  Formation of Three-Way Scanning Electron Microscope Moiré on Micro/Nanostructures 
The Scientific World Journal  2014;2014:281954.
Three-way scanning electron microscope (SEM) moiré was first generated using a designed three-way electron beam (EB) in an SEM. The spot-type three-way SEM moiré comes from the interference between the three-way EB and the specimen grating in which the periodic cells are arranged in a triangular manner. The deformation and the structure information of the specimen grating in three directions can be simultaneously obtained from the three-way SEM moiré. The design considerations of the three-way EB were discussed. As an illustration, the three-way SEM moiré spots produced on a silicon slide were presented. The proposed three-way SEM moiré method is expected to characterize micro/nanostructures in triangular or hexagonal arrangements in three directions at the same time.
doi:10.1155/2014/281954
PMCID: PMC3944902
4.  L1cam Is Crucial for Cell Locomotion and Terminal Translocation of the Soma in Radial Migration during Murine Corticogenesis 
PLoS ONE  2014;9(1):e86186.
L1cam (L1) is a cell adhesion molecule associated with a spectrum of human neurological diseases, the most well-known being X-linked hydrocephalus. Although we recently demonstrated that L1 plays an important role in neuronal migration during cortical histogenesis, the mechanisms of delayed migration have still not been clarified. In this study, we found that cell locomotion in the intermediate zone and terminal translocation in the primitive cortical zone (PCZ) were affected by L1-knockdown (L1-KD). Time-lapse analyses revealed that L1-KD neurons produced by in utero electroporation of shRNA targeting L1 (L1-shRNAs) molecules showed decreased locomotion velocity in the intermediate zone, compared with control neurons. Furthermore, L1-KD neurons showed longer and more undulated leading processes during translocation through the primitive cortical zone. The curvature index, a quantitative index for curvilinearity, as well as the length of the leading process, were increased, whereas the somal movement was decreased in L1-KD neurons during terminal translocation in the PCZ. These results suggest that L1 has a role in radial migration of cortical neurons.
doi:10.1371/journal.pone.0086186
PMCID: PMC3904877  PMID: 24489698
5.  THE 3rd SCHIZOPHRENIA INTERNATIONAL RESEARCH SOCIETY CONFERENCE, 14-18 APRIL 2012, FLORENCE, ITALY: SUMMARIES OF ORAL SESSIONS 
Schizophrenia research  2012;141(1):10.1016/j.schres.2012.07.024.
The 3rd Schizophrenia International Research Society Conference was held in Florence, Italy, April 14-18, 2012.and this year had as its emphasis, “The Globalization of Research”. Student travel awardees served as rapporteurs for each oral session and focused their summaries on the most significant findings that emerged and the discussions that followed. The following report is a composite of these summaries. We hope that it will provide an overview for those who were present, but could not participate in all sessions, and those who did not have the opportunity to attend, but who would be interested in an update on current investigations ongoing in the field of schizophrenia research.
doi:10.1016/j.schres.2012.07.024
PMCID: PMC3877922  PMID: 22910407
schizophrenia; genetics; gene-environment interaction; brain imaging; treatment; conference
6.  Dedifferentiated fat cells differentiate into osteoblasts in titanium fiber mesh 
Cytotechnology  2012;65(1):15-22.
Mature adipocyte-derived dedifferentiated fat (DFAT) cells rapidly differentiate into osteoblasts under three-dimensional culture conditions. However, it has not been demonstrated that DFAT cells can differentiate into osteoblasts in a rigid scaffold consisting of titanium fiber mesh (TFM). We examined the proliferation and osteogenic differentiation ability of DFAT cells using TFM as a scaffold. DFAT cells derived from rabbit subcutaneous fat were seeded into TFM and cultured in osteogenic medium containing dexamethasone, l-ascorbic acid 2-phosphate and β-glycerophosphate for 14 days. In scanning electron microscopy (SEM) analysis, well-spread cells covered the titanium fibers on day 3, and appeared to increase in number from day 3 to 7. Numerous globular accretions were found and almost completely covered the fibers on day 14. Cell proliferation, as measured by DNA content in the TFM, was significantly higher on day 7 compared with that of day 1. Osteocalcin and calcium content in the TFM were significantly higher on day 14 compared to those of days 1, 3, and 7, indicating DFAT cells differentiated into osteoblasts. We theorize that globular accretions observed in SEM analysis may be calcified matrix resulting from osteocalcin secreted by osteoblasts binding calcium contained in fetal bovine serum. In this study, we demonstrated that DFAT cells differentiate into osteoblasts and deposit mineralized matrices in TFM. Therefore, the combination of DFAT cells and TFM may be an attractive option for bone tissue engineering.
doi:10.1007/s10616-012-9456-z
PMCID: PMC3536869  PMID: 22526493
Dedifferentiated fat cells; Ceiling culture; Titanium fiber mesh; Bone tissue engineering
7.  TGF-β3 modulates the inflammatory environment and reduces scar formation following vocal fold mucosal injury in rats 
Disease Models & Mechanisms  2013;7(1):83-91.
Transforming growth factor (TGF)-β1 and TGF-β3 have been reported to exert differential effects on wound healing, and possibly even account for tissue-specific differences in scar formation. Scarring is particularly detrimental in the vocal fold mucosa (VFM), where destruction of the native extracellular matrix causes irreparable biomechanical changes and voice impairment. Here, in a series of in vitro and in vivo experiments, we identified differences in TGF-β1 and TGF-β3 transcription and immunolocalization to various cell subpopulations in naïve and injured rat VFM, compared with oral mucosa (which undergoes rapid healing with minimal scar) and skin (which typically heals with scar). Treatment of cultured human vocal fold fibroblasts with TGF-β3 resulted in less potent induction of profibrotic gene transcription, extracellular matrix synthesis and fibroblast-myofibroblast differentiation, compared with treatment with TGF-β1 and TGF-β2. Finally, delivery of exogenous TGF-β3 to rat VFM during the acute injury phase modulated the early inflammatory environment and reduced eventual scar formation. These experiments show that the TGF-β isoforms have distinct roles in VFM maintenance and repair, and that TGF-β3 redirects wound healing to improve VFM scar outcomes in vivo.
doi:10.1242/dmm.013326
PMCID: PMC3882051  PMID: 24092879
Fibrosis; Larynx; Tissue repair; Wound healing
8.  Group involvement and self-rated health among the Japanese elderly: an examination of bonding and bridging social capital 
BMC Public Health  2013;13:1189.
Background
To date, only a small amount of research on bonding/bridging social capital has separately examined their effects on health though they have been thought to have differential effects on health outcomes. By using a large population-based sample of elderly Japanese people, we sought to investigate the association between bonding and bridging social capital and self-rated health for men and women separately.
Methods
In August 2010, questionnaires were sent to all residents aged ≥65 years in three municipalities in Okayama prefecture (n = 21232), and 13929 questionnaires were returned (response rate: 65.6%). Social capital was measured from survey responses to questions on participation in six different types of groups: a) the elderly club or sports/hobby/culture circle; b) alumni association; c) political campaign club; d) citizen’s group or environmental preservation activity; e) community association; and f) religious organization. Participant perception of group homogeneity (gender, age, and previous occupation) was used to divide social capital into bonding or bridging. Odds ratios (ORs) and 95% confidence intervals (CIs) for poor self-rated health were calculated.
Results
A total of 11146 subjects (4441 men and 6705 women) were available for the analysis. Among men, bonding and bridging social capital were inversely associated with poor self-rated health (high bonding social capital; OR: 0.55, 95% CI: 0.31–0.99; high bridging social capital; OR: 0.62, 95% CI: 0.48–0.81) after adjusting for age, educational attainment, smoking status, frequency of alcohol consumption, overweight, living arrangements, and type-D personality. The beneficial effect among women was more likely limited to bonding social capital (high bonding social capital; OR: 0.34, 95% CI: 0.12–1.00), and the association between bridging social capital and self-rated health was less clear (high bridging social capital; OR: 0.69, 95% CI: 0.44–1.07).
Conclusions
Bonding/bridging social capital could have differential associations with self-rated health among the Japanese elderly depending on the individual’s sex. Considering the lack of consensus on how to measure bonding and bridging social capital, however, we need to carefully assess the generalizability of our findings. Further research is warranted to identify health-relevant dimensions of social capital in different cultural or economic settings.
doi:10.1186/1471-2458-13-1189
PMCID: PMC3878629  PMID: 24341568
Social capital; Bonding; Bridging; Self-rated health; Elderly
9.  Katanin p60 Contributes to Microtubule Instability around the Midbody and Facilitates Cytokinesis in Rat Cells 
PLoS ONE  2013;8(11):e80392.
The completion of cytokinesis is crucial for mitotic cell division. Cleavage furrow ingression is followed by the breaking and resealing of the intercellular bridge, but the detailed mechanism underlying this phenomenon remains unknown. Katanin is a microtubule-severing protein comprised of an AAA ATPase subunit and an accessory subunit designated as p60 and p80, respectively. Localization of katanin p60 was observed at the midzone to midbody from anaphase to cytokinesis in rat cells, and showed a ring-shaped distribution in the gap between the inside of the contractile ring and the central spindle bundle in telophase. Katanin p60 did not bind with p80 at the midzone or midbody, and localization was shown to be dependent on microtubules. At the central spindle and the midbody, no microtubule growth plus termini were seen with katanin p60, and microtubule density was inversely correlated with katanin p60 density in the region of katanin p60 localization that seemed to lead to microtubule destabilization at the midbody. Inhibition of katanin p60 resulted in incomplete cytokinesis by regression and thus caused the appearance of binucleate cells. These results suggest that katanin p60 contributes to microtubule instability at the midzone and midbody and facilitates cytokinesis in rat cells.
doi:10.1371/journal.pone.0080392
PMCID: PMC3841192  PMID: 24303010
10.  A Community-Based, Case-Control Study Evaluating Mortality Reduction from Gastric Cancer by Endoscopic Screening in Japan 
PLoS ONE  2013;8(11):e79088.
Aims
Although the incidence of gastric cancer has decreased in the last 3 decades, it remains the second leading cause of cancer death worldwide. In Asian countries, the burden of gastric cancer has remained, and cancer screening is normally expected to reduce gastric cancer death. We conducted a community-based, case-control study to evaluate the reduction of mortality from gastric cancer by endoscopic screening.
Methods
Case subjects were defined as individuals who had died of gastric cancer between 2003 and 2006 in 4 cities in Tottori Prefecture, and between 2006 and 2010 in Niigata City, Japan. Up to 6 control subjects were matched by sex, birth year (±3 years), and the residence of each corresponding case subject from the population lists in the study areas. Control subjects were required to be disease-free at the time when the corresponding case subjects were diagnosed as having gastric cancer. The odds ratios (ORs) were calculated for those who had participated in endoscopic or radiographic screening before the reference date when the case subjects were diagnosed as having gastric cancer, compared with subjects who had never participated in any screening. Conditional logistic-regression models for matched sets were used to estimate the ORs and 95% confidence intervals (CIs).
Results
The case subjects consisted of 288 men and 122 women for case subjects, with 2,292 matched control subjects. Compared with those who had never been screened before the date of diagnosis of gastric cancer in the case subjects, the ORs within 36 months from the date of diagnosis were 0.695 (95% CI: 0.489–0.986) for endoscopic screening and 0.865 (95% CI : 0.631–1.185) for radiographic screening.
Conclusions
The results suggest a 30% reduction in gastric cancer mortality by endoscopic screening compared with no screening within 36 months before the date of diagnosis of gastric cancer.
doi:10.1371/journal.pone.0079088
PMCID: PMC3827316  PMID: 24236091
11.  Development of a Clinically-Precise Mouse Model of Rectal Cancer 
PLoS ONE  2013;8(11):e79453.
Currently-used rodent tumor models, including transgenic tumor models, or subcutaneously growing tumors in mice, do not sufficiently represent clinical cancer. We report here development of methods to obtain a highly clinically-accurate rectal cancer model. This model was established by intrarectal transplantation of mouse rectal cancer cells, stably expressing green fluorescent protein (GFP), followed by disrupting the epithelial cell layer of the rectal mucosa by instilling an acetic acid solution. Early-stage tumor was detected in the rectal mucosa by 6 days after transplantation. The tumor then became invasive into the submucosal tissue. The tumor incidence was 100% and mean volume (±SD) was 1232.4 ± 994.7 mm3 at 4 weeks after transplantation detected by fluorescence imaging. Spontaneous lymph node metastasis and lung metastasis were also found approximately 4 weeks after transplantation in over 90% of mice. This rectal tumor model precisely mimics the natural history of rectal cancer and can be used to study early tumor development, metastasis, and discovery and evaluation of novel therapeutics for this treatment-resistant disease.
doi:10.1371/journal.pone.0079453
PMCID: PMC3827128  PMID: 24265772
12.  Lithium Chloride Enhances Cathepsin H Expression and BMP-4 Degradation in C3H10T1/2 Cells 
BioMed Research International  2013;2013:143742.
The effect of canonical Wnt/β-catenin signaling on chondrogenic differentiation induced by transfection of BMP4 expressing plasmid was analyzed. Lithium chloride (LiCl) which mimics canonical Wnt/β-catenin signaling was added to cells transfected with BMP4 expressing plasmid. Although BMP4 mRNA expression was not affected by LiCl, LiCl decreased BMP4 protein accumulation. Gene expression analysis exhibited upregulation of cathepsin H by LiCl treatment. Gene silencing of cathepsin H enhanced BMP4 protein accumulation from BMP4 expressing cells. These results suggested that cathepsin H is regulated by Wnt/β-catenin signaling and plays an important role in the regulation of BMP4 biological activity.
doi:10.1155/2013/143742
PMCID: PMC3842059  PMID: 24312905
13.  Primary Neuroendocrine Carcinoma of Ocular Adnexa 
We present our findings in a case of primary neuroendocrine carcinoma (NEC) of the lacrimal gland and a case of primary Merkel cell carcinoma (MCC) of the eyelid. An 86-year-old man noticed a swelling of the left upper eyelid three months earlier. We performed excision biopsy and histopathological examination indicated that he had a primary NEC of the left lacrimal gland. He underwent chemotherapy followed by excision including the clinically visible margins and 50 Gy radiotherapy of the surgical margins. He had neither recurrence nor metastasis for 6 months since the last radiotherapy. An 80-year-old man noticed a nodule in the right upper eyelid and was referred to our hospital because the size was increasing rapidly. A complete surgical excision of the margins of the tumor was performed with histopathological confirmation of negative margins. The final diagnosis was a primary MCC of the right upper eyelid. After surgery, he underwent 50 Gy radiotherapy on the neck to prevent metastasis. No recurrence or metastasis was found for two years. Although primary NEC of the ocular adnexa is extremely rare, the tumor has high malignancy and readily metastasizes. Thus, combined therapy including surgery, radiotherapy, and/or chemotherapy is needed for complete management of NEC.
doi:10.1155/2013/281351
PMCID: PMC3835809  PMID: 24294530
14.  MAJOR LIVER RESECTION STIMULATES STROMAL RECRUITMENT AND METASTASIS COMPARED TO REPEATED MINOR RESECTION 
The Journal of surgical research  2012;178(1):280-287.
Background
This study examines the effects of types of liver resection on the growth of liver and lung metastasis.
Materials and Methods
Experimental liver metastases were established by spleen injection of the Colon 26 murine adenocarcinoma cell line expressing GFP into transgenic nude mice expressing RFP. Experimental lung metastases were established by tail vein injection with Colon 26-GFP. Three days after cell injection, groups of mice underwent liver resection (35%+35% [repeated minor resection] vs. 70% [major resection]). Metastatic tumor growth was measured by color-coded fluorescence imaging of the GFP-expressing cancer cells and RFP-expressing stroma.
Results
Although major and repeated minor resection removed the same volume of liver parenchyma, the two procedures had very different effects on metastatic tumor growth: major resection, stimulated liver and lung metastatic growth as well as recruitment of host-derived stroma compared to repeated minor resection. Repeated minor resection did not stimulate metastasis or stromal recruitment. There was no significant difference in liver regeneration between the two groups. Host-derived stroma density, which is stimulated by major resection compared to repeated minor resection, may stimulate growth in the liver-metastatic tumor. TGF-β is also preferentially stimulated by major resection and may play a role in stroma and metastasis stimulation.
Conclusions
The results of this study indicate that when liver resection is necessary, repeated minor liver resection is superior to major liver resection, since major resection, in contrast to repeated minor resection, stimulates metastasis, which should be taken into consideration in clinical situations indicating liver resection.
doi:10.1016/j.jss.2012.03.020
PMCID: PMC3396724  PMID: 22487397
Nude mice; liver resection; lung metastasis; liver metastasis; stroma; green fluorescent protein; red fluorescent protein; color-coded imaging
15.  Attenuation of Limb Loss in an Experimentally Induced Hindlimb Ischemic Model by Fibroblast Growth Factor-2/Fragmin/Protamine Microparticles as a Delivery System 
Tissue Engineering. Part A  2012;18(21-22):2239-2247.
Fibroblast growth factor-2 (FGF-2) is a well-characterized protein that is used in the treatment of healing-impaired wounds. We previously reported that fragmin/protamine microparticles (F/P MPs) are useful as biodegradable carriers for the controlled release of cytokines. We examined the ability of FGF-2-containing (FGF-2/) F/P MPs to prevent limb loss in an experimentally induced ischemic hindlimb model using adult Balb/c-nu/nu male mice. One day after inducing ischemia, intramuscular injections of 100 μL of FGF-2/F/P MPs turbid suspension (10 μg/mL FGF-2 and 6 mg/mL F/P MPs) were administered into eight sites of the ischemic hindlimb. A 100-μL suspension of each of the following—10 μg/mL FGF-2, 6 mg/mL F/P MPs, and phosphate-buffered saline (PBS; the control)—was similarly injected into the hindlimb. From 5 days onward after the injections, recovery from ischemia was observed in the FGF-2/F/P MP-treated group, but only partial recovery occurred in the FGF-2-treated group. The F/P MP-treated and PBS-treated groups (i.e., control) exhibited no recovery from the ischemia. The histological evaluations of the hindlimbs also confirmed that the capillary (i.e., mature vessels) density was significantly higher in the FGF-2/F/P MP-treated group than in the other groups. The mice injected with FGF-2/F/P MPs also recovered hindlimb blood flow, as reflected by oxygen saturation and surface temperature evaluation. Our present approach using FGF-2/F/P MPs could be considered a valuable option for the therapeutic treatment of peripheral ischemic diseases.
doi:10.1089/ten.tea.2011.0741
PMCID: PMC3482845  PMID: 22655590
16.  Outbreak of Adverse Reactions Associated with Contaminated Heparin 
The New England journal of medicine  2008;359(25):10.1056/NEJMoa0806450.
BACKGROUND
In January 2008, the Centers for Disease Control and Prevention began a nationwide investigation of severe adverse reactions that were first detected in a single hemodialysis facility. Preliminary findings suggested that heparin was a possible cause of the reactions.
METHODS
Information on clinical manifestations and on exposure was collected for patients who had signs and symptoms that were consistent with an allergic-type reaction after November 1, 2007. Twenty-one dialysis facilities that reported reactions and 23 facilities that reported no reactions were included in a case–control study to identify facility-level risk factors. Unopened heparin vials from facilities that reported reactions were tested for contaminants.
RESULTS
A total of 152 adverse reactions associated with heparin were identified in 113 patients from 13 states from November 19, 2007, through January 31, 2008. The use of heparin manufactured by Baxter Healthcare was the factor most strongly associated with reactions (present in 100.0% of case facilities vs. 4.3% of control facilities, P<0.001). Vials of heparin manufactured by Baxter from facilities that reported reactions contained a contaminant identified as oversulfated chondroitin sulfate (OSCS). Adverse reactions to the OSCS-contaminated heparin were often characterized by hypotension, nausea, and shortness of breath occurring within 30 minutes after administration. Of 130 reactions for which information on the heparin lot was available, 128 (98.5%) occurred in a facility that had OSCS-contaminated heparin on the premises. Of 54 reactions for which the lot number of administered heparin was known, 52 (96.3%) occurred after the administration of OSCS-contaminated heparin.
CONCLUSIONS
Heparin contaminated with OSCS was epidemiologically linked to adverse reactions in this nationwide outbreak. The reported clinical features of many of the cases further support the conclusion that contamination of heparin with OSCS was the cause of the outbreak.
doi:10.1056/NEJMoa0806450
PMCID: PMC3810025  PMID: 19052120
17.  A nonclassical vitamin D receptor pathway suppresses renal fibrosis 
The Journal of Clinical Investigation  2013;123(11):4579-4594.
The TGF-β superfamily comprises pleiotropic cytokines that regulate SMAD and non-SMAD signaling. TGF-β–SMAD signal transduction is known to be involved in tissue fibrosis, including renal fibrosis. Here, we found that 1,25-dihydroxyvitamin D3–bound [1,25(OH)2D3-bound] vitamin D receptor (VDR) specifically inhibits TGF-β–SMAD signal transduction through direct interaction with SMAD3. In mouse models of tissue fibrosis, 1,25(OH)2D3 treatment prevented renal fibrosis through the suppression of TGF-β–SMAD signal transduction. Based on the structure of the VDR-ligand complex, we generated 2 synthetic ligands. These ligands selectively inhibited TGF-β–SMAD signal transduction without activating VDR-mediated transcription and significantly attenuated renal fibrosis in mice. These results indicate that 1,25(OH)2D3-dependent suppression of TGF-β–SMAD signal transduction is independent of VDR-mediated transcriptional activity. In addition, these ligands did not cause hypercalcemia resulting from stimulation of the transcriptional activity of the VDR. Thus, our study provides a new strategy for generating chemical compounds that specifically inhibit TGF-β–SMAD signal transduction. Since TGF-β–SMAD signal transduction is reportedly involved in several disorders, our results will aid in the development of new drugs that do not cause detectable adverse effects, such as hypercalcemia.
doi:10.1172/JCI67804
PMCID: PMC3809783  PMID: 24135137
18.  An open-label study of algorithm-based treatment versus treatment-as-usual for patients with schizophrenia 
Objective
The use of an algorithm may facilitate measurement-based treatment and result in more rational therapy. We conducted a 1-year, open-label study to compare various outcomes of algorithm-based treatment (ALGO) for schizophrenia versus treatment-as-usual (TAU), for which evidence has been very scarce.
Methods
In ALGO, patients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, fourth edition) were treated with an algorithm consisting of a series of antipsychotic monotherapies that was guided by the total scores in the positive and negative syndrome scale (PANSS). When posttreatment PANSS total scores were above 70% of those at baseline in the first and second stages, or above 80% in the 3rd stage, patients proceeded to the next treatment stage with different antipsychotics. In contrast, TAU represented the best clinical judgment by treating psychiatrists.
Results
Forty-two patients (21 females, 39.0 ± 10.9 years-old) participated in this study. The baseline PANSS total score indicated the presence of severe psychopathology and was significantly higher in the ALGO group (n = 25; 106.9 ± 20.0) than in the TAU group (n = 17; 92.2 ± 18.3) (P = 0.021). As a result of treatment, there were no significant differences in the PANSS reduction rates, premature attrition rates, as well as in a variety of other clinical measures between the groups. Despite an effort to make each group unique in pharmacologic treatment, it was found that pharmacotherapy in the TAU group eventually became similar in quality to that of the ALGO group.
Conclusion
While the results need to be carefully interpreted in light of a hard-to-distinguish treatment manner between the two groups and more studies are necessary, algorithm-based antipsychotic treatments for schizophrenia compared well to treatment-as-usual in this study.
doi:10.2147/NDT.S46108
PMCID: PMC3798204  PMID: 24143104
algorithm; open-label clinical trial; measurement-based treatment; schizophrenia; treatment-as-usual
19.  Contaminated Heparin Associated with Adverse Clinical Events and Activation of the Contact System 
The New England journal of medicine  2008;358(23):2457-2467.
Background
There is an urgent need to determine whether oversulfated chondroitin sulfate (OSCS), a compound contaminating heparin supplies worldwide, is the cause of the severe anaphylactoid reactions that have occurred after intravenous heparin administration in the United States and Germany.
Methods
Heparin procured from the Food and Drug Administration, consisting of suspect lots of heparin associated with the clinical events as well as control lots of heparin, were screened in a blinded fashion both for the presence of OSCS and for any biologic activity that could potentially link the contaminant to the observed clinical adverse events. In vitro assays for the activation of the contact system and the complement cascade were performed. In addition, the ability of OSCS to recapitulate key clinical manifestations in vivo was tested in swine.
Results
The OSCS found in contaminated lots of unfractionated heparin, as well as a synthetically generated OSCS reference standard, directly activated the kinin–kallikrein pathway in human plasma, which can lead to the generation of bradykinin, a potent vasoactive mediator. In addition, OSCS induced generation of C3a and C5a, potent anaphylatoxins derived from complement proteins. Activation of these two pathways was unexpectedly linked and dependent on fluid-phase activation of factor XII. Screening of plasma samples from various species indicated that swine and humans are sensitive to the effects of OSCS in a similar manner. OSCS-containing heparin and synthetically derived OSCS induced hypotension associated with kallikrein activation when administered by intravenous infusion in swine.
Conclusions
Our results provide a scientific rationale for a potential biologic link between the presence of OSCS in suspect lots of heparin and the observed clinical adverse events. An assay to assess the amidolytic activity of kallikrein can supplement analytic tests to protect the heparin supply chain by screening for OSCS and other highly sulfated polysaccharide contaminants of heparin that can activate the contact system.
doi:10.1056/NEJMoa0803200
PMCID: PMC3778681  PMID: 18434646
20.  Wide Host Ranges of Herbivorous Beetles? Insights from DNA Bar Coding 
PLoS ONE  2013;8(9):e74426.
There are very few studies that have investigated host-specificity among tropical herbivorous insects. Indeed, most of the trophic interactions of herbivorous insects in Southeast Asian tropical rainforests remain unknown, and whether polyphagous feeding is common in the herbivores of this ecosystem has not been determined. The present study employed DNA bar coding to reveal the trophic associations of adult leaf-chewing chrysomelid beetles in a Bornean rainforest. Plant material ingested by the adults was retrieved from the bodies of the insects, and a portion of the chloroplast rbcL sequence was then amplified from this material. The plants were identified at the family level using an existing reference database of chloroplast DNA. Our DNA-based diet analysis of eleven chrysomelid species successfully identified their host plant families and indicated that five beetle species fed on more than two families within the angiosperms, and four species fed on several families of gymnosperms and/or ferns together with multiple angiosperm families. These findings suggest that generalist chrysomelid beetles associated with ecologically and taxonomically distant plants constitute a part of the plant-insect network of the Bornean rainforest.
doi:10.1371/journal.pone.0074426
PMCID: PMC3779210  PMID: 24073210
21.  Complete Genomic DNA Sequence of the East Asian Spotted Fever Disease Agent Rickettsia japonica 
PLoS ONE  2013;8(9):e71861.
Rickettsia japonica is an obligate intracellular alphaproteobacteria that causes tick-borne Japanese spotted fever, which has spread throughout East Asia. We determined the complete genomic DNA sequence of R. japonica type strain YH (VR-1363), which consists of 1,283,087 base pairs (bp) and 971 protein-coding genes. Comparison of the genomic DNA sequence of R. japonica with other rickettsiae in the public databases showed that 2 regions (4,323 and 216 bp) were conserved in a very narrow range of Rickettsia species, and the shorter one was inserted in, and disrupted, a preexisting open reading frame (ORF). While it is unknown how the DNA sequences were acquired in R. japonica genomes, it may be a useful signature for the diagnosis of Rickettsia species. Instead of the species-specific inserted DNA sequences, rickettsial genomes contain Rickettsia-specific palindromic elements (RPEs), which are also capable of locating in preexisting ORFs. Precise alignments of protein and DNA sequences involving RPEs showed that when a gene contains an inserted DNA sequence, each rickettsial ortholog carried an inserted DNA sequence at the same locus. The sequence, ATGAC, was shown to be highly frequent and thus characteristic in certain RPEs (RPE-4, RPE-6, and RPE-7). This finding implies that RPE-4, RPE-6, and RPE-7 were derived from a common inserted DNA sequence.
doi:10.1371/journal.pone.0071861
PMCID: PMC3767692  PMID: 24039725
22.  Fucoidan enhances intestinal barrier function by upregulating the expression of claudin-1 
AIM: To evaluate the protective effects of fucoidan on oxidative stress-induced barrier disruption in human intestinal epithelial cells.
METHODS: In Caco-2 cell monolayer models, the disruption of barrier function by oxidative stress is mediated by H2O2. The integrity of polarized Caco-2 cell monolayers was determined by measuring the transepithelial resistance (TER) and permeability was estimated by measuring the paracellular transport of FITC-labeled 4-kDa dextran (FD4). The protective effects of fucoidan on epithelial barrier functions on polarized Caco-2 cell monolayers were evaluated by TER and FD4 flux. The expression of tight junction (TJ) proteins was assessed using reverse-transcription polymerase chain reaction (RT-PCR) and immunofluorescence staining.
RESULTS: Without H2O2 treatment, fucoidan significantly increased the TER compared to control (P < 0.05), indicating a direct enhancement of intestinal epithelial barrier function. Next, H2O2 disrupted the epithelial barrier function in a time-dependent manner. Fucoidan prevented the H2O2-induced destruction in a dose-dependent manner. Fucoidan significantly decreased H2O2-induced FD4 flux (P < 0.01), indicating the prevention of disruption in paracellular permeability. RT-PCR showed that Caco-2 cells endogenously expressed claudin-1 and -2, and occludin and that H2O2 reduced the mRNA expression of these TJ proteins. Treatment with fucoidan attenuated the reduction in the expressions of claudin-1 and claudin-2 but not occludin. Immunofluorescence staining revealed that the expression of claudin-1 was intact and high on the cell surface. H2O2 disrupted the integrity of claudin-1. Treatment with fucoidan dramatically attenuated the expression of claudin-1.
CONCLUSION: Fucoidan enhanced intestinal epithelial barrier function by upregulating the expression of claudin-1. Thus, fucoidan may be an appropriate therapy for the treatment of inflammatory bowel diseases.
doi:10.3748/wjg.v19.i33.5500
PMCID: PMC3761103  PMID: 24023493
Fucoidan; Tight junction; Intestinal epithelial cells; Oxidative stress; Inflammatory bowel diseases
25.  The 2nd edition of consensus statements for the diagnosis and management of intestinal Behçet’s disease: indication of anti-TNFα monoclonal antibodies 
Journal of Gastroenterology  2013;49:156-162.
Background
Clinical evidence regarding intestinal Behçet’s disease (BD) management is lacking and intestinal lesions are a poor prognostic factor. In 2007, the Japan consensus statement for diagnosis and management of intestinal BD was developed. Recently, the efficacy of anti-tumor necrosis factor (TNF)α monoclonal antibodies (mAbs), and infliximab (IFX) was reported and adalimumab (ADA) was approved for intestinal BD in Japan. This study renewed consensus-based practice guidelines for diagnosis and treatment of intestinal BD focusing on the indication of anti-TNFα mAbs.
Methods
An expert panel of Japanese gastroenterology and rheumatology specialists was involved. Clinical statements for ratings were extracted from the literature, a professional group survey, and by an expert panel discussion, which rated clinical statements on a nine-point scale. After the first round of ratings, a panelist meeting discussed areas of disagreement and clarified areas of uncertainty. The list of clinical statements was revised after the panelist meeting and a second round of ratings was conducted.
Results
Fifteen relevant articles were selected. Based on the first edition consensus statement, improved clinical statements regarding indications for anti-TNFα mAbs use were developed. After a two-round modified Delphi approach, the second edition of consensus statements was finalized.
Conclusions
In addition to standard therapies in the first edition, anti-TNFα mAbs (ADA and IFX) should be considered as a standard therapy for intestinal BD. Colchicines, thalidomide, other pharmacological therapy, endoscopic therapy, and leukocytapheresis were deemed experimental therapies.
doi:10.1007/s00535-013-0872-4
PMCID: PMC3895195  PMID: 23955155
Intestinal Behçet’s disease; Anti-TNFα mAb; Consensus statements

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