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1.  Brain structural changes and neuropsychological impairments in male polydipsic schizophrenia 
BMC Psychiatry  2012;12:210.
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.
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).
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.
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.
PMCID: PMC3532364  PMID: 23181904
Schizophrenia; Polydipsia; Volumetry; MRI; Neuropsychological impairment; Brief assessment of cognition in schizophrenia
2.  Long-Acting Injectable vs Oral Antipsychotics for Relapse Prevention in Schizophrenia: A Meta-Analysis of Randomized Trials 
Schizophrenia Bulletin  2012;40(1):192-213.
Background: While long-acting injectable antipsychotics (LAIs) are hoped to reduce high relapse rates in schizophrenia, recent randomized controlled trials (RCTs) challenged the benefits of LAIs over oral antipsychotics (OAPs). Methods: Systematic review/meta-analysis of RCTs that lasted ≥6 months comparing LAIs and OAPs. Primary outcome was study-defined relapse at the longest time point; secondary outcomes included relapse at 3, 6, 12, 18, and 24 months, all-cause discontinuation, discontinuation due to adverse events, drug inefficacy (ie, relapse + discontinuation due to inefficacy), hospitalization, and nonadherence. Results: Across 21 RCTs (n = 5176), LAIs were similar to OAPs for relapse prevention at the longest time point (studies = 21, n = 4950, relative risk [RR] = 0.93, 95% confidence interval [CI]: 0.80–1.08, P = .35). The finding was confirmed restricting the analysis to outpatient studies lasting ≥1 year (studies = 12, RR = 0.93, 95% CI:0.71–1.07, P = .31). However, studies using first-generation antipsychotic (FGA)-LAIs (studies = 10, RR = 0.82, 95% CI:0.69–0.97, P = .02) and those published ≤1991 (consisting exclusively of all 8 fluphenazine-LAI studies; RR = 0.79, 95% CI: 0.65–0.96, P = 0.02) were superior to OAPs regarding the primary outcome. Pooled LAIs also did not separate from OAPs regarding any secondary outcomes. Again, studies using FGA-LAIs and those published ≤1991 were associated with LAI superiority over OAPs, eg, hospitalization and drug inefficacy. Conclusions: In RCTs, which are less representative of real-world patients than naturalistic studies, pooled LAIs did not reduce relapse compared with OAPs in schizophrenia patients. The exceptions were FGA-LAIs, mostly consisting of fluphenazine-LAI studies, which were all conducted through 1991. Because this finding is vulnerable to a cohort bias, studies comparing FGA-LAI vs second-generation antipsychotics-LAI and LAI vs OAP RCTs in real-world patients are needed.
PMCID: PMC3885289  PMID: 23256986
antipsychotics; adherence; depot; long-acting injection; meta-analysis; relapse; schizophrenia; treatment discontinuation
3.  In vitro evaluation of immunological properties of extracellular polysaccharides produced by Lactobacillus delbrueckii strains 
We investigated the variation in immunological properties of the extracellular polysaccharides (EPSs) produced by different Lactobacillus delbrueckii strains as well as that of their monosaccharide composition. The monosaccharide composition of each EPS produced by L. delbrueckii strains, as determined by thin layer chromatography (TLC), showed an appreciable variation in a strain-dependent manner, which could be broadly assigned to 4 TLC groups. Meanwhile, the immunological properties of the EPSs produced by 10 L. delbrueckii strains were evaluated in a semi-intestinal model using a Transwell co-culture system, which employed human intestinal epithelial Caco-2 cells on the apical side and murine macrophage RAW264.7 cells on the basolateral side. Each EPS was added to the apical side to allow direct contact with Caco-2 cells and incubated for 6 hr. After incubation, the amounts of TNF-α and several cytokines that had been released by either RAW264.7 or Caco-2 cells were then quantified by cytotoxic activity on L929 cells or the RT-PCR method. It was found that the EPS-stimulated RAW264.7 cells express different profiles of cytokine production via Caco-2 cells but that the profile difference could not be related to the above TLC grouping. The evidence suggests that the EPSs of L. delbrueckii strains are diverse not only in their biochemical structure but also in their immunological properties.
PMCID: PMC4300312  PMID: 25625033
extracellular polysaccharide; Lactobacillus delbrueckii; immunological properties; Transwell
4.  Clinical Significance of Soluble CD26 in Malignant Pleural Mesothelioma 
PLoS ONE  2014;9(12):e115647.
There is no established single diagnostic marker for malignant pleural mesothelioma (MPM). CD26 is a 110 kDa, multifunctional, membrane-bound glycoprotein that has dipeptidyl peptidase IV (DPPIV) enzyme activity. The aim of this study was to evaluate the clinical significance of soluble CD26 (sCD26) in patients with MPM. The study included 80 MPM patients, 79 subjects with past asbestos exposure (SPE), and 134 patients with other benign pleural diseases (OPD) that were included as a control group. sCD26 levels and DPPIV activity in serum and/or pleural fluid were determined using an ELISA kit. Serum sCD26 levels and DPPIV enzyme activity in patients with MPM were significantly decreased compared with those in the SPE group (P = 0.000). The level of serum sCD26 was significantly decreased in patients with advanced stages of MPM compared with those with earlier stages (P = 0.047). The median OS of patients with MPM who had higher DPPIV enzyme activity was significantly longer than that of those with lower DPPIV enzyme activity (P = 0.032). The sCD26 levels in the pleural fluid of MPM patients with an epithelioid subtype were significantly increased compared with the OPD cohort (P = 0.012). Moreover, DPPIV enzyme activity in the pleural fluid of patients with MPM with an epithelioid subtype were significantly increased compared with those in the OPD cohort (P = 0.009). Patients with MPM who had lower specific DPPIV activity, determined as DPPIV/sCD26, showed significantly prolonged survival compared with those with higher specific DPPIV activity (P = 0.028). Serum sCD26 and DPPIV enzyme activity appear to be useful biomarkers for differentiating patients with MPM from SPE. The sCD26 levels or DPPIV enzyme activity in pleural fluid appear to be biomarkers in patients with an epithelioid subtype of MPM. DPPIV activity in serum or pleural fluid appears to be predictive for the prognosis of patients with MPM.
PMCID: PMC4272261  PMID: 25526639
5.  Identifying associations between sedentary time and cardio-metabolic risk factors in working adults using objective and subjective measures: a cross-sectional analysis 
BMC Public Health  2014;14(1):1307.
Sedentary behavior has been reported to be associated with metabolic and vascular health independent of moderate-to-vigorous physical activity (MVPA). In order to select appropriate options to measure sedentary behavior in practice and research settings, it is worthwhile to characterize the extent to which objective and subjective measures of sedentary behavior quantify adverse health risks in the same population. This cross-sectional analysis compared accelerometer-derived and self-reported sedentary time to identify their association with cardio-metabolic risk factors.
Cross-sectional analysis was conducted using data from 661 Japanese workers (145 women) aged 20–64 years. Participants wore a tri-axial accelerometer device for 10 consecutive days and completed the Japan Atherosclerosis Longitudinal Study Physical Activity Questionnaire. Data on body mass index, waist circumference, resting blood pressure, triglycerides, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, total:HDL cholesterol ratio, blood glucose, and glycosylated hemoglobin (HbA1c) were obtained from annual health examinations.
Both accelerometer-derived and self-reported sedentary time were deleteriously associated with triglycerides, HDL-cholesterol, total:HDL ratio, and HbA1c after adjustment for potential confounders including MVPA. There were no significant differences in regression coefficients between the two measures. Thus, the magnitude of the associations of both measures with cardio-metabolic risk factors was similar, despite poor agreement between them. Occupational sedentary time was correlated with both measures of total sedentary time, and more consistently associated with cardio-metabolic risk factors than sedentary leisure time.
Both accelerometer and self-report measurements are similarly associated with cardio-metabolic risk factors in a Japanese working adult population. Subjective and objective measures of sedentary behaviors appear to capture different aspects of behaviors. Further efforts to establish data processing methods integrating objective and subjective measures are needed to more effectively assess sedentary time’s relationship to health outcomes.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2458-14-1307) contains supplementary material, which is available to authorized users.
PMCID: PMC4302076  PMID: 25526746
Sedentary behavior; Physical activity; Accelerometry; Self-report questionnaire; Cardiovascular risk factors; Workers
6.  Additive Effects of Miglitol and Anagliptin on Insulin-Treated Type 2 Diabetes Mellitus: A Case Study 
Clinical Drug Investigation  2014;35:141-147.
The aim of this case study was to examine the efficacy of a dipeptidyl peptidase-4 inhibitor (anagliptin) and an α-glucosidase inhibitor (miglitol) when added to ongoing insulin treatment in patients with type 2 diabetes mellitus. Continuous glucose monitoring was performed in four Japanese insulin-treated inpatients with type 2 diabetes. Baseline data were collected on day 1. Miglitol was administered on days 2 and 3. On day 4, miglitol and anagliptin were coadministered before breakfast. On days 1, 3, and 5, blood was drawn for plasma glucose, serum C-peptide, plasma glucagon, total and active glucagon-like peptide-1 (GLP-1), and total and active glucose-dependent insulinotropic peptide (GIP) measurements. Coadministration of anagliptin with miglitol resulted in additional improvements in glycemic control over the entire day in three of the four patients. The C-peptide, glucagon, and total and active GLP-1 and GIP responded differently to the medications for each patient, suggesting interindividual differences in hormonal responses, which may be complicated by multifactorial effects.
Electronic supplementary material
The online version of this article (doi:10.1007/s40261-014-0260-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4300407  PMID: 25511640
7.  Magnifying Endoscopy with Narrow Band Imaging to Determine the Extent of Resection in Transoral Robotic Surgery of Oropharyngeal Cancer 
Case Reports in Otolaryngology  2014;2014:604737.
Transoral robotic surgery (TORS) is a less invasive treatment that is becoming popular all over the world. One of the most important factors for achieving success in TORS is the ability to determine the extent of resection during the procedure as the extent of resection in the laryngopharynx not only affects oncological outcomes but also directly affects swallowing and voice functions. Magnifying endoscopy with narrow band imaging (ME-NBI) is an innovative optical technology that provides high-resolution images and is useful in detecting early superficial pharyngeal cancers, which are difficult to detect by standard endoscopy. A 55-year-old male with superficial oropharyngeal cancer has been successfully treated by combining MB-NBI with TORS and MB-NBI was useful in determining the extent of resection. ME-NBI with TORS will make it possible to achieve a higher ratio of minimally invasive treatment in pharyngeal cancer.
PMCID: PMC4276113  PMID: 25574412
8.  Crystal structure of Escherichia coli YidC, a membrane protein chaperone and insertase 
Scientific Reports  2014;4:7299.
Bacterial YidC, an evolutionally conserved membrane protein, functions as a membrane protein chaperone in cooperation with the Sec translocon and as an independent insertase for membrane proteins. In Gram-negative bacteria, the transmembrane and periplasmic regions of YidC interact with the Sec proteins, forming a multi-protein complex for Sec-dependent membrane protein integration. Here, we report the crystal structure of full-length Escherichia coli YidC. The structure reveals that a hydrophilic groove, formed by five transmembrane helices, is a conserved structural feature of YidC, as compared to the previous YidC structure from Bacillus halodurans, which lacks a periplasmic domain. Structural mapping of the substrate- or Sec protein-contact sites suggested the importance of the groove for the YidC functions as a chaperone and an insertase, and provided structural insight into the multi-protein complex.
PMCID: PMC4252904  PMID: 25466392
9.  Early Nonresponse Determined by the Clinical Global Impressions Scale Predicts Poorer Outcomes in Youth with Schizophrenia Spectrum Disorders Naturalistically Treated with Second-Generation Antipsychotics 
Objective: The use of early response/nonresponse (ER/ENR) to antipsychotics as a predictor for ultimate response/nonresponse (UR/UNR) may help decrease inefficacious treatment continuation. However, data have been limited to adults, and ER/ENR has only been determined using time-consuming psychopathology rating scales. In the current study, we assessed if early improvement on the Clinical Global Impressions-Improvement (CGI-I) scale predicted UR/UNR in psychiatrically ill youth started on antipsychotic treatment.
Methods: Seventy-nine youth aged 6–19 years, with schizophrenia spectrum disorders, treated naturalistically with aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone and evaluated monthly, were divided into ER/ENR groups at week 4, using at least “minimally improved” on the CGI-I scale. Prediction using week 4 ER/ENR status for UR (CGI-I=at least “much improved”), effectiveness and adverse effect outcomes at 8–12 weeks were assessed.
Results: At 4 weeks, 45.6% of subjects were ER and 54.4% were ENR without differences regarding baseline demographic, illness, and treatment variables, except for higher age (p=0.034) and maximum risperidone dose (p=0.0043) in ENR. ER/ENR status at 4 weeks predicted UR/UNR at week 12 significantly (p<0.0001): Sensitivity=68.9%, specificity=85.3%, positive predictive value=86.1%, negative predictive value=67.4%. At weeks 4, 8, and 12, ER patients improved significantly more on the CGI-I, CGI-Severity, and Children's Global Assessment of Functioning scales, and more ER patients reached UR compared with ENR patients (83.3% vs. 34.9%, all p<0.0001). ENR patients had more extrapyramidal side effects (EPS) at weeks 4, 8, and 12 (p=0.0019–0.0079). UR was independently associated with ER (odds ratio [OR]=18.09; 95% confidence interval [CI]=4.71–91.68, p<0.0001) and psychosis not otherwise specified (NOS) (OR=4.82 [CI: 1.31–21.41], p=0.017) (r2=0.273, p<0.0001).
Conclusions: Older age and EPS were associated with ENR; ENR and schizophrenia were associated with UNR in naturalistically treated youth with schizophrenia spectrum disorders. Early CGI-I-based treatment decisions require further consideration and study.
PMCID: PMC3870605  PMID: 24266529
10.  Establishment of a Method to Measure Length of the Ulnar Nerve and Standardize F-wave Values in Clinically Normal Beagles 
We designed a new method of measuring the length of the ulnar nerve and determining standard values for F-wave parameters of the ulnar nerve in clinically normal beagles. Nerve length must be precisely measured to determine F-wave latency and conduction velocity. The length of the forelimb has served as the length of the ulnar nerve for F-wave assessments, but report indicates that F-wave latency is proportional to the length of the pathway traveled by nerve impulses. Therefore, we measured the surface distance from a stimulus point to the spinous process of the first thoracic vertebra (nerve length 1) and the anterior horn of the scapula (nerve length 2) as landmarks through the olecranon and the shoulder blade acromion. The correlation coefficients between the shortest F-wave latency and the length of nerves 1, 2 or the forelimb were 0.61, 0.7 and 0.58. Nerve length 2 generated the highest value. Furthermore, the anterior horn of the scapula was easily palpated in any dog regardless of well-fed body. We concluded that nerve length 2 was optimal for measuring the length of the ulnar nerve.
PMCID: PMC4300375  PMID: 25649942
canine; central nerve; forelimb; latency; motor nerve
11.  Adjunctive Use of Nonsteroidal Anti-inflammatory Drugs for Schizophrenia: A Meta-analytic Investigation of Randomized Controlled Trials 
Schizophrenia Bulletin  2013;39(6):1230-1241.
Objective: To meta-analytically assess the efficacy and tolerability of nonsteroidal anti-inflammatory drugs (NSAIDs) vs placebo in schizophrenia. Method: Searching PubMed, PsycINFO, ISI Web of Science, and the US National Institute of Mental Health clinical trials registry from database inception to December 31, 2012, we conducted a systematic review/meta-analysis of randomized placebo-controlled studies assessing the efficacy of adjunctive NSAIDs. Primary outcome was the change in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcomes included change in PANSS positive and negative subscores, all-cause discontinuation, and tolerability outcomes. Random effects, pooled, standardized mean changes (Hedges’ g) and risk ratios were calculated. Results: Across 8 studies, including 3 unpublished reports (n = 774), the mean effect size for PANSS total score was −0.236 (95% CI: −0.484 to 0.012, P = .063, I2 = 60.6%), showing only trend-level superiority for NSAIDs over placebo. The mean effect sizes for the PANSS positive and negative scores were −0.189 (95% CI: −0.373 to −0.005, P = .044) and −0.026 (95% CI: −0.169 to 0.117, P = .72), respectively. The relative risk for all-cause discontinuation was 1.13 (95% CI: 0.794 to 1.599, P = .503). Significant superiority of NSAIDs over placebo regarding PANSS total scores was moderated by aspirin treatment (N = 2, P = .017), inpatient status (N = 4, P = .029), first-episode status (N = 2, P = .048), and (in meta-regression analyses) lower PANSS negative subscores (N = 6, P = .026). Interpretation: These results indicate that adjunctive NSAIDs for schizophrenia may not benefit patients treated with first-line antipsychotics judged by PANSS total score change. NSAIDs may have benefits for positive symptoms, but the effect was minimal/small. However, due to a limited database, further controlled studies are needed, especially in first-episode patients.
PMCID: PMC3796088  PMID: 23720576
schizophrenia; inflammation; treatment resistance; augmentation; concomitant; nonsteroidal anti-inflammatory
12.  Antipsychotic polypharmacy: a Japanese survey of prescribers’ attitudes and rationales 
Psychiatry research  2013;209(3):406-411.
While combining antipsychotics is common in schizophrenia treatment, the literature on the reasons for antipsychotic polypharmacy (APP) is limited. We aimed to identify prescriber attitudes and rationales for APP in Japan where high APP utilization is reported. Two-hundred-seventeen psychiatrists participated in the survey, which assessed APP attitudes and behaviors. Prescribing APP to 47.7±24.7% (mean±SD) of their patients, psychiatrists reported that they were “moderately” concerned about APP. The most APP-justifiable factors were (1=“not at all” to 5=“extreme”): cross titration (4.50±0.67), randomized controlled evidence (3.67±0.83), and treatment of comorbid conditions (3.31±0.83). Conversely, APP-discouraging factors were: chronic side effects (4.14±0.64), difficulty determining cause and effect (4.07±0.74), and acute side effects (3.99±0.81). Comparing high to low APP prescribers (>50% vs. ≤50% of patients), no differences emerged regarding APP justification and concerns. In multivariate analyses, high APP use was associated with practice at a psychiatric hospital (OR: 2.70, 95%CI: 1.29-5.67, p=0.009), concern about potential drug-drug interactions (OR: 1.56, 95%CI: 1.04-2.35, p=0.031), and less reliance on case reports of APP showing efficacy (OR: 0.64, 95%CI: 0.44-0.92, p=0.017) (r2=0.111, p=0.001). High and low APP prescribers shared a comparable degree of justifications and concerns. Future research should examine the impact of cultural determinants on APP.
PMCID: PMC3791180  PMID: 23602697
Antipsychotic combination therapy; polypharmacy; attitudes; concerns; schizophrenia; survey
13.  Urinary Neutrophil Gelatinase-Associated Lipocalin: A Useful Biomarker for Tacrolimus-Induced Acute Kidney Injury in Liver Transplant Patients 
PLoS ONE  2014;9(10):e110527.
Tacrolimus is widely used as an immunosuppressant in liver transplantation, and tacrolimus-induced acute kidney injury (AKI) is a serious complication of liver transplantation. For early detection of AKI, various urinary biomarkers such as monocyte chemotactic protein-1, liver-type fatty acid-binding protein, interleukin-18, osteopontin, cystatin C, clusterin and neutrophil gelatinase-associated lipocalin (NGAL) have been identified. Here, we attempt to identify urinary biomarkers for the early detection of tacrolimus-induced AKI in liver transplant patients. Urine samples were collected from 31 patients after living-donor liver transplantation (LDLT). Twenty recipients developed tacrolimus-induced AKI. After the initiation of tacrolimus therapy, urine samples were collected on postoperative days 7, 14, and 21. In patients who experienced AKI during postoperative day 21, additional spot urine samples were collected on postoperative days 28, 35, 42, 49, and 58. The 8 healthy volunteers, whose renal and liver functions were normal, were asked to collect their blood and spot urine samples. The urinary levels of NGAL, monocyte chemotactic protein-1 and liver-type fatty acid-binding protein were significantly higher in patients with AKI than in those without, while those of interleukin-18, osteopontin, cystatin C and clusterin did not differ between the 2 groups. The area under the receiver operating characteristics curve of urinary NGAL was 0.876 (95% confidence interval, 0.800–0.951; P<0.0001), which was better than those of the other six urinary biomarkers. In addition, the urinary levels of NGAL at postoperative day 1 (p = 0.0446) and day 7 (p = 0.0006) can be a good predictive marker for tacrolimus-induced AKI within next 6 days, respectively. In conclusion, urinary NGAL is a sensitive biomarker for tacrolimus-induced AKI, and may help predict renal event caused by tacrolimus therapy in liver transplant patients.
PMCID: PMC4203804  PMID: 25329716
14.  The factors that limit activities of certified diabetes educators in Japan: a questionnaire survey 
SpringerPlus  2014;3:611.
The certified diabetes educator (CDE) is a qualification awarded to health professionals with specialized knowledge, skills, and experiences in diabetes management and education. To clarify whether CDEs consider themselves to be working sufficiently, in other words, making sufficient use of their specialized skills or not, a questionnaire survey was conducted.
The participants were persons involved in diabetes-related educational seminars and medical personnel engaged in diabetes care at the National Center for Global Health and Medicine. They were asked to complete a questionnaire regarding self -perception of CDE’s activities and to describe the reasons for their answers.
Fewer than 40% of the responding CDEs in each of the professions surveyed were satisfied with the current state of their activities and contributions as a CDE. For CDEs, “lack of labor” is the most concerning issue that limits their satisfactory activities as CDEs, followed by “condition of facilities”. Other factors such as insufficient “interprofessional teamwork”, “limited personal ability”, “mismatched allocation”, and “low recognition for CDEs” also limited their activities.
Many CDEs perceived they are not working sufficiently. Further efforts should be made to support CDEs to improve their working conditions.
PMCID: PMC4203788  PMID: 25392782
Certified diabetes educators; Japan; Job satisfaction; Self-perception
15.  Draft Genome Sequence of the Ionic Liquid-Tolerant Bacterium Bacillus amyloliquefaciens CMW1 
Genome Announcements  2014;2(5):e01051-14.
Here, we report the draft genome sequence of an ionic liquid-tolerant bacterium, Bacillus amyloliquefaciens CMW1, which is newly isolated from a Japanese fermented soybean paste. The genome sequence will allow for a characterization of the molecular mechanism of its ionic liquid tolerance.
PMCID: PMC4200159  PMID: 25323721
16.  Prediction of response to GLP-1 receptor agonist therapy in Japanese patients with type 2 diabetes 
Glucagon-like peptide-1 (GLP-1) receptor agonists can maintain good glycemic control in some diabetic. Here we compared the clinical characteristics and parameters reflecting glucose metabolism at the time of the initiation of GLP-1 receptor agonist therapy between patients who responded well to therapy and those who did not.
The records of 43 patients with type 2 diabetes who started receiving GLP-1 receptor agonist therapy during hospitalization were retrospectively reviewed. Glucagon stimulation tests were performed, and patients were started on liraglutide or exenatide therapy. Preprandial blood glucose levels were measured on days 2 and 3 of GLP-1 receptor agonist therapy. We used the Cox proportional hazard model to compare clinical parameters between responders (HbA1c level <8% at more than 3 months after the initiation of treatment) and non-responders (HbA1c level ≥8% at more than 3 months after the initiation of treatment or a switch to insulin therapy at any time).
Twenty-six of the 43 patients were classified as non-responders. At baseline, mean HbA1c levels were 9.9% among responders and 9.7% among non-responders. Compared with treatment with only diet or metformin, the hazard ratio [HR] for non-response was 5.3 (95% confidence interval [CI]: 1.16-24.6, P = 0.03) for insulin therapy and 5.0 (95% CI: 1.13-22.16, P = 0.03) for sulfonylurea therapy. Compared with the lowest tertile, the HRs for non-response in the highest tertile were 3.1 (95% CI: 1.04-8.97, P = 0.04) for the mean preprandial blood glucose level on days 2 and 3 and 3.4 (95% CI: 1.05-11.01, P = 0.04) for the body mass index. The response was not significantly associated with the duration of diabetes or the glucagon stimulation test results. A receiver operating curve analysis showed that the mean preprandial blood glucose level had the highest area under the curve value (=0.72) for the prediction of non-responders.
In patients with poorly controlled diabetes, the response to GLP-1 receptor agonist therapy was significantly associated with the treatment used before the initiation of therapy, the body mass index, and the mean preprandial blood glucose level during the 2 days after the initiation of therapy.
PMCID: PMC4209043  PMID: 25349635
Glycemic control; Glucagon-like peptide-1 agonist; Predictors of response; Preprandial blood glucose level; Liraglutide; Exenatide
17.  Levetiracetam improves disinhibitory behavior in nonconvulsive status epilepticus 
Nonconvulsive status epilepticus (NCSE) is a severe medical condition and heterogeneous disorder defined by different seizure types and diverse etiologies. NCSE occurs commonly in the elderly and is potentially misdiagnosed as a psychiatric disorder. Current treatment options for NCSE are still unsatisfactory.
Case presentation
We report a case of NCSE in a 55-year-old epileptic male patient with a history of infectious encephalitis, disinhibitory behavior, and a suspected diagnosis of frontotemporal dementia. Add-on levetiracetam (LEV) to carbamazepine treatment improved clinical manifestations and abnormal electroencephalographic discharge.
With disinhibitory behavior in the elderly, the possibility of NCSE should be considered. Moreover, LEV may be an effective and well-tolerated pharmacotherapy for elderly NCSE patients.
PMCID: PMC4205286  PMID: 25339976
Disinhibitory behavior; Levetiracetam; Nonconvulsive status epilepticus; Psychiatric disorder; Infectious encephalitis
18.  Draft Genome Sequence of a Deep-Sea Bacterium, Bacillus niacini Strain JAM F8, Involved in the Degradation of Glycosaminoglycans 
Genome Announcements  2014;2(5):e00983-14.
Here, we report the draft genome sequence of Bacillus niacini JAM F8, which was newly isolated from deep-sea sediment at a depth of 2,759 m from the Izu-Ogasawara Trench. An array of genes related to degradation of glycosaminoglycans in this bacterium was identified by whole-genome analysis.
PMCID: PMC4183874  PMID: 25278530
19.  Angiogenin mediates androgen-stimulated growth of prostate cancer cells and correlates with castration resistance 
Molecular cancer research : MCR  2013;11(10):1203-1214.
Androgen receptor (AR) is a critical effector of prostate cancer (PCa) development and progression. Androgen-dependent PCa rely on the function of AR for growth and progression. Many castration-resistant PCa continue to depend on AR signaling for survival and growth. Ribosomal RNA (rRNA) is essential for both androgen-dependent and castration-resistant growth of PCa cells. During androgen-dependent growth of prostate cells, androgen-AR signaling leads to the accumulation of rRNA. However, the mechanism by which AR regulates rRNA transcription is unknown. We have found that angiogenin (ANG), the 5th member of the vertebrate-specific, secreted ribonuclease superfamily that is upregulated in PCa, mediates androgen-stimulated rRNA transcription in PCa cells. Upon androgen stimulation, ANG undergoes nuclear translocation in androgen-dependent PCa cells where it binds to the ribosomal DNA (rDNA) promoter and stimulates rRNA transcription. ANG antagonists inhibit androgen-induced rRNA transcription and cell proliferation in androgen-dependent PCa cells. ANG also mediates androgen-independent rRNA transcription. It undergoes constitutive nuclear translocation in androgen-insensitive PCa cells, resulting in a constant rRNA overproduction thereby stimulating cell proliferation. ANG overexpression in androgen-dependent PCa cells enables castration-resistant growth of otherwise androgen-dependent cells. Thus, ANG-stimulated rRNA transcription is not only an essential component for androgen-dependent growth of PCa, but also contributes to the transition of PCa from androgen-dependent to castration-resistant growth status.
PMCID: PMC3800479  PMID: 23851444
Angiogenin; PCa; castration-resistant; ribosomal RNA; androgen receptor
20.  Pyruvate Induces Transient Tumor Hypoxia by Enhancing Mitochondrial Oxygen Consumption and Potentiates the Anti-Tumor Effect of a Hypoxia-Activated Prodrug TH-302 
PLoS ONE  2014;9(9):e107995.
TH-302 is a hypoxia-activated prodrug (HAP) of bromo isophosphoramide mustard that is selectively activated within hypoxic regions in solid tumors. Our recent study showed that intravenously administered bolus pyruvate can transiently induce hypoxia in tumors. We investigated the mechanism underlying the induction of transient hypoxia and the combination use of pyruvate to potentiate the anti-tumor effect of TH-302.
The hypoxia-dependent cytotoxicity of TH-302 was evaluated by a viability assay in murine SCCVII and human HT29 cells. Modulation in cellular oxygen consumption and in vivo tumor oxygenation by the pyruvate treatment was monitored by extracellular flux analysis and electron paramagnetic resonance (EPR) oxygen imaging, respectively. The enhancement of the anti-tumor effect of TH-302 by pyruvate treatment was evaluated by monitoring the growth suppression of the tumor xenografts inoculated subcutaneously in mice. TH-302 preferentially inhibited the growth of both SCCVII and HT29 cells under hypoxic conditions (0.1% O2), with minimal effect under aerobic conditions (21% O2). Basal oxygen consumption rates increased after the pyruvate treatment in SCCVII cells in a concentration-dependent manner, suggesting that pyruvate enhances the mitochondrial respiration to consume excess cellular oxygen. In vivo EPR oxygen imaging showed that the intravenous administration of pyruvate globally induced the transient hypoxia 30 min after the injection in SCCVII and HT29 tumors at the size of 500–1500 mm3. Pretreatment of SCCVII tumor bearing mice with pyruvate 30 min prior to TH-302 administration, initiated with small tumors (∼550 mm3), significantly delayed tumor growth.
Our in vitro and in vivo studies showed that pyruvate induces transient hypoxia by enhancing mitochondrial oxygen consumption in tumor cells. TH-302 therapy can be potentiated by pyruvate pretreatment if started at the appropriate tumor size and oxygen concentration.
PMCID: PMC4177858  PMID: 25254649
21.  Intussusception due to rectal adenocarcinoma in a young adult: A case report 
World Journal of Gastroenterology : WJG  2014;20(35):12678-12681.
An intussusception due to colonic adenocarcinoma has sometimes been reported. However, to the best of our knowledge, reports of intussusception due to rectal adenocarcinoma are extremely rare. In this report, the case of a young man with rectal adenocarcinoma causing intussusception is described. A 24-year-old man visited a hospital complaining of abdominal pain, and an upper rectal cancer was diagnosed by colonoscopy. Computed tomography showed intussusception caused by a large tumor in the pelvis and absence of distant metastases. Locally advanced rectal cancer causing intussusception was diagnosed, and a low anterior resection was performed. Intraoperatively, repair of the invagination could not be accomplished easily; therefore, the repair was abandoned. Instead, the tumor was removed en bloc to avoid dissemination of the cancer. Histopathologically, the tumor was diagnosed as a poorly differentiated adenocarcinoma, pStage IIA. The patient has no evidence of recurrence at 10 mo after the operation.
PMCID: PMC4168108  PMID: 25253975
Adult intussusception; En bloc resection; Low anterior resection; Rectal adenocarcinoma; Young cancer
22.  Cyclin B–Cdk1 inhibits protein phosphatase PP2A-B55 via a Greatwall kinase–independent mechanism 
The Journal of Cell Biology  2014;204(6):881-889.
The role of Greatwall kinase in autoregulatory activation of cyclin B–Cdk1 at M phase onset can be bypassed by cyclin B–Cdk1–mediated direct phosphorylation of Arpp19, leading to PP2A-B55 inhibition.
Entry into M phase is governed by cyclin B–Cdk1, which undergoes both an initial activation and subsequent autoregulatory activation. A key part of the autoregulatory activation is the cyclin B–Cdk1–dependent inhibition of the protein phosphatase 2A (PP2A)–B55, which antagonizes cyclin B–Cdk1. Greatwall kinase (Gwl) is believed to be essential for the autoregulatory activation because Gwl is activated downstream of cyclin B–Cdk1 to phosphorylate and activate α-endosulfine (Ensa)/Arpp19, an inhibitor of PP2A-B55. However, cyclin B–Cdk1 becomes fully activated in some conditions lacking Gwl, yet how this is accomplished remains unclear. We show here that cyclin B–Cdk1 can directly phosphorylate Arpp19 on a different conserved site, resulting in inhibition of PP2A-B55. Importantly, this novel bypass is sufficient for cyclin B–Cdk1 autoregulatory activation. Gwl-dependent phosphorylation of Arpp19 is nonetheless necessary for downstream mitotic progression because chromosomes fail to segregate properly in the absence of Gwl. Such a biphasic regulation of Arpp19 results in different levels of PP2A-B55 inhibition and hence might govern its different cellular roles.
PMCID: PMC3998810  PMID: 24616226
23.  A key regulatory role of Vav1 in controlling LPS endotoxemia via macrophage derived IL-6 
Macrophages are centrally involved in the pathogenesis of acute inflammatory diseases, peritonitis, endotoxemia and septic shock. The molecular mechanisms controlling such macrophage activation are incompletely understood, however. Here, we provide evidence that Vav1, a member of the RhoGEF family, plays a crucial role in macrophage activation and septic endotoxemia. Vav1 deficient mice demonstrated a significantly increased susceptibility for LPS endotoxemia that could be abrogated by anti-IL-6R antibody treatment. Subsequent studies showed that Vav1 deficient macrophages display augmented production of the proinflammatory cytokine IL-6. Nuclear Vav1 was identified as key negative regulator of macrophage derived IL-6 production. In fact, Vav1 formed a nuclear DNA binding complex with Heat Shock Transcription Factor 1 at the HSE2 region of the IL-6 promoter to suppress IL-6 gene transcription in macrophages. These findings provide new insights into the pathogenesis of endotoxemia and suggest new avenues for therapy.
PMCID: PMC3951479  PMID: 24532586
24.  Alloparenting for chimpanzee twins 
Scientific Reports  2014;4:6306.
In April 2009, a female chimpanzee named Sango, living in a captive group at the Noichi Zoo, Japan, gave birth to dizygotic male-female twin chimpanzees (male: Daiya, female: Sakura). The extent to which adult group members cared for the twins was investigated using a focal animal sampling method targeting six adults (one male) when the twin chimpanzees were two years old. Data were collected for an average of 6.78 h (SD = 0.79) per focal participant. An unaffiliated female adult of Sango was engaged in parenting Sakura as much as Sango. Given that Sakura was in lesser proximity to Sango than Daiya, Sakura's departures from her mother and her ability to gesture requests might have enabled non-kin adults to provide her care.
PMCID: PMC4158332  PMID: 25200656
25.  The cardiovascular action of hexarelin 
Hexarelin, a synthetic growth hormone-releasing peptide, can bind to and activate the growth hormone secretagogue receptor (GHSR) in the brain similar to its natural analog ghrelin. However, the peripheral distribution of GHSR in the heart and blood vessels suggests that hexarelin might have direct cardiovascular actions beyond growth hormone release and neuroendocrine effects. Furthermore, the non-GHSR CD36 had been demonstrated to be a specific cardiac receptor for hexarelin and to mediate its cardioprotective effects. When compared with ghrelin, hexarelin is chemically more stable and functionally more potent. Therefore, it may be a promising therapeutic agent for some cardiovascular conditions. In this concise review, we discuss the current evidence for the cardiovascular action of hexarelin.
PMCID: PMC4178518  PMID: 25278975
Hexarelin; Cardiovascular disease; Growth hormone secretagogue receptor; CD36

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