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Aim To evaluate the safety and pharmacokinetics of cotadutide, a dual glucagon-like peptide-1 (GLP-1) and glucagon receptor agonist, in overweight Asian participants with or without type 2 diabetes (T2D). Materials and methods In the phase 1, randomized, blinded, single-ascending dose study, 24 Japanese and eight Chinese healthy adults (body mass index [BMI] 23-40 kg/m2 ) received one subcutaneous dose of cotadutide (50-150 or 100 μg, respectively) or placebo. The primary endpoint was safety. In the phase 2a, randomized, double-blinded, parallel dose-ranging study with forced uptitration, 61 Japanese adults with T2D (BMI 24-40 kg/m2 ; HbA1c 7.0%-10.5%) received cotadutide (100, 200, 300 μg) or placebo for 48 days. Co-primary endpoints were safety/tolerability, change in glucose AUC0-4h and body weight. Results Significant reductions from baseline to day 48 were observed with cotadutide for glucose AUC0-4h (33.6%-42.1% reduction vs. +2.5% with placebo; 95% CIs: 100 μg -45.7%, -33.7%; 200 μg -35.6%, -23.7%; 300 μg -45.0%, -30.8%; placebo 3.4%, 8.3%) and body weight (1.3%-2.5% decrease vs. +0.8% with placebo; 95% CIs: 100 μg -3.4%, -0.8%; 200 μg -4.7%, -2.0%; 300 μg -4.6%, -2.1%; placebo -2.1%, 0.4%). The most common adverse events with cotadutide were mild gastrointestinal symptoms with no serious adverse events. Increased pulse rate with cotadutide versus placebo is consistent with GLP-1 monoagonists. Conclusions Once-daily cotadutide was effective and well tolerated up to 300 μg in overweight Japanese patients with T2D. Further evaluation in Asian populations is warranted.

Aim To examine the long‐term efficacy and safety of dapagliflozin, a sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor used to treat type 1 diabetes, in the Japanese subpopulation of the DEPICT‐2 study. Materials and Methods Patients with type 1 diabetes were randomized to dapagliflozin 5 mg (n = 55), dapagliflozin 10 mg (n = 41) or placebo (n = 58) plus insulin for a 24‐week, double‐blind period followed by a 28‐week, single‐blind extension phase. Results From baseline to 24 weeks, dapagliflozin reduced HbA1c compared with placebo (mean change of −0.58% and −0.80% for 5 and 10 mg, respectively), and an HbA1c reduction was observed up to 52 weeks. Compared with placebo, dapagliflozin 5 and 10 mg increased the proportion of patients achieving HbA1c reductions of 0.5% or more without severe hypoglycaemia events and reduced glycaemic variability assessed via continuous glucose monitoring. Both dapagliflozin doses decreased body weight and total daily insulin dose at 24 weeks compared with placebo; these reductions were maintained up to 52 weeks. Diabetic ketoacidosis occurred in both dapagliflozin groups (one and two cases, respectively) but not with placebo. Conclusions Efficacy and safety results from the Japanese subpopulation of the DEPICT‐2 study were generally consistent with those from the overall population, indicating that long‐term dapagliflozin adjunct to insulin therapy improves glycaemic control without an increased risk of hypoglycaemia but with a risk of diabetic ketoacidosis in Japanese patients with type 1 diabetes.

Synesthesia is a condition in which the perception of a stimulus in one modality automatically triggers a secondary sensation in another modality or processing stream. Our study focused on grapheme-color synesthesia, in which the visual perception of letters or numbers (graphemes) induces a specific color sensation (the synesthetic color). Grapheme-color synesthetes do not typically experience colors for novel graphemes. However, synesthetic colors associated with familiar graphemes can be transferred to graphemes learned later, even in adulthood. A previous study has shown that such a transfer can take place after only a 10-min writing exercise. In this study, we found that this immediate transfer occurs only when the synesthetic colors for familiar graphemes contribute to the discrimination of the graphemes to be learned. Synesthetes learned six novel graphemes, each of which was arbitrarily associated with one of six familiar graphemes. Half of the synesthetes were assigned to the heterogeneous condition, in which the synesthetic colors of one group of familiar graphemes were different from one another. The other half of the synesthetes were assigned to the homogeneous condition, in which the various colors of a whole group of familiar graphemes were categorically the same. After this learning session, less transfer of synesthetic colors to novel graphemes from the corresponding familiar graphemes occurred in the homogeneous condition than in the heterogeneous condition. These results support the view that synesthetic colors for graphemes may function as a grapheme acquisition aid.

Aims To investigate the safety and tolerability of 5 and 10 mg dapagliflozin added to insulin therapy over 52 weeks in Japanese patients with inadequately controlled type 1 diabetes mellitus (T1DM). Materials and methods This randomized, open‐label, parallel‐group, multicentre phase III clinical trial was conducted from October 26, 2015 to June 15, 2017. The primary endpoint was the occurrence of adverse events such as hypoglycaemia and diabetic ketoacidosis. Secondary endpoints included changes in glycaemic parameters, total daily insulin dosage and body weight over time. The efficacy of dapagliflozin in patients stratified by body mass index (BMI)

Grapheme-color synesthetes experience graphemes as having a consistent color (e.g., “N is turquoise”). Synesthetes’ specific associations (which letter is which color) are influenced by linguistic properties (letter frequency, phonetic similarity, etc.), and plausibly reveal the characteristics of underlying letter representations. Despite their clear linguistic origin, these influences (termed “Regulatory Factors”, RFs) are almost always studied in a single language, typically English. Here, we measure the influence of three RFs (previously examined only in English) in Dutch, English, Greek, Japanese, Korean, Russian, and Spanish synesthetes. For two RFs, effect size significantly differed between languages. In contrast, an RF which we predicted to be universal (because it is shaped by prelinguistic shape-color associations) did not differ between languages. Our results suggest that monolingual synesthesia studies should be interpreted with caution. Furthermore, they show how synesthetic associations offer an exceptional opportunity to study linguistic and prelinguistic influences on letter representations in different languages.

Aims To assess the pharmacokinetics/pharmacodynamics (PK/PD) of dapagliflozin, a sodium-glucose co-transporter 2 inhibitor that increases urinary glucose excretion (UGE) and its major metabolite, dapagliflozin-3-O-glucuronide (D3OG), in Japanese patients with type 1 diabetes (T1D) and inadequate glycaemic control (HbA1c 7%-10%). Materials and methods Japanese patients (18-65 years) with inadequately controlled T1D were randomized 1:1:1 to dapagliflozin 5 mg, 10 mg or placebo (n = 14 each) once daily for 7 days, with adjustable insulin. The PK/PD characteristics of dapagliflozin and D3OG were assessed on Day 7. Patients underwent follow-up evaluation on Days 8 and 14. Adverse events (AEs), hypoglycaemic episodes and events of diabetic ketoacidosis (DKA) were recorded over the treatment and follow-up periods. Results A total of 42 randomized patients received dapagliflozin or placebo. PK variables increased in a dose-dependent manner. D3OG was generated rapidly, with a median time to maximum plasma concentration of 2.0 hours (1.0-3.0). The dapagliflozin dose-UGE relationship was attenuated, with larger insulin dose reductions than anticipated. Mean percent (standard error) changes in total daily insulin dose from baseline to Day 7 were - 36.86% (3.32), -39.13% (2.68) and - 4.97% (5.28) for dapagliflozin 5 mg and 10 mg and for placebo, respectively. No DKA was reported. AEs were consistent with the established dapagliflozin safety profile. There was no increase in hypoglycaemia. Conclusions The PK and safety profiles of dapagliflozin in Japanese patients with T1D were consistent with previous studies, but with an unanticipated attenuation of the PD dose-response measured as UGE.

A 65-year-old woman visited our hospital due to right chest pain and dyspnea on exertion. Chest radiography revealed decreased permeability of the right lung. Computed tomography demonstrated a huge mass in the right upper lobe and right pleural effusion. Right pleural effusion cytology yielded a diagnosis of adenocarcinoma and was positive for mutation of epidermal growth factor receptor (EGFR; exon 21 L858R). Afatinib was selected for the initial treatment. Multiple tumors regressed remarkably, but then rapidly progressed 3 months later. We performed re-biopsy to detect the mechanism of resistance to afatinib. Histopathology revealed a mixture of small cell carcinoma (SCC) and adenocarcinoma harboring same EGFR mutation. To the best of our knowledge, this is the first report of transformation to SCC after treatment with afatinib.

A 73-year-old man was referred to our hospital after a 2-week history of bloody sputum and cough. Computed tomography (CT) images of the chest showed a mass grouped with mediastinal lymph nodes, and bronchoscopy showed a projecting mass in the right main bronchus. After a transbronchial biopsy, the patient was diagnosed with squamous cell carcinoma (T4N2M0 stage IIIB). The patient was treated with systemic chemotherapy, consisting of cisplatin (40 mg/m2, days 1 and 8) and docetaxel (30 mg/m2, days 1 and 8), and concurrent thoracic irradiation at a daily dose of 2 Gy. On day 35 of treatment, the patient complained of a sore throat and cough. A CT of the chest showed punctate low-attenuation foci between the esophagus and bronchus. Gastrointestinal endoscopy and bronchoscopy demonstrated a fistula in the middle intrathoracic esophagus and the left main bronchus. The patient’s symptoms gradually improved, and the fistula was closed after the suspension of chemoradiotherapy. Radiotherapy was resumed and completed on day 82. However, on day 108, he developed a fever and cough, and a tumor with fistula was revealed in the right main bronchus. He had an esophageal stent inserted, but he later died of sudden hemoptysis.

Aims To evaluate the efficacy and safety of dapagliflozin as add-on to insulin in Japanese patients with type 2 diabetes. Materials and methods Insulin-treated Japanese patients were randomized to 5 mg dapagliflozin or placebo during a 16-week double-blind treatment period. Both groups then received dapagliflozin 5 or 10 mg (the dose was increased at or after week 24 if glycated haemoglobin [HbA1c] at the previous visit was >7.5%) during a 36-week open-label extension period. The exploratory efficacy endpoint was to assess the maintenance efficacy of 5/10 mg dapagliflozin + insulin over 52 weeks of treatment. Safety was assessed in terms of adverse events, laboratory variables and vital signs. Results The changes in HbA1c from baseline to weeks 16 and 52 were −0.62% and −0.74%, respectively, in the dapagliflozin group, vs −0.08% and −0.83%, respectively, in the placebo–dapagliflozin group. Body weight decreased at both time points in the dapagliflozin group and after switching to open-label dapagliflozin in the placebo–dapagliflozin group. The total insulin dose decreased slightly after starting dapagliflozin. Adverse events occurred in 82.9% and 71.7% of patients in the dapagliflozin and placebo–dapagliflozin groups, respectively. Hypoglycaemia occurred in 35.0% and 41.7% of patients in the dapagliflozin and placebo–dapagliflozin groups, respectively, but the incidence was not increased by use of dapagliflozin in either trial period. Genital/urinary tract infections, renal impairment/failure, volume depletion, fracture and hepatic disorders occurred in ≤5% of patients. Conclusion This trial showed that administration of dapagliflozin as an add-on to insulin therapy was effective, was well tolerated and had insulin-sparing effects in Japanese patients with type 2 diabetes.

Grapheme-color synesthesia is a condition in which the visual perception of letters or numbers induces a specific color sensation. The consistency of grapheme-color association has been considered as a fundamental characteristic of synesthesia. However, recent studies have indicated that this association can change across the adult lifespan, and it has become necessary to investigate the factors behind the changes within each synesthete. We conducted a longitudinal study of Japanese adult synesthetes to investigate long-term (5–8 years) changes in color responses to 300 graphemes (alphanumeric and Japanese characters). Graphemes with lower long-term consistency of synesthetic association also tended to have lower short-term consistency, indicating that grapheme-color association's consistency is determined for each grapheme. Further, less familiar graphemes had less consistent associations with their synesthetic colors. These findings suggest that a stronger grapheme-color association is formed for more familiar graphemes, leading to the consolidation of synesthetic color for such graphemes.

Introduction Dapagliflozin treatment when added to insulin therapy in Japanese patients with type 2 diabetes remains to be evaluated. Materials and Methods This was a multicenter, randomized, double-blind, parallel-group, placebo-controlled study to evaluate efficacy (at 16 weeks) and long-term safety (at 52 weeks) of dapagliflozin in addition to insulin therapy. The interim analysis was carried out at week 16 to assess the efficacy and safety profiles. The patients receiving insulin (n = 182) were randomized to either dapagliflozin 5 mg or a placebo at a 2:1 ratio. The primary efficacy end-point was the change in hemoglobin A1c (HbA1c) from baseline at week 16. Results Patients in the dapagliflozin group showed an adjusted decrease in HbA1c of −0.55% from baseline, whereas the placebo showed a marginal increase of 0.05%. The placebo-corrected mean change of HbA1c from baseline to week 16 in dapagliflozin was −0.60% (P < 0.0001). In addition, the placebo-corrected mean change of fasting plasma glucose and bodyweight from baseline to week 16 in the dapagliflozin group was −22.7 mg/dL (P < 0.0001) and −1.21 kg (P < 0.0001), respectively. The placebo-corrected mean daily insulin dose in the dapagliflozin group was numerically decreased (treatment difference: −0.72 IU/day; P = 0.0743). No major episodes or discontinuations as a result of hypoglycemia were reported during the study period. Conclusions Dapagliflozin used as add-on treatment to insulin therapy showed significantly greater reduction of HbA1c, fasting plasma glucose and bodyweight without severe hypoglycemia compared with the placebo at week 16. These results show the clinical benefit of prescribing dapagliflozin for Japanese patients with insufficient glycemic control even with insulin therapy.

Videogame play (VGP) has been associated with numerous preferred and non-preferred effects. However, the effects of VGP on the development of microstructural properties in children, particularly those associated with negative psychological consequences of VGP, have not been identified to date. The purpose of this study was to investigate this issue through cross-sectional and longitudinal prospective analyses. In the present study of humans, we used the diffusion tensor imaging mean diffusivity (MD) measurement to measure microstructural properties and examined cross-sectional correlations with the amount of VGP in 114 boys and 126 girls. We also assessed correlations between the amount of VGP and longitudinal changes in MD that developed after 3.0±0.3 (s.d.) years in 95 boys and 94 girls. After correcting for confounding factors, we found that the amount of VGP was associated with increased MD in the left middle, inferior and orbital frontal cortex; left pallidum; left putamen; left hippocampus; left caudate; right putamen; right insula; and thalamus in both cross-sectional and longitudinal analyses. Regardless of intelligence quotient type, higher MD in the areas of the left thalamus, left hippocampus, left putamen, left insula and left Heschl gyrus was associated with lower intelligence. We also confirmed an association between the amount of VGP and decreased verbal intelligence in both cross-sectional and longitudinal analyses. In conclusion, increased VGP is directly or indirectly associated with delayed development of the microstructure in extensive brain regions and verbal intelligence.

The empathizing-systemizing model describes human cognitive style using empathizing (the drive to identify another's mental state and respond appropriately) and systemizing (the drive to assess or construct rule-based systems). 'Brain type' was envisioned to explain individual differences in cognitive style based on the discrepancy of the two drives. In this model, individuals with autism spectrum disorder (ASD), a neurodevelopmental disorder, have extremely stronger systemizing. Revealing the underlying mechanisms of individual differences in cognitive style might contribute to elucidation of the pathology of ASD. We used voxel-based morphometry to compare the brain structures among the brain types (those who have stronger empathizing, those who have equally stronger drive to both, and those who have stronger systemizing) in 207 healthy children (age range: 5-15). Results showed that children with stronger systemizing had significantly greater grey matter volume of the right superior temporal gyrus (rSTG) than the others. The brain region, a distinctive brain structure of those with stronger systemizing, was overlapped with that of children with ASD. The rSTG is involved in detailed perceptual processing in social cognition, which is partially related to stronger systemizing. Our results contribute to elucidation of the underlying mechanisms of individual differences in cognitive style.

Children often personify non-living objects, such as puppets and stars. This attribution is considered a healthy phenomenon, which can simulate social exchange and enhance children's understanding of social relationships. In this study, we considered that the tendency of children to engage in personification could potentially be observed in abstract entities, such as numbers. We hypothesized that children tend to attribute personalities to numbers, which diminishes during the course of development. By consulting the methodology to measure ordinal linguistic personification (OLP), which is a type of synesthesia, we quantified the frequency with which child and adult populations engage in number personification. Questionnaires were completed by 151 non-synesthetic children (9-12 years old) and 55 non-synesthetic adults. Children showed a higher tendency than adults to engage in number personification, with respect to temporal consistency and the frequency of choosing meaningful answers. Additionally, children tended to assign unique and exclusive descriptions to each number from zero to nine. By synthesizing the series of analyses, we revealed the process in which number personification diminishes throughout development. In the discussion, we examined the possibility that number personification serves as a discrimination clue to aid children's comprehension of the relationships between numbers.

A 74-year-old man with a history of occupational asbestos exposure in a shipyard was diagnosed with lymphohistiocytoid mesothelioma (LHM). Systemic chemotherapy consisted of cisplatin, and pemetrexed was administered. After six courses of chemotherapy, multiple tumours had regressed. Six months after chemotherapy, the tumours on the pleura exhibited regrowth and partly invaded the liver. Salvage chemotherapies, including irinotecan and vinorelbine, were administered and his disease was stable for several months. Then he suddenly vomited and complained of abdominal pain. Contrast CT showed small intestine intussusception. Partial resection of the small intestine was performed. We found a tumour in the resected small intestine. Review the …

The brain is a rare site of metastasis in malignant pleural mesothelioma (MPM), and its clinical features and prognosis remain unclear. The aim of this study was to investigate the incidence, prognosis, and risk factors for brain metastases (BM) in MPM patients. Between July 1993 and October 2014, 150 patients with histologically proven MPM were included in this retrospective study. The cumulative incidence of BM was estimated with the Kaplan-Meier method, and differences between groups were analyzed by the log-rank test. Multivariate logistic regression analysis was applied to assess risk factors for BM. The median follow-up time was 11 months (range 0-154.0 months). A total of eight patients (5.3 %) developed BM during the course of their illness. Multivariate analysis identified age

Chronic inflammation plays a key role in the pathogenesis of malignant pleural mesothelioma (MPM) as a result of asbestos exposure. Several inflammation-based prognostic scores including the lymphocyte-to-monocyte ratio (LMR), Glasgow Prognostic Score (GPS), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) reportedly predict survival in many malignancies, while the role of LMR in MPM remains unclear. The aim of this study was to evaluate the clinical value of LMR and to compare the prognostic value of these inflammation-based scores in predicting overall survival (OS) in MPM.One hundred and fifty patients with histologically proven MPM were included in this retrospective study. Kaplan-Meier curves and multivariate Cox-regression analyses were calculated for OS. The area under the receiver operating characteristics curve (AUC) was calculated to compare the discriminatory ability of each scoring system.An elevated LMR was significantly associated with prolonged OS. Patients with LMR2.74 had significantly poor survival compared with LMR ≥2.74 (median, 5.0 versus 14.0 months; p=0.000). The LMR consistently had a higher AUC value at 6 months (0.722), 12 months (0.712), and 24 months (0.670), compared with other scores. Multivariate analysis showed that the LMR was independently associated with OS.The LMR is an independent prognostic marker for OS in patients with MPM and is superior to other inflammation-based prognostic scores with respect to prognostic ability.

We report a very rare case of primary endobronchial peripheral T-cell lymphoma (PTCL) not otherwise specified (NOS), which presented as an endobronchial tumor obstructing the main airway. An 81-year-old man was referred to our hospital for a 1-month history of productive cough and wheeze. Computed tomography revealed chronic pyothorax with calcified foci in the right lung and a mass inside the bronchus intermedius. Flexible bronchoscopy identified an endobronchial tumor obstructing the bronchus intermedius. The biopsy specimen showed an infiltration composed predominantly of small atypical lymphocytes. Immunohistochemical analyses demonstrated that the proliferating cells were positive for CD3, CD4, and CD5 and negative for CD8 and CD20. Pathological tests confirmed that the case was PTCL-NOS. PTCL-NOS should be considered in the differential diagnosis of endobronchial tumors.

An 81-year-old woman visited a local clinic due to chest pain and a skin induration on the right precordia. She had a history of right breast cancer, and she had undergone a mastectomy and radiation therapy 10 years prior. Computed tomography (CT) imaging of the chest demonstrated a lobular mass that involved the right anterior thoracic wall and partially extruded from the thoracic cavity into the subcutaneous tissue. The tumor was surgically excised, and pathological analyses yielded a diagnosis of angiosarcoma. Five months after the operation, CT imaging showed multiple masses on the right pleura, indicating a local relapse and pleural dissemination of the angiosarcoma. Systemic chemotherapy composed of nanoparticle albumin-bound paclitaxel (nab-PTX) (80 mg/m(2)) was delivered weekly. After 4 courses of chemotherapy, the tumors regressed remarkably. Nab-PTX may be an effective treatment option for recurrent or metastatic angiosarcoma.

Grapheme-color synesthesia is a neurological phenomenon in which viewing a grapheme elicits an additional, automatic, and consistent sensation of color. Color-to-letter associations in synesthesia are interesting in their own right, but also offer an opportunity to examine relationships between visual, acoustic, and semantic aspects of language. Research using large populations of synesthetes has indeed found that grapheme-color pairings can be influenced by numerous properties of graphemes, but the contributions made by each of these explanatory factors are often confounded in a monolingual dataset (i.e., only English-speaking synesthetes). Here, we report the first demonstration of how a multilingual dataset can reveal potentially-universal influences on synesthetic associations, and disentangle previously-confounded hypotheses about the relationship between properties of synesthetic color and properties of the grapheme that induces it. Numerous studies have reported that for English-speaking synesthetes, “A” tends to be colored red more often than predicted by chance, and several explanatory factors have been proposed that could explain this association. Using a five-language dataset (native English, Dutch, Spanish, Japanese, and Korean speakers), we compare the predictions made by each explanatory factor, and show that only an ordinal explanation makes consistent predictions across all five languages, suggesting that the English “A” is red because the first grapheme of a synesthete's alphabet or syllabary tends to be associated with red. We propose that the relationship between the first grapheme and the color red is an association between an unusually-distinct ordinal position (“first”) and an unusually-distinct color (red). We test the predictions made by this theory, and demonstrate that the first grapheme is unusually distinct (has a color that is distant in color space from the other letters' colors). Our results demonstrate the importance of considering cross-linguistic similarities and differences in synesthesia, and suggest that some influences on grapheme-color associations in synesthesia might be universal.

A 76-year-old woman came to us because of staggering, fever, dysarthria, and appetite loss. Magnetic resonance imaging (MRI) of the brain revealed multiple masses with surrounding edema. Chest X-ray and computed tomography demonstrated a mass-like lesion in the left lung and left pleural effusion. Lung cancer and multiple brain metastases were suspected. However, the brain lesions demonstrated a high intensity through diffusion-weighted MRI. The finding was an important key to differentiate brain abscesses from lung cancer metastases.

Determinants of synesthetic color choice for Japanese phonetic characters were studied in six Japanese synesthetes. The study used Hiragana and Katakana characters, which represent the same set of syllables although their visual forms are dissimilar. From a palette of 138 colors, synesthetes selected a color corresponding to each character. Results revealed that synesthetic color choices for Hiragana characters and those for their Katakana counterparts were remarkably consistent, indicating that color selection depended on character-related sounds and not visual form. This Hiragana–Katakana invariance cannot be regarded as the same phenomenon as letter case invariance, usually reported for English grapheme-color synesthesia, because Hiragana and Katakana characters have different identities whereas upper and lower case letters have the same identity. This involvement of phonology suggests that cross-activation between an inducer (i.e., letter/character) brain region and that of the concurrent (i.e., color) area in grapheme-color synesthesia is mediated by higher order cortical processing areas.

Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm primarily arising from surface serosal cells of the pleura and is strongly associated with asbestos exposure. Patients with MPM often develop pleural fluid as initial presentation. However, cytological diagnosis using pleural fluid is usually difficult and has limited utility. A useful molecular marker for differential diagnosis particularly with lung cancer (LC) is urgently needed. The aim of the present study was to investigate the diagnostic value of soluble mesothelin-related protein (SMRP) in pleural fluid. Pleural fluids were collected from 23 patients with MPM, 38 with LC, 26 with benign asbestos pleurisy (BAP), 5 with tuberculosis pleurisy (TP) and 4 with chronic heart failure (CHF), and the SMRP concentration was determined. All data were analyzed by using non-parametric two-sided statistical tests. The median concentration of SMRP in MPM, LC, BAP, TP and CHF were 11.5 (range 0.90-82.80), 5.20 (0.05-36.40), 6.65 (1.45-11.25), 3.20 (1.65-6.50) and 2.03 (1.35-2.80) nmol/l, respectively. The SMRP concentration was significantly higher in MPM than in the other diseases (P=0.001). The area under the ROC curve (AUC) values of the MPM diagnosis was 0.75 for the differential diagnosis from the other groups. Based on the cut-off value of 8 nmol/l, the sensitivity and specificity for diagnosis of MPM were 70.0 and 68.4%, respectively. These results indicate that the SMRP concentration in pleural fluid is a useful marker for the diagnosis of MPM.

A 59-year-old man was referred to our hospital because of left pleural effusion detected at a regular medical checkup. A chest X-ray showed left pleural effusion. A thoracoscopic pleural biopsy specimen from the left side gave a pathological diagnosis of malignant pleural mesothelioma (MPM), epithelioid type. Then thoracoscopic exploration of the right pleura was performed because of fluorodeoxyglucose accumulation along the right dorsal pleura. Thoracoscopic exploration of the right indicated no visible tumor formation, but a pleural biopsy specimen revealed epithelioid MPM. In this case, MPM in each thorax was confined to the parietal pleura and was classified as stage I. We therefore suggest that MPM may develop simultaneously in both thoraxes.

A 59-year-old man who was diagnosed with small cell lung cancer (SCLC), achieved a complete response to the induction chemoradiotherapy and received prophylactic cranial irradiation (PCI) (25 Gy at 250 cGy per fraction) in October 2008. Three months later, he complained of anorexia, weight loss, fatigue, and short-term memory loss and developed dementia and systemic muscle weakness. Magnetic resonance imaging in April and July 2009 revealed the progression of the diffuse brain atrophy without evidence of the metastasis of SCLC. Paraneoplastic neurological syndrome was suspected because anti-Hu antibody was detected in his serum and cerebrospinal fluid, but the adverse effects of chemotherapy and/or radiotherapy were also suspected as the cause of his neurological disorder.

Recent progress in grapheme-color synesthesia research has revealed that certain regularities, as well as individual differences, figure into grapheme-color associations. Although several factors are known to regulate grapheme-color associations, the impact of factors, including their interrelationships, on synesthesia remains unclear. We investigated determinants of synesthetic color for graphemes (characters, letters) of Hiragana, a phonetic script in the Japanese language, and the English alphabet. Results revealed that grapheme ordinality was the strongest predictor of synesthetic colors for Hiragana characters, followed by character sound, and visual shape. Ordinality and visual shapes also significantly predicted synesthetic colors for English alphabet letters, however, sounds did not. The relative impact of grapheme properties on grapheme-color associations and the differences between these two writing systems are accounted for by considering the way graphemes are processed in the brain and introduced during an individual's development. A new model is proposed which takes into account the developmental process of grapheme learning. The model provides comprehensive explanation of synesthetic grapheme-color association determination processes, including the differences across writing systems.

The effects of elevated glucose and aldose reductase inhibitor (ARI:ONO-2235) on nitric oxide (NO) production in cultured human umbilical endothelial cells (HUVEC) were evaluated. Aldose reductase and nitric oxide synthase(NOS) share NADPH as an obligate cofactor, therefore it is suggested that the enhanced of glucose flux (27.5 mM) by aldose reductase inhibited NO production by blunting NOS activity. However, the addition of ONO-2235 (100 μM) prevented the inhibition of [NO 2 − ] production. Since ARI decreases glucose-mediated inhibition of NO production in HUVEC, this agent might ameliorate endothelial function associated with diabetes.

The mechanisms responsible for the abnormalities in the vascular wall associated with long standing diabetes mellitus are incompletely understood. The aim of this investigation was to assess the effects of angiotensin II and high glucose on the production of platelet-derived growth factor (PDGF) in human endothelial cells. For this purpose, a primary culture was obtained from fresh human umbilical cords by collagenase digestion of the vein interior. A high glucose medium increased the production of PDGF and a similar effect was observed by the addition of mannitol. These data are consistent with a stimulatory effect of glucose on PDGF that is mediated by the osmotic effect of this substance. Angiotensin II significantly increased PDGF in human endothelial cells and the effect was accompanied by a transient increase in cytosolic calcium. The angiotensin II-induced intracellular Ca2+ increases, PDGF production were completely abolished by saralasin and neomycin, respectively. We postulate that the increased production of PDGF by the vascular endothelium in response to high glucose and angiotensin II may participate in the development of the diabetic angiopathy.

Background We retrospectively analyzed hyaluronic acid (HA) concentrations in pleural fluid and evaluated its utility for the differential diagnosis of malignant pleural mesothelioma (MPM). Methods Pleural fluid HA concentrations were measured in 334 patients, including 50, 48, 85, 18, 86, 6, and 41 patients with MPM, benign asbestos pleurisy (BAP), lung cancer (LC), other malignant conditions (OMCs), infectious pleuritis (IP), collagen disease (CD), and other conditions, respectively. Results The median (range) HA concentrations in pleural fluid were 78,700 (7920–2,630,000)ng/ml in the MPM group, 35,950 (900–152,000)ng/ml in the BAP group, 19,500 (2270–120,000)ng/ml in the LC group, 14,200 (900–101,000)ng/ml in the OMC group, 23,000 (900–230,000)ng/ml in the IP group, 24,600 (9550–80,800)ng/ml in the CD group, and 8140 (900–67,800)ng/ml in the other diseases group. HA levels were significantly higher in the MPM group than in the other groups. Receiver operating characteristic (ROC) analysis revealed an area under the ROC curve value of 0.832 (95% confidence interval, 0.765–0.898) for the differential diagnosis of MPM. With a cutoff value of 100,000ng/ml, the sensitivity and specificity were 44.0 and 96.5%, respectively. In the MPM group, HA values were significantly higher for the epithelioid subtype than for the sarcomatous subtype ( p =0.007), and higher in earlier stages (I and II) than in advanced stages (III and IV) ( p =0.007). Conclusions A diagnosis of MPM should be strongly considered in patients with pleural fluid HA concentrations exceeding 100,000ng/ml.

We present two cases of relapsed adenocarcinoma of the lung: a 50-year-old male and a 67-year-old male. Both patients had previously been treated with platinum-containing systemic chemotherapy. In both cases, significant clinical efficacy was demonstrated with combination chemotherapy consisting of pemetrexed, carboplatin, and bevacizumab as salvage treatment. Adverse events were mild. This regimen might be a viable therapeutic option even after heavy treatment such as platinum-containing chemotherapy, especially for patients with preserved organ function and good performance status.

YOSHIDA, M. and ASANO, M. Direct Compression by Megadolichobasilar Anomaly as a Cause of Trigeminal Neuralgia, A Case Diagnosed by MRI. Tohoku J. Exp. Med., 1994, 172 (4), 327-332 A 49 year-old man with trigeminal neuralgia caused by megadolichobasilar anomaly was described. The patient having neuralgic attacks in the second branch of the right trigeminal nerve for two and a half years showed the angiographic evidence of a tortuous and elongated vertebrobasilar artery and MRI of the brain clearly visualized the root entry zone of the nerve having been compressed by the main trunk of ectatic basilar artery. Cases of trigeminal neuralgia due to the compression by the basilar artery itself have been rarely described previously. In order to evaluate trigeminal neuralgia, MRI is essential to determine the relationship of the involvedsite of nerve to the pathogenic artery.

We report a case with a history of occupational asbestos exposure in which malignant pleural mesothelioma (MPM) was suspected clinically and diagnosed postmortem as pleural involvement of extrapulmonary small cell carcinoma (SCC). An 85-year-old man with a 65 pack-year history of smoking was referred to our hospital in June 2011. The patient had been exposed to asbestos in the iron production industry over the course of 30 years, and an irregular thickening of the right pleura was observed on chest CT at a medical check-up. The patient had a history of chronic hepatitis C and had been undergone transurethral resection for urothelial bladder cancer five times since 2006. Chest CT revealed neoplastic thickening of the right pleura, which had grown over 6 months (figure 1). The CT scan demonstrated bilateral pleural plaques, but no mass-like lesion in other organs, including the lungs, or mediastinal lymphadenopathy. The patient was suspected as having MPM and scheduled for thoracoscopic pleural biopsy, but his general condition worsened rapidly and he …

Background —It has been suggested that intracellular Ca 2+ overload in cardiac myocytes leads to the development of diabetic cardiomyopathy. Troglitazone, an insulin-sensitizing agent, is a promising therapeutic agent for diabetes and has been shown to prevent diabetes-induced myocardial changes. To elucidate the underlying mechanism of troglitazone action on cardiac myocytes, the effects of troglitazone on voltage-dependent Ca 2+ currents were examined and compared with classic Ca 2+ antagonists (verapamil and nifedipine). Methods and Results —Whole-cell voltage-clamp techniques were applied in single guinea pig atrial myocytes. Under control conditions with CsCl internal solution, the voltage-dependent Ca 2+ currents consisted of both T-type ( I Ca,T ) and L-type ( I Ca,L ) Ca 2+ currents. Troglitazone effectively reduced the amplitude of I Ca,L in a concentration-dependent manner. Troglitazone also suppressed I Ca,T , but the effect of troglitazone on I Ca,T was less potent than that on I Ca,L . The current-voltage relationships for I Ca,L and the reversal potential for I Ca,L were not altered by troglitazone. The half-maximal inhibitory concentration of troglitazone on I Ca,L measured at a holding potential of −40 mV was 6.3 μmol/L, and 30 μmol/L troglitazone almost completely inhibited I Ca,L . Troglitazone 10 μmol/L did not affect the time courses for inactivation of I Ca,L and inhibited I Ca,L mainly in a use-independent fashion, without shifting the voltage-dependency of inactivation. This effect was different from those of verapamil and nifedipine. Troglitazone also reduced isoproterenol- or cAMP-enhanced I Ca,L . Conclusions —These results demonstrate that troglitazone inhibits voltage-dependent Ca 2+ currents (T-type and L-type) and then antagonizes the effects of isoproterenol in cardiac myocytes, thus possibly playing a role in preventing diabetes-induced intracellular Ca 2+ overload and subsequent myocardial changes.

It is unclear whether the abnormal relaxation seen in diabetes is due to decreased levels of nitric oxide (NO) and how eicosapentaenoic acid (EPA, C20:5 omega 3) affects the endothelial production of NO. We investigated the effects of EPA ethyl ester (EPA-E) and elevated glucose on NO production by human endothelial cells (HUE). EPA-E (0.3 mM) significantly enhanced [NO2] production and the intracellular concentration of free Ca2+ within 3 min after EPA-E was added to the cultures. High levels of glucose (27.5 mM) significantly increased endothelial glucose, sorbitol and fructose, and inhibited [NO2-] production. However, EPA-E (0.3 mM) prevented the inhibition of [NO2-] production due to the activation of the Ca(2+)-calmodulin system of NO synthase. EPA-E decreased the glucose-mediated inhibition of NO production by HUE. These results suggest this agent might ameliorate endothelial dysfunction associated with diabetes.

The acute effects of beraprost sodium (sodium (±)-(1R ∗ , 2R, 3aS ∗ , 8bS ∗ )-2, 3, 3a 8b-tetrahydro-2-hydroxy-l-((E)-(3S ∗ )-3-hydroxy-4-methylI-octen-6-yny1] -1H-cyclopenta [b] bensofuran-5-butyrate), a stable analogue of prostaglandin I 2 which works as a vasodilator and anti-platelet agent, were investigated in patients with non-insulin dependent diabetes mellitus. Its effects on the dorsal pedis artery were examined using a new real-time two-dimensional Doppler ultrasonographic technique and by laser blood flowmetry. Before and 60 min after oral administration of beraprost sodium (Dolner ® 40 μg) and elastase (Elaszym ® 1800 U), the cross-sectional area (CSA) of the dorsal pedis artery and its blood flow index (BFI), calculated from the maximum flow velocity and area, were determined. Dermal microcirculatory blood volume (MBV) was also measured by laser blood flowmetry. In the beraprost sodium group, the CSA, BFI and MBV were significantly increased, while in the elastase group, no significant changes were observed. These result suggest that beraprost sodium has a beneficial effect on diabetic macro- and microangiopathy.

The present study was undertaken to investigate the efficacy of a new, highly purified (purity greater than 91%), ethyl esterification product from natural eicosapentaenoic acid (EPA-E, C20:5 omega 3) in patients with type II diabetes mellitus (NIDDM). Hemodynamic changes were assessed at the level of the dorsalis pedis artery using an ultrasonic color Doppler duplex system before and after oral administration of EPA-E at a dose of 1800 mg/day for 48 weeks. The cross-sectional area of the dorsalis pedis artery increased significantly from 2.5 +/- 0.2 to 3.9 +/- 0.4 mm2 (48 weeks, mean +/- SE, p < 0.05). Moreover, EPA-E improved the clinical symptom (coldness, numbness) as well as the vibration perception threshold sense of the lower extremities [from 32.1 +/- 8.5 to 16.1 +/- 4.8 (48 weeks) microns]. A significant decrease of serum triglycerides was also noted by EPA-E administration. Furthermore, significant decrease of the excretion of albumin in urine [from 24.4 +/- 3.3 to 13.9 +/- 1.8 (48 weeks) mg/g.Cr, p < 0.05]. The results of this study suggest that EPA-E has significant beneficial effects on diabetic neuropathy and serum lipids as well as other diabetic complications such as nephropathy and macroangiopathy.

Ibudilast is a prostacyclin-mediated vasodilator and antiplatelet agent. The hemodynamic effects of ibudilast were evaluated in 41 patients with non-insulin-dependent diabetes mellitus by means of two-dimensional Doppler ultrasonography and laser Doppler blood flowmetry. Before and one hour after oral administration of ibudilast (10 mg), or elastase (1800 U) as a control, the cross-sectional area (CSA) of the dorsal pedis artery, its blood flow index (BFI), and dermal microcirculatory blood volume (MBV) were measured. In the ibudilast group, all of the parameters (CSA, BFI, and MBV) significantly increased as compared with the elastase group. These data suggest that ibudilast is effective in amelio rating diabetic macroangiopathy and microangiopathy of the lower limbs.

A 67-year-old man with SIADH complicated by slowly progressing autonomic failure was described. The patient noticed constipation at the age of 57. In the following years, he suffered from urinary incontinence, depletion of sweating, impotence, sleeplessness with snore, and dizziness while walking. Physical examination revealed a masked oily face with slight cerebellar disturbance. Abnormality of autonomic function tests was recognized and he was diagnosed as Shy-Drager syndrome with gradually progressing, diffuse autonomic failure accompanied by slight cerebellar ataxia and Parkinsonism. Both serum sodium level and plasma osmotic pressure were reduced, whereas daily sodium excretion was more than 100mEq and urinary osmolality was about 500mOsm/kgH2O. His renal function was intact, and the adrenocortical and thyroid hormone levels were normal, then criteria of SIADH was fulfilled. SIADH was thought to have occurred on the basis of Shy-Drager syndrome. Water load test showed failure of adequate water diuresis, but intravenous phenytoin administration following the water load test ameliorated the diuresis to normal. The relationship between plasma osmolality and the ADH response indicates that ADH was adequately secreted in response to the increase in plasma osmolality but not suppressed in response to the decrease in plasma osmolality below 280mOsm/kgH2O. These results suggest that ADH synthesis in the hypothalamus and its secretion from the pituitary gland were both intact. The response of ADH secretion to the orthostatic hypotension induced by head-up tilt was quite blunted, being compatible with Shy-Drager Syndrome. Sleep disturbance was studied by polysomnography and laryngoscopy, and was revealed to be based upon severe sleep apnea due to incomplete paralysis of the bilateral vocal cords. Sleep apnea due to vocal cord paralysis is sometimes found to be complicated in patients with multiple system atrophy (MSA) including Shy-Drager syndrome, and is known as Gerhardt syndrome. This is the first report on a case of Shy-Drager syndrome complicated with SIADH and bilateral vocal cord paralysis. In this case, SIADH is caused by impaired afferent pathways from baroreceptors to the hypothalamus, which transfer inhibitory stimuli on ADH secretion. It is suggested that Shy-Drager syndrome should be considered one of the causes of SIADH.