Insulin resistance assessed by short insulin tolerance test and its association with obesity and insulin resistance-related parameters in humans: A pilot randomized trial.

The aim of this study was to examine the association of insulin resistance (evaluated by the short insulin tolerance test [SITT]) with parameters related to obesity and insulin resistance. We prospectively recruited controls and patients with type 2 diabetes mellitus (T2DM), subjected them to the SITT, and calculated the K indices of the intravenous insulin tolerance test (KITT(iv)) and the subcutaneous insulin tolerance test (KITT(sc)). We compared KITT(iv) results between the volunteers and patients and examined its correlation with KITT(sc). We also examined the association of KITT(iv) with obesity, insulin resistance-related parameters, and the insulin dose required for glycemic control. A total of 24 participants (seven controls and 17 patients with T2DM) were studied. The mean KITT(iv) was significantly lower in patients with T2DM than in the controls (2.5%±2.1% vs. 4.5%±1.8%). In all participants, KITT(iv) was significantly correlated with the homeostasis model assessment for insulin resistance (HOMA-IR) values (r = -0.601, p<0.05) but not with KITT(sc) (p = 0.62). KITT(iv) was correlated positively with the serum adiponectin concentration, but negatively with the visceral fat area and serum concentrations of tumor necrosis factor-α and branched-chain amino acids. In patients with T2DM, KITT(iv) and HOMA-IR values were significantly correlated with the total insulin dose required for glycemic control. Insulin resistance evaluated using KITT(iv) was correlated with the HOMA-IR values, but not with the resistance evaluated using KITT(sc). The degree of insulin resistance was associated with biomarkers, such as adiponectin, tumor necrosis factor-α, branched-chain amino acids, the visceral fat area, and the dose of insulin required for glycemic control.

[A CHILD CASE OF EGOMA (PERILLA FRUTESCENS) ALLERGY DUE TO SCHOOL LUNCH, PROBABLY CAUSED BY PERCUTANEOUS SENSITIZATION].

Herein, we report the case of a 7-year-old girl with a history of atopic dermatitis because of infancy. Her grandfather grew Egoma (Perilla frutescens), and her family frequently consumed food items prepared using Egoma; however, she never consumed them because she did not enjoy these food items; she experienced vomiting, facial swelling, and oral discomfort upon ingesting Egoma during school lunch for the first time. Her food oral challenge test was positive, as well as a skin-prick test with sesame powder. Egoma antigen protein was extracted and reacted with patient serum by immunoblotting, which detected a positive band of approximately 26kDa. She was brought up in an environment with high exposure to Egoma; hence, she most likely developed an allergy to Egoma because of percutaneous sensitization. This is the first time an Egoma allergen analysis has been conducted in Japan, and we consider it to be a valuable case.

Underdiagnosis of cardiac sarcoidosis by ECG and echocardiography in cases of extracardiac sarcoidosis.

Background: Although screening with 12-lead electrocardiography and transthoracic echocardiography for cardiac involvement has been recommended for patients with biopsy-proven extracardiac sarcoidosis, cardiac sarcoidosis has been reported even in patients with normal electrocardiography and echocardiography findings. We investigated the prevalence and characteristics of these patient cohorts. Methods: We studied 112 consecutive patients (age, 55±17 years, 64% females) with biopsy-proven extracardiac sarcoidosis who had undergone 18F-fluorodeoxyglucose positron emission tomography and cardiac magnetic resonance imaging for cardiac sarcoidosis evaluation. The patients were categorised as those showing normal findings both in electrocardiography and transthoracic echocardiography (normal group) and those showing abnormal findings in one or both examinations (abnormal group). Results: 33 (29%) and 79 (71%) patients were categorised into the normal and abnormal groups, respectively, of which 6 (18%) and 43 (54%) patients, respectively, were diagnosed with cardiac sarcoidosis (p<0.01). Of these six patients in the normal group, two with multiple-organ sarcoidosis showed clinical deterioration of cardiac involvement and required steroid therapy; three with small cardiac involvement showed natural remission over follow-up assessments; and one underwent steroid therapy and showed an improvement in the left ventricular ejection fraction to within normal limits. Conclusions: The prevalence of cardiac sarcoidosis in patients with biopsy-proven extracardiac sarcoidosis and normal electrocardiography and transthoracic echocardiography findings was ∼20%. Electrocardiography and transthoracic echocardiography may not detect cardiac sarcoidosis in patients without conduction and morphological abnormalities. However, some of these patients may subsequently show clinically manifested cardiac sarcoidosis. Physicians should be mindful of this population.

The Impact of Ascidian (Halocynthia roretzi)-derived Plasmalogen on Cognitive Function in Healthy Humans: A Randomized, Double-blind, Placebo-controlled Trial.

OBJECTIVES: Plasmalogen, phospholipids with previously shown associations with dementia, has attracted attention as a substance found in some studies to improve cognitive function. The effects of ascidian-derived plasmalogens on cognitive performance improvement were assessed in a randomized, double-blind, placebo-controlled study including Japanese adult volunteers with mild forgetfulness. METHODS: Participants consumed either the active food containing ascidian-derived plasmalogen (1 mg as plasmalogen) or the placebo food for 12 weeks, and their cognitive performance was assessed by Cognitrax. Participants were randomly allocated into the intervention (ascidian-derived plasmalogen; 8 males, and 17 females; 45.6 ± 11.1 years) or the placebo (9 males, and 15 females; mean age, 46.4 ± 10.8 years) group. RESULTS: Compared to the placebo group, the intervention group showed a significant increase score in composite memory (eight weeks: 3.0 ± 16.3 points, 12 weeks: 6.7 ± 17.5 points), which was defined as the sum of verbal and visual memory scores. CONCLUSIONS: These results indicate the consumption of ascidian-derived plasmalogen maintains and enhances memory function. This study was registered at the University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR, registry no. UMIN000026297). This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Host-parasite relationships between seabirds and the haemadipsid leech Chtonobdella palmyrae (Annelida: Clitellata) inhabiting oceanic islands in the Pacific Ocean.

The duognathous haemadipsid leeches of the genus Chtonobdella show a trans-oceanic distribution throughout the Indo-Pacific region. Although passive long-distance dispersal (LDD) of Chtonobdella leeches by birds has been suggested, little is known about the host-parasite relationships between avian hosts and Chtonobdella leeches. In the current study, we investigated Chtonobdella leech infestations of the eyes and other mucus membranes of migratory procellariiform seabirds, Pterodroma hypoleuca and Oceanodroma tristrami, captured at six locations in the Bonin Islands, Honshu and Okinawa Island, Japan. Analyses of the partial sequences of 18S rRNA, 28S rRNA, and mitochondrial cytochrome c oxidase subunit I (COI) and morphological examination of the specimens demonstrated that the Chtonobdella leeches belonged to Chtonobdella palmyrae, which is indigenous to Palmyra Atoll in the Northern Line Islands. A dominant COI sequence type was observed in samples from all six sites; therefore, C. palmyrae almost surely dispersed approximately 1000 km by infesting the eyes and mucus membranes of procellariiform seabirds. The host-parasite relationships between procellariiform seabirds and C. palmyrae provide explicit evidence of the LDD of duognathous haemadipsid leeches. The taxonomic status of Haemadipsa zeylanica ivosimae from the Volcano Islands is also briefly discussed.

[SUMMER-TYPE HYPERSENSITIVITY PNEUMONITIS CAUSED BY A HUMIDIFIER INDUCED IN SPRING, IN A 5-YEAR-OLD GIRL LIVING IN FUKUSHIMA-A CASE REPORT].

A 5-year-old girl living in Koriyama, Fukushima Prefecture was admitted in April with cough persisting for 1 month and fever. Chest X-ray showed diffuse ground-glass shadows in both lungs. After treatment with antibiotics, her fever went down on the 2nd day, and her cough subsided gradually. She was discharged on the 7th day, but her symptoms relapsed on the 8th day. Due to her worsening symptoms, she was readmitted on the 16th day. Chest CT scans showed enhancement of interstitial density. Serum anti-Trichosporon asahii antibody was positive. Her symptoms rapidly improved on a steroid regimen, and she was discharged on the 23th day. She was diagnosed as having summer-type hypersensitivity pneumonitis (SHP). She was instructed not to use a moldy humidifier and not to go to her grandmother's 57 years old wooden house. She has had no symptom after discharge. However, suspected mold was not found at her grandmother's house, and a provocation test there was negative. The HLA typing of the patient showed HLA-DQ8, which was previously described as SHP-sensitive.

[Multidisciplinary Treatment Aids Long-Term Stage â £ Pancreatic Cancer Survival-A Case Report].

A 56-year-old man presented at a local hospital with nausea, vomiting, epigastric pain, and white stool. CT scan showed hypovascular mass in pancreatic uncinate process and multiple peritoneal nodules. The diagnosis was stage Ⅳ pancreatic cancer(unresectable), and the patient underwent chemotherapy with GEM plus nab-PTX. He also claimed a severe cancer pain at presentation and was prescribed oxycodone 60 mg/day. After 43 months of chemotherapy, the duodenum was obstructed by tumor growth on CT scan, then he underwent duodenal stent placement. He eventually needed a total of 3 duodenal stenting for re-obstruction. He could keep adequate oral intake after the treatment. He also suffered from severe pain by progressed tumor, then underwent celiac plexus block and palliative radiation therapy(20 Gy/5 Fr). Afterwards his cancer pain has been under control. He underwent chemotherapy with FOLFIRINOX for next step. A patient with stage Ⅳ pancreatic cancer may survive for a long period with adequate QOL as a result of multidisciplinary treatment.

Analysis of Complexation Interactions between Metal Ions and Drugs under Pseudo-physiological pH Conditions by a High-throughput Screening Method Using a Solid-phase Extraction Cartridge.

A high-throughput screening method for the complexation between metal ions and drugs was established by combining solid-phase extraction (SPE) using a nitrilotriacetic acid (NTA) modified silica spin cartridge with subsequent HPLC analysis. First, a test metal ion solution was passed through the NTA cartridge, then a test drug solution diluted in phosphate buffered saline (pH 7.4) was passed through the metal-chelated NTA cartridge. The complexation behavior between the metal and the drug on the NTA cartridge was evaluated by HPLC quantification of the drug in the SPE eluate. Comprehensive analysis of the complexation behavior between 11 different metal ions and 55 drugs showed that Cu2+, Ni2+, Co2+, Zn2+, Cr3+ and Fe3+ formed complexes with 12, 5, 4, 2, 1 and 1 kinds of drugs, respectively. Bromazepam selectively formed complexes with Cu2+, Ni2+ and Co2+.

Successful implantation of leadless pacemaker in patient with the Günther Tulip inferior vena cava filter.

Leadless pacemakers have many advantages for some patients in preventing lead- and pocket-related complications. The traveling of the femoral vein is important in the context of normal approach site choice for leadless pacemakers. In this case, the leadless pacemaker could be successfully implanted without disrupting the inferior vena cava filter by using intravascular ultrasound in a hemodialysis patient with complete atrioventricular block and atrial fibrillation who had obstruction of the bilateral subclavian and right femoral veins, and travel abnormality of the left common iliac vein. .

Effects of MaquiBright® on improving eye dryness and fatigue in humans: A randomized, double-blind, placebo-controlled trial.

This study aims to investigate the effects of MaquiBright®, also known as BrightSight®, a standardized maqui berry extract, on improving eye dryness and fatigue in Japanese subjects (aged 30-60 years) experiencing eye dryness, eye fatigue, and ≥4 h of visual display terminal (VDT) work daily. Seventy-four participants were equally but randomly assigned to either a MaquiBright® (MB) or a placebo (P) group, wherein each participant consumed one capsule daily for 4 weeks of the appropriate treatment (MaquiBright® 60 or 0 mg). Eye dryness and fatigue were measured using the Schirmer's test, tear break-up time (BUT) test, pupillary response, and flicker test before intake and 4 weeks after intake. Furthermore, subjective symptoms were assessed using the Visual Analogue Scale (VAS) method and the Dry Eye-related Quality of Life Score (DEQS) questionnaire. The MB group demonstrated a significantly higher lacrimal fluid production in both eyes (increased 6.4 ±â€¯8.1 mm, P = 0.005) in Schirmer's test compared to the P group before VDT load (playing a video game) at 4 weeks after intake. In the VAS method after VDT load, the reduction of subjective symptoms in eye fatigue (P = 0.047) and stiff shoulders (P = 0.035) were significantly higher in the MB group than in the P group as well as bothersome ocular symptoms (P = 0.037) by the DEQS. No adverse events were reported. Thus, the consumption of 60 mg of MaquiBright® per day for 4 weeks reduced eye dryness and seemed to alleviate eye fatigue.

Impact of Acacia bark extract tablets on the skin of healthy humans: a randomized, double-blind, placebo-controlled study.

This study investigated the effects of proanthocyanidins derived from Acacia (Acacia mearnsii) bark extract in healthy Japanese adult subjects experiencing uncomfortable skin symptoms. All subjects were randomly allocated into two groups (n = 33 each) using a computerized random-number generator. The subjects received either Acacia bark extract tablets or placebo for 8 weeks. Evaluations included water content in the stratum corneum, transepidermal water loss (TEWL), Skindex-16, dermatology life quality index (DLQI), visual analog scale for desire to scratch, and blood tests. At 4 weeks, the symptom/feeling score of DLQI, subjective symptoms related to uncomfortable skin, and the desire to scratch were significantly reduced in the intervention group than in the placebo group. At 8 weeks, the intervention group exhibited significantly lower TEWL on facial skin than that in the placebo group. In conclusion, the intake of Acacia bark extract tablets reduced TEWL and improved dry and uncomfortable skin.

A case-control questionnaire survey of decompression sickness risk in Okinawa divers.

BACKGROUND: Decompression sickness (DCS) is a rare condition that is often difficult to diagnose in deep-sea divers. Because of this, prevention and early diagnosis are important. In this case-control study, we examined the risk and preventive factors associated with DCS. METHODS: Our original questionnaire survey was conducted among 269 recreational divers in Okinawa. Divers who were diagnosed with DCS by a physician (n = 94) were compared with healthy recreational divers (n = 175). The questionnaire consisted of 30 items and included a dive profile. Odds ratios and multiple logistic regression analysis were used to estimate the relative risk of DCS. RESULTS: Logistic regression analysis revealed the following risk factors for DCS: a past history of DCS, drinking alcohol the evening before diving, indicating decompression stops, cold exposure after the dive, and maximum depth. Preventive factors included hydration before the dive, deep stops, safety stops and using nitrox gas. The results were reliable according to the Hosmer-Lemeshow and omnibus tests. CONCLUSION: We identified certain risk factors, together with their relative risks, for DCS. These risk factors may facilitate prevention of DCS among Okinawa divers.

Sustained Activation of Guanylate Cyclase-A with TDT, a Natriuretic Peptide Derivative, Exhibits Cardiorenal Protection in Dahl Salt-Sensitive Hypertensive Rats.

Heart failure often presents with prognosis-relevant impaired renal function. To investigate whether the chronic activation of guanylate cyclase-A (GC-A) protects both heart and kidney, we examined the effects of TDT, a neprilysin (NEP)-resistant natriuretic peptide (NP) derivative, on cardiac and renal dysfunction in Dahl salt-sensitive hypertensive (DS) rats. Pretreatment with NEP or NEP inhibitor did not influence GC-A activation by TDT both in vitro and in vivo, resulting in a long-acting profile of TDT compared with native human atrial NP (hANP). The repeated administration of TDT to DS rats suppressed the progress of cardiac hypertrophy, systolic/diastolic dysfunction, and proteinuria in a dose-dependent manner. Compared with vehicle and hANP, salt diet-induced podocyte injury was reduced by TDT, as analyzed by urinary podocalyxin concentration, renal expression of nephrin mRNA, and glomerular expression of desmin protein. Since glomerular TRPC6 plays detrimental roles in podocyte homeostasis, we examined the renal expression of TRPC6 in DS rats and found that salt diet upregulated the expression of TRPC6. Importantly, TRPC6 induction was significantly decreased in TDT-treated rats, compared with vehicle and hANP. Consistently, in primary-culture podocytes from DS rats, TDT inhibited ATP-induced calcium influx, similar to TRPC inhibitor SKF96365. Finally, TDT-mediated protection of podocytes was abolished by protein kinase G inhibitor KT5823. In conclusion, TDT treatment attenuated heart and kidney dysfunction, accompanied by podocyte protection through inhibition of TRPC6. Thus, long-acting NPs could be a new avenue for treatment of heart failure.

FANTOM5 CAGE profiles of human and mouse samples.

In the FANTOM5 project, transcription initiation events across the human and mouse genomes were mapped at a single base-pair resolution and their frequencies were monitored by CAGE (Cap Analysis of Gene Expression) coupled with single-molecule sequencing. Approximately three thousands of samples, consisting of a variety of primary cells, tissues, cell lines, and time series samples during cell activation and development, were subjected to a uniform pipeline of CAGE data production. The analysis pipeline started by measuring RNA extracts to assess their quality, and continued to CAGE library production by using a robotic or a manual workflow, single molecule sequencing, and computational processing to generate frequencies of transcription initiation. Resulting data represents the consequence of transcriptional regulation in each analyzed state of mammalian cells. Non-overlapping peaks over the CAGE profiles, approximately 200,000 and 150,000 peaks for the human and mouse genomes, were identified and annotated to provide precise location of known promoters as well as novel ones, and to quantify their activities.

Chemokine Ligand 5 (CCL5) Derived from Endothelial Colony-Forming Cells (ECFCs) Mediates Recruitment of Smooth Muscle Progenitor Cells (SPCs) toward Critical Vascular Locations in Moyamoya Disease.

The etiology and pathogenesis of moyamoya disease (MMD) are still obscure. Previous studies indicated that angiogenic chemokines may play an important role in the pathogenesis of the disease. Recently, it was discovered that peripheral blood-derived endothelial colony-forming cells (ECFCs) and smooth muscle progenitor cells (SPCs) have defective functions in MMD patients. Therefore, the interaction of ECFCs and SPCs, the precursors of two crucial cellular components of vascular walls, with some paracrine molecules is an intriguing subject. In this study, co-culture of ECFCs and SPCs from MMD patients and healthy normal subjects revealed that MMD ECFCs, not SPCs, are responsible for the defective functions of both ECFCs and SPCs. Enhanced migration of SPCs toward MMD ECFCs supported the role for some chemokines secreted by MMD ECFCs. Expression arrays of MMD and normal ECFCs suggested that several candidate cytokines differentially produced by MMD ECFCs. We selected chemokine (C-X-C motif) ligand 6 (CXCR6), interleukin-8 (IL8), chemokine (C-C motif) ligand 2 (CCL2), and CCL5 for study, based on the relatively higher expression of these ligands in MMD ECFCs and their cognate receptors in MMD SPCs. Migration assays showed that only CCL5 significantly augmented the migration activities of SPCs toward ECFCs. Treatment with siRNA for the CCL5 receptor (CCR5) abrogated the effect, confirming that CCL5 is responsible for the interaction of MMD ECFCs and SPCs. These data indicate that ECFCs, not SPCs, are the major players in MMD pathogenesis and that the chemokine CCL5 mediates the interactions. It can be hypothesized that in MMD patients, defective ECFCs direct aberrant SPC recruitment to critical vascular locations through the action of CCL5.

[Feasibility Study of a One-Day Educational Program to Train Advance Care Planning Facilitators(ACPFs)in Regional Areas].

Promoting advance care planning in regional areas is important. Education For Implementing End-of-Life Discussion(EFIELD) is a two-day educational program for Advance Care Planning Facilitators(ACPFs)developed by the National Center for Geriatrics and Gerontology. Unfortunately, some trainers experience difficulties implementing the content of the program, and some trainees feel the program is too long for implementation in many regional areas. The purpose of the research is to clarify the feasibility of ACPFs education using a one-day program in regional areas. The methods involved documenting the process of a one-day program from implementation to evaluation from May of 2015 to March of 2016 and then evaluating the effectiveness of the program 3 months after the implementation using meeting minutes from 7 local hospitals. The results indicated a need for 5 steps from program implementation to evaluation as well as 5 categories for final evaluation. The most important finding is that E-FIELD challenged trainers to shorten and simplify their expressions in order to teach the content more efficiently. The second finding is that Group for Promoting Advance Care Planning & End Of Life Discussion in Chita(GACPEL) activities encouraged ACPimplementation within each hospital. The limitations of this research are related to small regional areas. In conclusion, a one-day regional ACPFs educational program is feasible.

Touch cytology smear of an inflammatory hepatocellular adenoma displaying an unusual pattern: A case report.

The cytological diagnosis of hepatocellular adenoma (HCA) is difficult since it is a very rare tumor and lacks characteristic cytological features. We have just reported a case of inflammatory HCA that displayed an unusual histological pattern (Clin J Gastroenterol 8:426-434, 2015). A touch cytology smear sample was obtained from the surgical specimen, and it also exhibited very unique features. A 56-year-old male underwent partial hepatectomy for an inflammatory HCA (diameter: 1.4 cm) in the right posterior lobe of the liver. The cytological sample displayed a characteristic two-cell pattern. One type of cells contained thick cytoplasm, a high nucleus/cytoplasmic (N/C) ratio, and well-defined cytoplasmic borders. The other type demonstrated small pyknotic nuclei and a lower N/C ratio. The immunohistochemical staining pattern of the histological specimen suggested that the latter cells might have been undergoing apoptosis. We report a case of inflammatory HCA with characteristic features. To diagnose this type of variant, it is important to recognize the unique pattern described in this study. Diagn. Cytopathol. 2016;44:1074-1077. © 2016 Wiley Periodicals, Inc.

Silent Cerebral Ischemic Lesions After Catheter Ablation of Atrial Fibrillation in Patients on 5 Types of Periprocedural Oral Anticoagulation　- Predictors of Diffusion-Weighted Imaging-Positive Lesions and Follow-up Magnetic Resonance Imaging.

BACKGROUND: The aim of this study was to identify the predictors of silent cerebral ischemic lesions (SCIL) after catheter ablation of atrial fibrillation (AF) and to determine whether SCIL develop into cerebral infarcts in patients with 5 types of oral anticoagulants (OAC). METHODS AND RESULTS: We retrospectively studied 286 consecutive patients (median, 67 years; 208 male; paroxysmal/persistent/long-standing persistent AF [LSP-AF], 147/90/49) who received periprocedural OAC and underwent MRI after the procedure. Warfarin (n=46) was continued, while dabigatran (n=47), rivaroxaban (n=89), apixaban (n=87), and edoxaban (n=17) were discontinued on the day of the procedure. I.v. heparin was infused to maintain an activated clotting time of 300-350 s during the procedure. Fifty-eight SCIL in 40 patients (14.0%) were identified on diffusion-weighted MRI. On multivariate logistic analysis, LSP-AF and dabigatran use were significant positive predictors of SCIL (OR, 2.912 and 2.287; P=0.006 and 0.042, respectively). Among 34 patients with 49 SCIL undergoing follow-up MRI, 45 (91.8%) of the lesions disappeared and 4 lesions developed into chronic cerebral infarcts. The SCIL with development into infarcts had a larger lesion diameter than those without (median, 6.55 mm vs. 4.2 mm; P=0.002). CONCLUSIONS: LSP-AF and dabigatran use were independent risk factors for post-ablation SCIL in patients with uninterrupted warfarin and interrupted non-vitamin K antagonist OAC, but the majority of SCIL disappeared.

Immunomodulation in Middle-Aged Humans Via the Ingestion of Physta® Standardized Root Water Extract of Eurycoma longifolia Jack--A Randomized, Double-Blind, Placebo-Controlled, Parallel Study.

This study was aimed to investigate the capacity of a standardized root water extract of Eurycoma longifolia (Tongkat Ali, TA), Physta® to modulate human immunity in a middle-aged Japanese population. This randomized, double-blind, placebo-controlled, parallel study was conducted for 4 weeks. Eighty-four of 126 subjects had relatively lower scores according to Scoring of Immunological Vigor (SIV) screening. Subjects were instructed to ingest either 200 mg/day of TA or rice powder as a placebo for 4 weeks [TA and Placebo (P) groups] and to visit a clinic in Tokyo twice (weeks 0 and 4). SIV, immunological grade, immunological age, and other immune parameters were measured. Eighty-three subjects completed the study; 40 in the TA group and 41 in the P group were statistically analyzed, whereas two were excluded from the analyses. At week 4, the SIV and immunological grade were significantly higher in the TA group than those in P group (p < 0.05). The numbers of total, naïve, and CD4(+) T cells were also higher in the TA group than those in P group (p < 0.05). No severe adverse events were observed. The results suggest that ingestion of the root water extract of TA (Physta®) enhances comprehensive immunity in both middle-aged men and women. This study is registered in UMIN-CTR (UMIN000011753).