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1.  Plexiform schwannoma involving the trachea and recurrent laryngeal nerve: a case report 
Surgical Case Reports  2015;1(1):67.
Plexiform schwannoma is an infrequent variant of schwannoma characterized grossly and microscopically by multi-nodular growth. Although plexiform schwannoma has such growth patterns, it is a benign tumor as well as a conventional schwannoma. It rarely infiltrates adjacent organs or arises from the organ itself. In this report, we describe a case in which plexiform schwannoma involved the tracheal wall and left recurrent laryngeal nerve to a great extent. As it was expected to be difficult to achieve complete resection even if the longer tracheal resection were performed, we preserved the trachea and resected as much of the tumor as possible. This report is thought to be the first to describe plexiform schwannoma infiltrating or growing from the trachea. Although the treatment decisions we made might be controversial, we believed we could make an accurate diagnosis and adequate treatment decision through surgery.
Electronic supplementary material
The online version of this article (doi:10.1186/s40792-015-0070-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4560149  PMID: 26366364
Tracheal tumor; Mediastinal tumor; Plexiform schwannoma
2.  Mutations in SCN10A Responsible for a Large Fraction of Brugada Syndrome Cases 
The purpose of this study was to test the hypothesis that SCN10A variants contribute to the development of Brugada syndrome (BrS).
BrS is an inherited sudden cardiac death syndrome. Fewer than 35% of BrS probands have genetically identified pathogenic variants. Recent evidence has implicated SCN10A, a neuronal sodium channel gene encoding Nav1.8 in the electrical function of the heart.
Clinical analysis and direct sequencing of BrS-susceptibility genes were performed on 150 probands, family members and >200 healthy controls. Expression and co-immunoprecipitation studies were performed to functionally characterize the putative pathogenic mutations.
We identified 17 SCN10A mutations in 25 probands (20 M/5 F); 23 of the 25 (92.0%) displayed overlapping phenotypes. SCN10A mutations were found in 16.7% of BrS probands, approaching our yield for SCN5A mutations (20.1%). BrS patients with SCN10A mutations were more symptomatic and displayed significantly longer PR and QRS intervals than SCN10A negative BrS probands. The majority of mutations localized to the transmembrane-spanning regions. Heterologous co-expression of wild-type (WT) SCN10A with WT-SCN5A in HEK cells caused a near doubling of sodium channel current (INa) compared with WT-SCN5A alone. In contrast, co-expression of SCN10A mutants (R14L and R1268Q) with WT-SCN5A caused a 79.4% and 84.4% reduction in INa, respectively. Co-immunoprecipitation studies performed provide evidence for co-association of Nav1.8 and Nav1.5 in the plasma membrane.
Our study identifies SCN10A as a major susceptibility gene for BrS, thus greatly enhancing our ability to genotype and risk stratify probands and family members.
PMCID: PMC4116276  PMID: 24998131
Electrophysiology; Cardiac Arrhythmias; Brugada syndrome; Cardiac Conduction disease; Sudden Cardiac Death; Genetics
3.  Ketamine Causes Mitochondrial Dysfunction in Human Induced Pluripotent Stem Cell-Derived Neurons 
PLoS ONE  2015;10(5):e0128445.
Ketamine toxicity has been demonstrated in nonhuman mammalian neurons. To study the toxic effect of ketamine on human neurons, an experimental model of cultured neurons from human induced pluripotent stem cells (iPSCs) was examined, and the mechanism of its toxicity was investigated.
Human iPSC-derived dopaminergic neurons were treated with 0, 20, 100 or 500 μM ketamine for 6 and 24 h. Ketamine toxicity was evaluated by quantification of caspase 3/7 activity, reactive oxygen species (ROS) production, mitochondrial membrane potential, ATP concentration, neurotransmitter reuptake activity and NADH/NAD+ ratio. Mitochondrial morphological change was analyzed by transmission electron microscopy and confocal microscopy.
Twenty-four-hour exposure of iPSC-derived neurons to 500 μM ketamine resulted in a 40% increase in caspase 3/7 activity (P < 0.01), 14% increase in ROS production (P < 0.01), and 81% reduction in mitochondrial membrane potential (P < 0.01), compared with untreated cells. Lower concentration of ketamine (100 μM) decreased the ATP level (22%, P < 0.01) and increased the NADH/NAD+ ratio (46%, P < 0.05) without caspase activation. Transmission electron microscopy showed enhanced mitochondrial fission and autophagocytosis at the 100 μM ketamine concentration, which suggests that mitochondrial dysfunction preceded ROS generation and caspase activation.
We established an in vitro model for assessing the neurotoxicity of ketamine in iPSC-derived neurons. The present data indicate that the initial mitochondrial dysfunction and autophagy may be related to its inhibitory effect on the mitochondrial electron transport system, which underlies ketamine-induced neural toxicity. Higher ketamine concentration can induce ROS generation and apoptosis in human neurons.
PMCID: PMC4447382  PMID: 26020236
4.  Interactions between rat alveolar epithelial cells and bone marrow-derived mesenchymal stem cells: an in vitro co-culture model 
Bone marrow-derived mesenchymal stem cells (BMSCs) reduced the severity of acute lung injury after transplantation in multiple experimental studies, and several paracrine soluble factors secreted by the cells likely contribute to their therapeutic effect. The direct interactions between BMSCs and alveolar epithelial cells (AECs) may be an important part of their beneficial effects. Therefore, we assessed the interactions between BMSCs and AECs using a co-culture model of these two cell types from rats.
BMSCs and AECs were co-cultured using a Transwell system under the following conditions: (1) separated co-culture—AECs seeded on the insert and BMSCs in the base of the well; and (2) mixed co-culture—AECs on top of the monolayer of BMSCs on the culture insert and no cells in the base of the well. After 21 days of culture, the cells on the membrane of the culture insert were fixed and stained with antibodies against the receptor for advanced glycation end-products (RAGE), surfactant protein D (SP-D), and zona occludens protein-1, and then analyzed by confocal microscopy.
In the separated co-culture condition, the phenotype of the AECs was maintained for 21 days, and cluster formation of SP-D-positive cells was induced in the AEC monolayer. We also found cluster formations of phospholipid-positive cells covered with RAGE-positive epithelial cells. In the mixed co-culture condition, the BMSCs induced alveolar-like structures covered with an epithelial cell layer. To determine the effect of keratinocyte growth factor (KGF) on this three-dimensional structure formation, we treated the mixed co-cultures with siRNA for KGF. While KGF siRNA treatment induced a significant reduction in surfactant protein transcript expression, formation of the alveolar-like structure was unaffected. We also assessed whether Gap26, a functional inhibitor of connexin-43, could mitigate the effect of the BMSCs on the AECs. However, even at 300 μM, Gap26 did not inhibit formation of the alveolar-like structure.
BMSCs release soluble factors that help maintain and sustain the AEC phenotype for 21 days, and direct interaction between these two cell types can induce a cyst-like, three-dimensional structure covered with AECs.
Electronic supplementary material
The online version of this article (doi:10.1186/s40635-015-0053-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4480799  PMID: 26215817
Bone marrow-derived mesenchymal stem cell; Alveolar epithelial cell; Three-dimensional structures; Co-culture; Receptor for advanced glycation end-products; Surfactant protein D
5.  Flow Mediated Dilatation Is Reduced with the Progressive Stages of Glomerular Filtration Rate and Albuminuria in Type 2 Diabetic Patients without Coronary Heart Disease 
Journal of Diabetes Research  2015;2015:728127.
We aimed to clarify the usefulness of measuring the flow mediated dilatation (FMD) in patients with type 2 diabetes mellitus without and with coronary heart disease (CHD). The FMD was measured in 480 patients with type 2 diabetes and in 240 nondiabetic subjects. The FMD was significantly lower in the subjects with CHD (n = 145, 5.4 ± 3.2%) than in those without CHD (n = 95, 6.9 ± 3.5%) among the nondiabetic subjects. The FMD was also lower in the subjects both with CHD (n = 161, 5.6 ± 2.8%) and without CHD (n = 319, 6.1 ± 3.3%) among the patients with diabetes compared to those without both diabetes and CHD. The FMD showed a significant positive correlation with the estimated glomerular filtration rate (eGFR) in the diabetic patients without CHD, while there was no significant association in those with CHD. The FMD was significantly lower with the progressive stages of the GFR or albuminuria in the patients without CHD among those with diabetes, although the FMD was not different in those with CHD. In conclusion, the FMD is considered to be useful for the detection of atherosclerosis in patients with type 2 diabetes, even if overt macroangiopathy is not diagnosed.
PMCID: PMC4429217  PMID: 26064988
6.  Risk Factors for Migration, Fracture, and Dislocation of Pancreatic Stents 
Aim. To analyze the risk factors for pancreatic stent migration, dislocation, and fracture in chronic pancreatitis patients with pancreatic strictures. Materials and Methods. Endoscopic stent placements (total 386 times) were performed in 99 chronic pancreatitis patients with pancreatic duct stenosis at our institution between April 2006 and June 2014. We retrospectively examined the frequency of stent migration, dislocation, and fracture and analyzed the patient factors and stent factors. We also investigated the retrieval methods for migrated and fractured stents and their success rates. Results. The frequencies of stent migration, dislocation, and fracture were 1.5% (5/396), 0.8% (3/396), and 1.2% (4/396), respectively. No significant differences in the rates of migration, dislocation, or fracture were noted on the patient factors (etiology, cases undergoing endoscopic pancreatic sphincterotomy, location of pancreatic duct stenosis, existence of pancreatic stone, and approach from the main or minor papilla) and stent factors (duration of stent placement, numbers of stent placements, stent shape, diameter, and length). Stent retrieval was successful in all cases of migration. In cases of fractured stents, retrieval was successful in 2 of 4 cases. Conclusion. Stent migration, fracture, and dislocation are relatively rare, but possible complications. A good understanding of retrieval techniques is necessary.
PMCID: PMC4402177  PMID: 25945085
7.  Prognostic impact of vascular invasion and standardization of its evaluation in stage I non-small cell lung cancer 
Diagnostic Pathology  2015;10:17.
Patients with pathologic stage (p-Stage) IA non-small cell lung cancer (NSCLC) have a good survival rate because of possible curative resection. However, up to 10% of these patients relapse postoperatively. To identify unfavorable prognostic factors, we retrospectively analyzed the clinicopathological features of p-Stage IA disease, focusing on vascular invasion.
Of 467 patients with p-Stage I NSCLC, 335 were diagnosed with p-Stage IA or IB disease based on a lesion size ≤3 cm and the presence of pleural invasion (PL). Univariate and multivariate analyses of recurrence-free survival (RFS) were performed with age, sex, PL, and vascular invasion (blood vessel invasion [v] and lymphatic vessel invasion [ly]) as variables. To examine vascular invasion, hematoxylin-eosin (HE), Elastica van Gieson staining, and immunostaining with anti-podoplanin antibody were performed. The presence or absence of v and ly was recorded; the number of involved vessels was counted. Survival rates were obtained using the Kaplan–Meier method and log-rank test. Multivariate analyses were performed using the Cox proportional hazards model.
RFS differed significantly between patients with no or one involved blood vessel (0 v or 1 v) and those with ≥2 involved vessels (≥2 v). Similarly, RFS differed significantly between patients with no lymphatic vessel involvement (0 ly) and those with one involved lymphatic vessel (1 ly). Thus, BVI(+) and BVI(−) were defined as ≥2 v and 0 v + 1 v, and LVI(+) and LVI(−) as ≥1 ly and 0 ly, respectively. BVI and LVI together represented tumor vessel invasion (TVI). On multivariate analyses, PL and TVI were independently associated with recurrence. Additionally, patients with p-Stage IA TVI(+) disease had a comparable recurrence rate to those with p-Stage IB disease.
Similar to PL, TVI is an important factor increasing the likelihood of recurrence. As HE staining alone is insufficient for evaluating vascular invasion, specific staining is necessary. Moreover, patients with p-Stage IA TVI(+) disease had a recurrence rate comparable to those with p-Stage IB disease; therefore, further studies should aim to elucidate whether patients with p-Stage IA TVI(+) disease should be administered postoperative chemotherapy similar to that received by p-Stage IB patients.
Virtual Slides
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PMCID: PMC4413537  PMID: 25884820
Non-small cell carcinoma; Stage I; Blood vessel invasion; Lymphatic vessel invasion; Hematoxylin-eosin staining; Elastica van Gieson staining; Podoplanin; D2-40
8.  Anagliptin in the treatment of type 2 diabetes: safety, efficacy, and patient acceptability 
Anagliptin is a novel dipeptidyl peptidase-4 inhibitor that has been available in Japan since 2012. Because anagliptin is not generally used in countries other than Japan, there are only a small number of reports investigating the effects of anagliptin. In the present article, we review the safety and efficacy of anagliptin according to data obtained from preclinical trials and postmarketing studies. The usual dose of anagliptin is 200 mg daily, and increases in the dose up to 400 mg daily have been approved in cases in which the blood glucose–lowering effect is insufficient. In a Phase II trial, the reduction in the HbA1c values from baseline after 12 weeks monotherapy with 200 mg and 400 mg of daily anagliptin was 0.75%±0.50% and 0.82%±0.46%, respectively, and more than 40% of the subjects receiving anagliptin at a dose of 200 mg or 400 mg daily achieved an HbA1c level below 6.9%. Furthermore, the levels of HbA1c, fasting blood glucose, and postprandial blood glucose were significantly decreased at 52 weeks compared with the baseline values in a Phase III trial investigating the effects of anagliptin included in combination therapy with other oral antidiabetic agents. In a pooled analysis of Phase II and Phase II/III trials, the goal achievement rates for an HbA1c level below 7.0% at 12 weeks were 40.3%, 39.4%, 30.0%, and 34.8% in the patients treated with anagliptin combined with α-glucosidase inhibitors, thiazolidinediones, sulfonylureas, and biguanides, respectively. Meanwhile, the serum lipid concentrations significantly improved after the administration of anagliptin in a pooled analysis of Phase III trials, and no serious adverse effects have been reported in preclinical trials. Therefore, the use of anagliptin in patients with type 2 diabetes is considered to be safe and effective for both monotherapy and combination therapy.
PMCID: PMC4370682  PMID: 25834461
dipeptidyl peptidase-4 inhibitor; type 2 diabetes mellitus; monotherapy; combination therapy; adverse effect
9.  A Case of Pancreatic Intraepithelial Neoplasia That Was Difficult to Diagnose Preoperatively 
Case Reports in Oncology  2015;8(1):30-36.
A 63-year-old female patient presented to a local physician with pain in her back and epigastric region. An abdominal computed tomography (CT) scan revealed a pancreatic tumor, and the patient was referred to our hospital. Multiple imaging studies that included ultrasonography (US), CT, MRI, and endoscopic US revealed a cystic lesion 3–4 cm in size with node-like projections in the body of the pancreas. The distal main pancreatic duct was also found to be dilated. Endoscopic retrograde pancreatography revealed an irregular stenosis of the main pancreatic duct proximal to the cystic lesion, and malignancy was suspected. The patient was preoperatively diagnosed with pancreatic ductal carcinoma concomitant with intraductal papillary mucinous carcinoma, and a distal pancreatectomy was performed. Rapid pathological diagnosis during surgery revealed positive surgical margins for pancreatic intraepithelial neoplasia (PanIN). Further resection was performed twice, her surgical margin was positive and total pancreatectomy was ultimately conducted. Histopathological findings revealed diffuse microinvasive cancerous lesions corresponding to PanIN-2 (moderate dysplasia) to PanIN-3 (carcinoma in situ) throughout the pancreas. PanIN involves microlesions of the ductal epithelium that may precede pancreatic cancer. Ascertaining changes in PanIN using images provided by diagnostic modalities such as CT and US is challenging. Ductal stenosis and distal cystic lesions resulting from atrophy and fibrosis of pancreatic tissue were noted around PanIN. Considering the possibility of PanIN, a precancerous lesion during differential diagnosis will help to improve early detection and prognosis for patients with pancreatic cancer.
PMCID: PMC4342858  PMID: 25762925
Pancreatic intraepithelial neoplasia; Pancreas cancer; Pancreatic duct stenosis; Pancreatic cyst; Diagnosis
10.  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
11.  Amenorrhea as a rare drug-related adverse event associated with everolimus for pancreatic neuroendocrine tumors 
World Journal of Gastroenterology : WJG  2014;20(42):15920-15924.
The patient was an asymptomatic 43-year-old woman. Abdominal ultrasonography and enhanced computed tomography showed a tumor lesion accompanied by multiple cystic changes in the liver and the pancreatic tail. Endoscopic ultrasound-fine needle aspiration was performed on the pancreatic tumor lesion and revealed pancreatic neuroendocrine tumor (PNET). As it was unresectable due to multiple liver metastases, the decision was made to initiate treatment with everolimus and transcatheter arterial chemoembolization. The patient ceased menstruating after the start of everolimus administration. When the administration was discontinued due to interstitial lung disease, menstruation resumed, but then again stopped with everolimus resumption. An association between everolimus and amenorrhea was highly suspected. Amenorrhea occurred as a rare adverse event of everolimus. As the younger women might be included in PNETs patients, we should put this adverse event into consideration.
PMCID: PMC4229560  PMID: 25400479
Amenorrhea; Everolimus; Neuroendocrine tumor; Pancreas; Adverse event
12.  Association Mapping and Validation of QTLs for Flour Yield in the Soft Winter Wheat Variety Kitahonami 
PLoS ONE  2014;9(10):e111337.
The winter wheat variety Kitahonami shows a superior flour yield in comparison to other Japanese soft wheat varieties. To map the quantitative trait loci (QTL) associated with this trait, association mapping was performed using a panel of lines from Kitahonami’s pedigree, along with leading Japanese varieties and advanced breeding lines. Using a mixed linear model corrected for kernel types and familial relatedness, 62 marker-trait associations for flour yield were identified and classified into 21 QTLs. In eighteen of these, Kitahonami alleles showed positive effects. Pedigree analysis demonstrated that a continuous pyramiding of QTLs had occurred throughout the breeding history of Kitahonami. Linkage analyses using three sets of doubled haploid populations from crosses in which Kitahonami was used as a parent were performed, leading to the validation of five of the eight QTLs tested. Among these, QTLs on chromosomes 3B and 7A showed highly significant and consistent effects across the three populations. This study shows that pedigree-based association mapping using breeding materials can be a useful method for QTL identification at the early stages of breeding programs.
PMCID: PMC4215981  PMID: 25360619
13.  Accessory Pancreatic Duct-Portal Vein Fistula: A Rare Complication of Chronic Pancreatitis during Endoscopic Retrograde Cholangiopancreatography 
Case Reports in Gastroenterology  2014;8(2):291-296.
Pancreatitis, hemorrhage and perforation are the most frequent complications associated with endoscopic retrograde cholangiopancreatography (ERCP). We report a rare case of accessory pancreatic duct-portal vein fistula, which occurred during ERCP in a patient with chronic pancreatitis. To our knowledge, this is the first report of accessory pancreatic duct-portal vein fistula created during ERCP by the use of a guide wire.
PMCID: PMC4241643  PMID: 25473386
Accessory pancreatic duct-portal vein fistula; Chronic pancreatitis; Endoscopic retrograde cholangiopancreatography
14.  Recurrence of atrial fibrillation within three months after pulmonary vein isolation for patients with paroxysmal atrial fibrillation: Analysis using external loop recorder with auto-trigger function 
Journal of Arrhythmia  2014;31(2):88-93.
Pulmonary vein isolation (PVI) via catheter ablation has been shown to be a highly effective treatment option for patients with symptomatic paroxysmal atrial fibrillation (AF). The recurrence of AF within 3 months after PVI is not considered to be the result of ablation procedure failure, because early recurrence of AF is not always associated with late recurrence. We examined the usefulness of an external loop recorder with an auto-trigger function (ELR-AUTO) for the detection of atrial fibrillation following PVI to characterize early recurrence and to determine the implications of AF occurrence within 3 months after PVI.
Fifty-three consecutive symptomatic patients with paroxysmal AF (age 61.6±12.6 years, 77% male) who underwent PVI and were fitted with ELR-AUTO for 7±2.0 days within 3 months after PVI were enrolled in this study.
Of the 33 (62.2%) patients who did not have AF recurrence within 3 months after PVI, only 1 patient experienced AF recurrence at 12 months. Seven (35%) of the 20 patients who experienced AF within 3 months of PVI experienced symptomatic AF recurrence at 12 months. The sensitivity, specificity, positive predictive value, and negative predictive value of early AF recurrence for late recurrence were 87.5%, 71.1%, 35.0%, and 96.9%, respectively.
AF recurrence measured by ELR-AUTO within 3 months after PVI can predict the late recurrence of AF. Freedom from AF in the first 3 months following ablation significantly predicts long-term AF freedom. ELR-AUTO is useful for the detection of symptomatic and asymptomatic AF.
PMCID: PMC4550125  PMID: 26336538
Atrial fibrillation; Pulmonary vein isolation; External loop recorder
15.  Clinicopathological features and EGFR gene mutation status in elderly patients with resected non–small-cell lung cancer 
BMC Cancer  2014;14:610.
The rapid aging of the population in Japan has been accompanied by an increased rate of surgery for lung cancer among elderly patients. It is thus an urgent priority to map out a treatment strategy for elderly patients with primary lung cancer. Although surgical resection remains standard treatment for early stage non–small-cell lung cancer (NSCLC), it is now essential to confirm the status of epidermal growth factor receptor (EGFR) gene mutations when planning treatment strategies. Furthermore, several studies have reported that EGFR mutations are an independent prognostic marker in NSCLC. However, the relations between age group and the molecular and pathological characteristics of NSCLC remain unclear. We studied the status of EGFR mutations in elderly patients with NSCLC and examined the relations of EGFR mutations to clinicopathological factors and outcomes according to age group.
A total of 388 consecutive patients with NSCLC who underwent complete tumor resection in our hospital from 2006 through 2008 were studied retrospectively. Formalin-fixed, paraffin-embedded tissue sections were used to isolate DNA from carcinoma lesions. Mutational analyses of EGFR gene exons 19, 20, and 21 and KRAS gene exons 12 and 13 were performed by loop-hybrid mobility shift assay, a highly sensitive polymerase chain reaction-based method.
EGFR mutations were detected in 185 (47.7%) and KRAS mutations were detected in 33 (8.5%) of the 388 patients. EGFR mutations were found in a significantly higher proportion of patients younger than 80 years (younger group; 178/359, 49.6%) than in patients 80 years or older (older group; 7/29, 24.1%) (P = 0.008). In contrast, KRAS mutations were more common in the older group (6/29, 20.7%) than in the younger group (27/359, 7.5%) (P = 0.014). The older group showed a trend toward a higher rate of 5-year overall survival among elderly patients with EGFR mutations (100%) than among those with wild-type EGFR (66.2%), but the difference was not significant.
Our results suggest that the EGFR status of patients with NSCLC differs between patients 80 years or older and those younger than 80 years. EGFR mutation status might be a prognostic marker in elderly patients with completely resected NSCLC.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-610) contains supplementary material, which is available to authorized users.
PMCID: PMC4161910  PMID: 25152277
16.  An Intraductal Papillary Neoplasm of the Bile Duct at the Duodenal Papilla 
Case Reports in Oncology  2014;7(2):417-421.
In recent years, the disease concept of intraductal papillary neoplasm of the bile duct (IPNB) has been attracting attention as a biliary lesion that is morphologically similar to intraductal papillary mucinous neoplasm (IPMN), which is considered to be a counterpart of IPMN. However, there are few reports on IPNB, and a consensus regarding the features of this disease is thus lacking. We experienced an extremely rare case of IPNB occurring in the bile duct at the duodenal papilla, which is a tumor presentation that has not previously been reported. Herein, we report this interesting case and discuss the possible association between IPMN and IPNB.
PMCID: PMC4130820  PMID: 25126070
Intraductal papillary neoplasm of the bile duct; Duodenal papilla; Intraductal papillary mucinous neoplasm; Intraductal ultrasound; Peroral cholangioscopy
17.  Severe Pulmonary Suppuration with Infection-Induced Systemic Inflammatory Response Syndrome following Tongue Cancer Surgery in a Patient Undergoing Tocilizumab Therapy for Rheumatoid Arthritis 
Case Reports in Dentistry  2014;2014:649086.
A 65-year-old woman with rheumatoid arthritis treated by tocilizumab (TCZ) presented with tongue squamous cell carcinoma. While surgery was performed without any complications the aspiration pneumonia rapidly worsened by postoperative day 2 and severe pulmonary suppuration in the right lung field with infection-induced systemic inflammatory response syndrome (SIRS) was diagnosed. Antibiotic and respirator treatment improved her condition. The anti-inflammatory effect of TCZ may mask the symptoms and signs of severe infection with SIRS.
PMCID: PMC4020557  PMID: 24872899
18.  Effects of switching from prandial premixed insulin therapy to basal plus two times bolus insulin therapy on glycemic control and quality of life in patients with type 2 diabetes mellitus 
The effects of switching from prandial premixed insulin therapy (PPT) injected three times a day to basal plus two times bolus insulin therapy (B2B) on glycemic control and quality of life were investigated in patients with type 2 diabetes mellitus.
The clinical course was prospectively observed during the first 16 weeks after switching to B2B (insulin glargine plus insulin glulisine before breakfast and dinner) in 27 subjects previously treated with PPT using 50/50 premixed insulin. The Diabetes Treatment Satisfaction Questionnaire (DTSQ) was administered at the start and end of the study.
The glycated hemoglobin (HbA1c) level (8.3%±1.8% to 8.2%±1.1%) and the DTSQ score did not change between the start and end of the study. An improvement in HbA1c level was found in nine (33%) subjects. The change in HbA1c showed a significant negative correlation with baseline HbA1c, and was significantly better in patients with a baseline HbA1c >8.0% than in those with an HbA1c ≤8.0% (−0.9±2.0 versus 0.3±0.6, respectively, P=0.02). The change in DTSQ score representing treatment satisfaction was significantly greater in patients whose HbA1c level was improved than in those in whom it was not (2.7±3.6 versus −0.8±3.5, P=0.04).
B2B was noninferior to PPT with regard to HbA1c levels in patients with type 2 diabetes mellitus. B2B should be considered particularly for subjects whose glycemic control is poor despite PPT.
PMCID: PMC4003145  PMID: 24790413
type 2 diabetes mellitus; insulin therapy; basal plus two times bolus insulin therapy; prandial premixed insulin therapy; Diabetes Treatment Satisfaction Questionnaire
19.  Significance of AT1 Receptor Independent Activation of Mineralocorticoid Receptor in Murine Diabetic Cardiomyopathy 
PLoS ONE  2014;9(3):e93145.
Diabetes mellitus (DM) has deleterious influence on cardiac performance independent of coronary artery disease and hypertension. The objective of the present study was to investigate the role of the renin-angiotensin-aldosterone system, especially angiotensin II type 1a receptor (AT1aR) and mineralocorticoid receptor (MR) signaling, in left ventricular (LV) dysfunction induced by diabetes mellitus (DM).
Methods and Results
DM was induced by intraperitoneal injection of streptozotocin (200 mg/kg BW) in wild-type (WT) or AT1aR knockout (KO) male mice, and they were bred during 6 or 12 weeks. Some KO mice were administered the MR antagonist eplerenone (100 mg/kg body weight). At 6 weeks, LV diastolic function was impaired in WT-DM, but preserved in KO-DM. At that time point MR mRNA expression was upregulated, NADPH oxidase subunit (p47phox) and glutathione peroxidase (GPx1) mRNA expression were upregulated, the staining intensities of LV tissue for 4-hydroxy-2-nonenal was stronger in immunohistochemistry, the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) positive cells was increased, Bcl-2 protein expression was significantly downregulated, and the expression of SERCA2a and phosphorylated phospholamban was depressed in WT-DM, while these changes were not seen in KO-DM. At 12 weeks, however, these changes were also noted in KO-DM. Eplerenone arrested those changes. The plasma aldosterone concentration was elevated in WT-DM but not in KO-DM at 6 weeks. It showed 3.7-fold elevation at 12 weeks even in KO-DM, which suggests “aldosterone breakthrough” phenomenon. However, the aldosterone content in LV tissue was unchanged in KO-DM.
DM induced diastolic dysfunction was observed even in KO at 12 weeks, which was ameliorated by minelarocorticoid receptor antagonist, eplerenone. AT1-independent MR activation in the LV might be responsible for the pathogenesis of diabetic cardiomyopathy.
PMCID: PMC3963989  PMID: 24664319
20.  Risk factors for proximal migration of biliary tube stents 
AIM: To analyze the risk factors for biliary stent migration in patients with benign and malignant strictures.
METHODS: Endoscopic stent placement was performed in 396 patients with bile duct stenosis, at our institution, between June 2003 and March 2009. The indications for bile duct stent implantation included common bile duct stone in 190 patients, malignant lesions in 112, chronic pancreatitis in 62, autoimmune pancreatitis in 14, trauma in eight, surgical complications in six, and primary sclerosing cholangitis (PSC) in four. We retrospectively examined the frequency of stent migration, and analyzed the patient factors (disease, whether endoscopic sphincterotomy was performed, location of bile duct stenosis and diameter of the bile duct) and stent characteristics (duration of stent placement, stent type, diameter and length). Moreover, we investigated retrieval methods for migrated stents and their associated success rates.
RESULTS: The frequency of tube stent migration in the total patient population was 3.5%. The cases in which tube stent migration occurred included those with common bile duct stones (3/190; 1.6%), malignant lesions (2/112; 1.8%), chronic pancreatitis (4/62; 6.5%), autoimmune pancreatitis (2/14; 14.3%), trauma (1/8; 12.5%), surgical complications (2/6; 33.3%), and PSC (0/4; 0%). The potential risk factors for migration included bile duct stenosis secondary to benign disease such as chronic pancreatitis and autoimmune pancreatitis (P = 0.030); stenosis of the lower bile duct (P = 0.031); bile duct diameter > 10 mm (P = 0.023); duration of stent placement > 1 mo (P = 0.007); use of straight-type stents (P < 0.001); and 10-Fr sized stents (P < 0.001). Retrieval of the migrated stents was successful in all cases. The grasping technique, using a basket or snare, was effective for pig-tailed or thin and straight stents, whereas the guidewire cannulation technique was effective for thick and straight stents.
CONCLUSION: Migration of tube stents within the bile duct is rare but possible, and it is important to determine the risk factors involved in stent migration.
PMCID: PMC3921514  PMID: 24574806
Migration; Endoscopic biliary stent; Risk factor; Endoscopic retrograde cholangiopancreatography; Retrieval
21.  A Case of a Giant Growing Serous Cystic Neoplasm of the Pancreas 
Case Reports in Oncology  2014;7(1):47-51.
Because of the widespread use of diagnostic imaging in recent years, serous cystic neoplasm (SCN) of the pancreas can often be detected even when small in diameter. SCNs are usually benign, but it is important to differentiate them from other types of cystic tumors. We report a case of a giant growing SCN that posed a challenge in differential diagnosis.
PMCID: PMC3934618  PMID: 24575016
Serous cystic neoplasm; Pancreas; Giant size; Diagnosis
22.  Effect of surrounding texture on the pursuit-pursuing illusion 
i-Perception  2014;5(1):20-40.
The pursuit-pursuing illusion is a visual illusion where a circular object placed in the centre of a radial pattern consisting of thin sectors is seen to move in the pursuit eye movement direction. The present study investigates the role of the surrounding texture, replacing the sectors with random dots or stripes in an orientation that was orthogonal, parallel or oblique to the pursuit direction. The experiments demonstrate that the acquired illusory effect was large for the orthogonal stripes. However, each surrounding texture produces a relatively smaller effect than the radial sectors. These results suggest that a hypothesis based on the property of a centre-surround relative-motion detector cannot fully explain the illusion and that the radial stimulus structure itself plays an important role in this illusion.
PMCID: PMC4130505  PMID: 25165514
motion illusion; smooth pursuit; eye movement; relative motion
23.  Effects of Angiotensin II Type 1 receptor blocker and adiponectin on adipocyte dysfunction in stroke-prone spontaneously hypertensive rats 
Hypoadiponectinemia in lipoatrophy may be related to worsening of hypertension in stroke-prone spontaneously hypertensive rats (SHRSP). One of the beneficial effects of candesartan (Angiotensin II Type 1 receptor blocker) for preventing hypertension may be increasing of adiponectin due to improvement of adipocyte dysfunction. In this study, we determined the effects of candesartan or adiponectin on pathophysiologic features and adipocyte dysfunction in SHRSP.
Candesartan was administered to male SHRSP from 16 to 20 weeks of age (2 mg/kg/day). Adiponectin was cloned and intravenously administered to male SHRSP from 16 to 20 weeks of age. We examined biological parameters, as well as the expression and release of adipokines.
The SHRSP exhibited severe atrophy of visceral fat and progression of severe hypertension. The expression and release of leptin and adiponectin were impaired at 6 and 20 weeks of age. Candesartan suppressed the development of lipoatrophy and reduced the incidence of stroke at 20 weeks of age. Candesartan also enhanced the expression of adiponectin and leptin by inducing the overexpression of peroxisome proliferator activated receptor γ. Circulating level of leptin was significantly higher in candesartan group than in the control group, whereas adiponectin was similar in both groups. Intravenous administration of adiponectin resulted in enhancement of adiponectin expression in adipose tissue, but no remarkable effects were found in pathophysiology in SHRSP.
Our results indicate that candesartan protects against hypertension and adipocyte dysfunction in SHRSP. The induction of leptin expression appeared to be important factor in the inhibition of stroke lesions, whereas adiponectin was not a major regulator of blood pressure in SHRSP with genetic hypertension. Further studies are needed to elucidate the role of the renin–angiotensin system in adipose tissue dysfunction in relation to hypertensive end-organ damage.
PMCID: PMC3750705  PMID: 23876211
Stroke-prone spontaneously hypertensive rats; Adipose tissue; Renin–angiotensin system; Angiotensin II type I receptor blocker; Lipoatrophy; Adipokines
24.  The Prevalence of the Risk Factors for Atherosclerosis among Type 2 Diabetic Patients Is Greater in the Progressive Stages of Chronic Kidney Disease 
Nephron Extra  2013;3(1):66-72.
The prevalence of the risk factors for atherosclerosis, other than diabetes mellitus, among type 2 diabetic patients with different stages of chronic kidney disease (CKD) determined by glomerular filtration rate (GFR) was investigated.
The prevalence of ten risk factors (age ≥65 years, history of smoking, male gender, obesity, albuminuria, hypertension, hypercholesterolemia, hypo-HDL-cholesterolemia, hyperuricemia and anemia) was determined in 2,107 Japanese type 2 diabetic patients with different stages of CKD (six stages according to GFR).
The risk factors for age ≥65 years and male gender were found in 49 and 62% of the study subjects, respectively. The percentages of subjects with a current history of smoking, obesity, albuminuria, hypertension, hypercholesterolemia, hypo-HDL-cholesterolemia, hyperuricemia and anemia were 35, 44, 47, 70, 61, 13, 21 and 26%, respectively. The prevalence of age ≥65 years, male gender, albuminuria, hypertension, hypo-HDL-cholesterolemia, hyperuricemia and anemia was greater in the later stages of GFR, whereas the prevalence of hypercholesterolemia and obesity did not differ between stages. The prevalence of a current history of smoking was lower in the later stages of GFR. The cumulative number of risk factors increased from 3.1 to 6.8 in the later stages of GFR.
Among type 2 diabetic patients with CKD, the total number of risk factors increases with the progression of renal dysfunction. It is important to pay attention to newly recognized risk factors for hyperuricemia and anemia, in addition to hypertension, albuminuria and hypo-HDL-cholesterolemia, in monitoring diabetic patients with later stages of CKD.
PMCID: PMC3728600  PMID: 23904855
Chronic kidney disease; Hyperuricemia; Atherosclerosis; Anemia; Diabetic nephropathy
25.  Vildagliptin is Effective for Glycemic Control in Diabetic Patients Undergoing either Hemodialysis or Peritoneal Dialysis 
Diabetes Therapy  2013;4(2):321-329.
Vildagliptin can be used in patients with type 2 diabetes mellitus and renal impairment. However, there have been few reports investigating the clinical effectiveness of vildagliptin in diabetic patients undergoing hemodialysis. No previous studies have evaluated the use of vildagliptin in patients undergoing peritoneal dialysis. The authors determined the usefulness of vildagliptin for treating type 2 diabetic patients receiving chronic dialysis, including peritoneal dialysis.
A retrospective study of ten diabetic patients undergoing peritoneal dialysis and five diabetic patients undergoing hemodialysis who were treated with 50 mg/day of vildagliptin was performed. Clinical parameters were investigated for a period of 6 months starting from the vildagliptin therapy.
The hemoglobin A1c (HbA1c) levels were significantly reduced after baseline in both the peritoneal dialysis and hemodialysis groups, whereas the hemoglobin levels did not change during the follow-up period. The mean change in the HbA1c level (ΔHbA1c) was −0.6 ± 0.9% and −0.5 ± 0.7% among the patients undergoing peritoneal dialysis and hemodialysis, respectively. The glycated albumin (GA) levels were also significantly reduced compared with baseline in the peritoneal dialysis group, although the serum albumin levels did not change. The mean change in the GA level (ΔGA) was −3.4 ± 3.1% and −2.1 ± 2.5% among the patients undergoing peritoneal dialysis and hemodialysis, respectively. Stepwise multivariate analyses demonstrated the level of HbA1c at baseline to be significantly associated with the ΔHbA1c and that the level of GA at baseline was significantly associated with the ΔGA.
Vildagliptin exhibits effectiveness in patients with type 2 diabetes mellitus undergoing peritoneal dialysis or hemodialysis. The degree of improvement in the HbA1c and GA levels was dependent on these levels at baseline, similar to the findings of previous reports of subjects without end-stage kidney disease.
PMCID: PMC3889330  PMID: 23801219
Diabetes; End-stage kidney disease; Hemodialysis; Hemoglobin A1c; Glycated albumin; Peritoneal dialysis; Renal impairment; Type 2 diabetes mellitus; Vildagliptin

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