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Neuroendocrine carcinoma (NEC) of the head and neck is a rare type of malignancy, accounting for only 0.3% of all head and neck cancers, and its clinicopathological and genomic features have not been fully characterized. We conducted a retrospective analysis of 27 patients with poorly differentiated NEC of the head and neck seen at our institution over a period of 15 years. Patient characteristics, adopted therapies, and clinical outcomes were reviewed based on the medical records. Pathological analysis and targeted sequencing of 523 cancer-related genes were performed using evaluable biopsied/resected specimens based on the clinical data. The most common tumor locations were the paranasal sinus (33%) and the oropharynx (19%). Eighty-one percent of the patients had locally advanced disease. The 3-year overall survival rates in all patients and in the 17 patients with locally advanced disease who received multimodal curative treatments were 39% and 53%, respectively. Histologically, large cell neuroendocrine carcinoma was the predominant subtype (58% of evaluable cases), and the Ki-67 labeling index ranged from 59 to 99% (median: 85%). Next-generation sequencing in 14 patients identified pathogenic/likely pathogenic variants in TP53, RB1, PIK3CA-related genes (PREX2, PIK3CA, and PTEN), NOTCH1, and SMARCA4 in six (43%), three (21%), two (14%), two (14%), and one (7%) patients, respectively. Sequencing also detected the FGFR3-TACC3 fusion gene in one patient. The median value of the total mutational burden (TMB) was 7.1/Mb, and three patients had TMB ≥ 10. Regardless of the aggressive pathological features, our data revealed favorable clinical characteristics in the patients with locally advanced disease who received curative treatment. The lower TP53 and RB1 mutation prevalence rates compared to those described for small cell lung cancer suggests the biological heterogeneity of NEC in different parts of the body. Furthermore, the FGFR3-TACC3 fusion gene and mutations in genes encoding the components of the NOTCH and PI3K/AKT/mTOR pathways found in our study may be promising targets for NEC of the head and neck.

BACKGROUND/AIM Lenvatinib is standard therapy for radioiodine-refractory differentiated thyroid cancer (RR-DTC), although the optimal timing for starting treatment is still controversial. The aim of this study was to evaluate the prognostic impact of baseline tumour size (BTS) in patients with RR-DTC treated with lenvatinib. PATIENTS AND METHODS Fifty-one RR-DTC patients who had at least one measurable lesion and treated with lenvatinib were retrospectively analysed. BTS was defined as the sum of the longest dimensions of all measurable target lesions. RESULTS Median progression-free survival (PFS) and overall survival (OS) in the larger BTS (≥42 mm) group were shorter than those in the smaller (

BACKGROUND Eribulin is widely used for the treatment of breast cancer and soft-tissue sarcoma (STS). Previous studies identified the pre-treatment absolute lymphocyte count, baseline neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein concentration as potential prognostic markers in patients with breast cancer treated with eribulin. However, prognostic factors for eribulin treatment in patients with STS have not been identified. PATIENTS AND METHODS This was a retrospective analysis of data collected prospectively from 53 patients who were treated with eribulin for recurrent or metastatic STS between March 2016 and August 2019. Univariate and multivariate analyses were performed to determine the predictive factors of durable clinical benefit, progression-free survival, and overall survival. RESULTS L-Sarcoma histology [hazard ratio (HR)=28.20, 95% confidence intervaI (CI)=1.67-476.00; p=0.021] and pre-treatment NLR

Cytotoxic chemotherapy, including cyclophosphamide, vincristine, and dacarbazine (CVD) therapy, is widely used to treat metastatic pheochromocytoma and paraganglioma. Because these diseases are rare, studies are needed to establish treatment strategies. This was a single-center and retrospective study to analyze the efficacy of chemotherapy for patients with metastatic pheochromocytoma and paraganglioma diagnosed in 1983-2020. Clinical characteristics, tumor volume response, biochemical response based on catecholamine level, overall survival, and progression-free survival were evaluated. Patients with a complete response or partial response in tumor volume or catecholamine level were classified as responders. Sixteen patients were administered chemotherapy for a median of 16.5 cycles (interquartile range, 10-42). The tumor volume response was classified as follows: partial response (N = 4), stable disease (N = 9), and progressive disease (N = 3) (disease control rate = 81%). The biochemical responses were as follows: complete response (N = 2), partial response (N = 5), no change (N = 3), and progressive disease (N = 1) (disease control rate = 91%). The 5-year survival rate was 50% (95% confidence interval [CI], 21-74%) and median overall survival was 4.4 years (95% CI, 2.4 years-not reached). Overall survival and progression-free survival between responders and nonresponders were not statistically different. One patient developed myelodysplastic syndrome during CVD therapy. In conclusion, chemotherapy achieved disease control among more than half of patients, although survival did not differ between responders and nonresponders. Further fundamental research and prospective trials are needed to analyze the efficacy of CVD therapy.

Background Head and neck squamous cell carcinoma (HNSCC) is a geriatric cancer. However, older adult patients are frequently underrepresented in large clinical trials. Aims The aim of this study is to assess the efficacy and safety of the EXTREME regimen (platinum + fluorouracil + cetuximab) in older and younger adult patients with HNSCC. Methods and results Patients with recurrent or metastatic HNSCC treated with the EXTREME regimen were retrospectively analyzed. We compare the efficacy and safety in older (aged ≥70 years) younger (aged

Background Age and sex based coronary artery calcium score (CAC) percentiles have been used to improve coronary artery disease (CAD) risk prediction. However, the main limitation of the CACs percentiles currently in use is that they are often based on single studies. We performed a pooled analysis of all available studies that reported on CAC percentiles, in order to develop more generalizable age and sex nomograms. Methods PubMed/Medline and Embase were searched for studies that reported nomograms of age and sex-based CACs percentiles. Studies were included if they reported data collected among asymptomatic individuals without a history of cardiovascular disease. Absolute CACs for each specific percentile stratum were pooled and new percentiles were generated taking into account the sample size of the study. Results We found 831 studies, of which 12 met the inclusion criteria. Data on CACs percentiles of 134,336 Western and 33,488 Asians were pooled separately, rendering a weighted CACs percentile nomogram available at https://www.calciumscorecalculator.com . Our weighted percentiles differed by up to 24% from the nomograms in use today. Conclusions Our pooled age and sex based CACs percentiles based on over 155,000 individuals should provide a measure of risk that is more applicable to a wider population than the ones currently in use and hopefully will lead to better risk assessment and treatment decisions.

Aim Trefoil factor 3 (TFF3) is a small peptide that is involved in mucosal protection. TFF3 is widely expressed in multiple tissues including kidney tissue. Previous studies have reported that the levels of urinary TFF3 are significantly increased in patients with chronic kidney disease. The aim of this study is to detect the TFF3 mRNA in kidney and elucidate the relationship between renal TFF3 mRNA and tubulointerstitial fibrosis in IgA nephropathy (IgAN). Methods We investigated the renal mRNA expression of TFF3 by real‐time PCR analysis in biopsy specimens from patients with IgAN, other glomerulonephritis (OGN) and minor glomerular abnormalities (MGA). We also determined the renal localization of TFF3 and the levels of urinary TFF3 by immunostaining and ELISA, respectively. Results The renal TFF3 mRNA expression was significantly associated with the urinary TFF3 secretion and the tubulointerstitial fibrosis score in the IgAN group alone. Immunostaining of the renal specimen of IgAN patients revealed that TFF3 is located in the renal tubular epithelial cells. The locations were almost the same as those that showed uromodulin positivity; specifically, the thick ascending limb (TAL) of the loop of Henle and the early portion of the distal tubule. The urinary TFF3 levels were positively correlated with the levels of urinary biomarkers of tubulointerstitial injury in such patients. Conclusion Renal TFF3 mRNA is associated with renal tubulointerstitial fibrosis in IgAN patients. The TFF3 located in the renal tubular epithelial cells may play a role in the progression of tubulointerstitial fibrosis in IgAN patients., Summary at a Glance Trefoil factor 3 is a peptide that, generally speaking, has protective functions in epithelial biology. This study reports that TFF3 is increased in IgA nephropathy and correlates with injury. Whether TFF3 is functionally a counter‐regulatory, protective factor or whether its overexpression denotes a pathogenic role remains an outstanding question.

Background/Aim: Neutrophil-to-lymphocyte ratio (NLR) has been reported to be associated with poor prognosis for radioactive iodine ablation refractory differentiated thyroid cancer (RR-DTC). Little is known whether NLR can be a tumor marker for RR-DTC patients treated with lenvatinib. Patients and Methods: We retrospectively analyzed RR-DTC patients treated with lenvatinib. NLR was calculated at 4 points before and during lenvatinib treatment. Results: The median NLR value increased at the start of lenvatinib treatment, compared to 6 months prior to initiation of lenvatinib treatment. The median overall survival was significantly longer in patients with the lower NLR (< 3) at the start of lenvatinib treatment. The median NLR values decreased when the patients achieved best tumor response, and increased again upon disease progression. Conclusion: NLR values vary before and during lenvatinib treatment, suggesting that this ratio can reflect disease activity of RR-DTC. NLR can supportively be used as a tumor marker of RR-DTC and an indicator for starting lenvatinib treatment.

The hallmark features of type 2 mucosal immunity include intestinal tuft and goblet cell expansion initiated by tuft cell activation. How infectious agents that induce type 2 mucosal immunity are detected by tuft cells is unknown. Published microarray analysis suggested that succinate receptor 1 (Sucnr1) is specifically expressed in tuft cells. Thus, we hypothesized that the succinate–Sucnr1 axis may be utilized by tuft cells to detect certain infectious agents. Here we confirmed that Sucnr1 is specifically expressed in intestinal tuft cells but not in other types of intestinal epithelial cells, and demonstrated that dietary succinate induces tuft and goblet cell hyperplasia via Sucnr1 and the tuft cell-expressed chemosensory signaling elements gustducin and Trpm5. Conventional mice with a genetic Sucnr1 deficiency (Sucnr1−/−) showed diminished immune responses to treatment with polyethylene glycol and streptomycin, which are known to enhance microbiota-derived succinate, but responded normally to inoculation with the parasitic worm Nippostrongylus brasiliensis that also produces succinate. Thus, Sucnr1 is required for microbiota-induced but not for a generalized worm-induced type 2 immunity.

// Erina Takai 1, * , Shinichi Yachida 1, * , Kyoko Shimizu 2 , Junji Furuse 3 , Emi Kubo 4 , Akihiro Ohmoto 1 , Masami Suzuki 1 , Ralph H. Hruban 5 , Takuji Okusaka 4 , Chigusa Morizane 4 , Toru Furukawa 6 1 Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan 2 Department of Gastroenterology, Institute of Gastroenterology, Tokyo Women’s Medical University, Tokyo, Japan 3 Department of Medical Oncology, Kyorin University School of Medicine, Mitaka, Japan 4 Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan 5 Department of Pathology and Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA 6 Institute for Integrated Medical Sciences, Tokyo Women’s Medical University, Tokyo, Japan * These authors have contributed equally to this work Correspondence to: Toru Furukawa, email: furukawa.toru@twmu.ac.jp Keywords: pancreatic cancer, familial predisposition, BRCA2, ATM, PALB2 Received: July 10, 2016 Accepted: September 29, 2016 Published: October 6, 2016 ABSTRACT Clinicopathologic and genetic features of familial pancreatic cancer (FPC) in Asian countries remain largely unknown. The main purpose of this study was to determine the prevalence of FPC and to define causative FPC-predisposition genes in a Japanese cohort with pancreatic ductal adenocarcinoma (PDAC).We reviewed 1,197 patients with a pathologically proven PDAC and found that 88 (7.3%) were FPC patients who had at least one first-degree relative with PDAC. There were no significant differences between the FPC cases and sporadic cases in terms of gender, age, tumor location, stage, family history of any cancer except PDAC, and personal history of smoking, other cancers, diabetes mellitus and chronic pancreatitis. In the FPC patients, we then investigated the prevalence of germline mutations in 21 genes associated with hereditary predispositions for pancreatic, breast and ovarian cancers by means of the next-generation sequencing using a custom multiple-gene panel. We found that eight (14.5%) of the 54 FPC patients with available germline DNA carried deleterious mutations in BRCA2 , PALB2 , ATM , or MLH1 . These results indicate that a significant fraction of patients with PDAC in Japan have a family history of pancreatic cancer, and some of them harbor deleterious causative mutations in known FPC predisposition genes.

Each olfactory sensory neuron (OSN) expresses a single odorant receptor (OR) gene from the class I or class II repertoire in mice. The mechanisms that regulate OR class choice in OSNs remain unknown. Here, we show that the transcription factor Bcl11b determines the OR class to be expressed in OSNs. Both loss- and gain-of-function analyses demonstrate that class I is a default fate of OSNs and that Bcl11b dictates a class II OR choice by suppressing the effect of the J-element, a class I-OR enhancer. We further demonstrate that OSN-specific genetic manipulations of Bcl11b bias the OR class choice, generating mice with “class I-dominant” and “class II-dominant” noses, which display contrasting innate olfactory behaviors to two distinct aversive odorants. Overall, these findings reveal a unique transcriptional mechanism mediating a binary switch for OR class choice that is crucial to both the anatomical and functional organization of the olfactory system., Enomoto et al. show that a transcription factor Bcl11b overrides a default fate of olfactory sensory neurons, class I, to dictate the class II by suppressing a class I-olfactory receptor (OR) enhancer. This study presents a transcriptional binary switch that chooses the OR class, which in turn functionally organizes the olfactory system in mice.

Objectives The median age of patients with pancreatic ductal adenocarcinoma (PDAC) is approximately 70 years, and PDAC rarely affects individuals younger than 40 years. Here, we investigated clinicopathologic features and genetic background of PDAC occurring in young patients (age ≤ 40 years) to determine whether any difference exists in comparison with those of older patients (>40 years). Methods We reviewed 908 patients with pathologically proven PDAC for clinicopathologic characteristics. In addition, we performed targeted sequencing of germline variants for 49 genes that are associated with a hereditary predisposition for cancer in 9 young patients with available DNA. Results Among the 908 patients, a total of 17 were diagnosed at age younger than 40 years. There were no significant differences between young and old groups in terms of sex, smoking history, tumor location, Union for International Cancer Control stage, family histories of any cancer and PDAC in first-degree relatives, and medical history of other cancer. Targeted sequencing analysis demonstrated no definite "pathogenic" variants. Conclusions The clinicopathologic features in young patients were generally similar to those in older patients. The rarity of family history of PDAC and the sequencing analysis for germline variants suggest that hereditary factors might have a weak, if any, relationship with early-onset PDAC.

Background Coronary artery calcium (CAC) is associated with a risk of coronary heart disease. The prevalence and distribution of the CAC score have been examined in Western countries, but few studies have been performed in Asia, and especially in Japan. The goal of this study was to investigate CAC scores in an asymptomatic Japanese population. Methods CAC score and risk factors were analyzed in 1834 asymptomatic subjects who underwent lung cancer screening computed tomography. Results CAC was present in 26.9% of all the subjects, 29.8% of the males, and 17.1% of the females. In all age groups, the CAC score was higher in males. In multivariate analysis, male gender [odds ratio (OR) 2.461, 95% confidence interval (CI) 1.361–4.452, p = 0.002], aging (OR 1.102, 95% CI 1.081–1.123, p p = 0.002), and fasting glucose (OR 1.008, 95% CI 1.002–1.015, p = 0.012) were significantly associated with a CAC score >100. Conclusion The results of this study provide a pattern of CAC distribution based on age and gender in asymptomatic Japanese subjects. This pattern was similar to that in Western countries, although the absolute CAC scores were lower. High CAC scores were associated with male gender, aging, dyslipidemia, and fasting glucose.

Association between pretransplant iron overload determined by bone marrow pathological analysis and bacterial infection

Introduction. Trefoil factor family (TFF) peptides are increased in serum and urine in patients with chronic kidney disease (CKD). However, whether the levels of TFF predict the progression of CKD remains to be elucidated.Methods. We determined the TFF levels using peptide-specific ELISA in spot urine samples and performed a prospective cohort study. The association between the levels of urine TFFs and other urine biomarkers as well as the renal prognosis was analyzed in 216 CKD patients (mean age: 53.7 years, 47.7% female, 56.9% with chronic glomerulonephritis, and mean eGFR: 58.5 ml/min/1.73 m2).Results. The urine TFF1 and TFF3 levels significantly increased with the progression of CKD stages, but not the urine TFF2 levels. The TFF1 and TFF3 peptide levels predicted the progression of CKD ≥ stage 3b by ROC analysis (AUC 0.750 and 0.879, resp.); however, TFF3 alone predicted CKD progression in a multivariate logistic regression analysis (odds ratio 3.854, 95% confidence interval 1.316–11.55). The Kaplan-Meier survival curves demonstrated that patients with a higher TFF1 and TFF3 alone, or in combination with macroalbuminuria, had a significantly worse renal prognosis.Conclusion. The data suggested that urine TFF peptides are associated with renal progression and the outcomes in patients with CKD.

Pancreatic cancer (PC) is categorized as a neoplasm associated with Lynch syndrome; however, the precise proportion of PC patients harboring DNA mismatch repair genes (MMR genes) remains unclear, especially in the Asian population. Among 304 Japanese patients with pathologically proven pancreatic ductal adenocarcinoma, we selected 20 (6.6%) patients with a personal or family history involving first- or second-degree relatives fulfilling the revised Bethesda guidelines (RBG), defined as RBG-compatible cases. We analyzed germline variants in 21 genes related to a hereditary predisposition for cancer as well as clinical features in all 20 cases. The RBG-compatible cases did not show any unique clinicopathological features. Targeted sequencing data revealed three patients carrying deleterious or likely deleterious variants. Specifically, these three patients harbored a nonsense variant in ATM, a frameshift variant in ATM, and a concurrent nonsense variant in PMS2 and missense variant in CHEK2 (double-mutation carrier), respectively. Although an MMR gene mutation was identified in only one of the 20 patients, up to 15% of the RBG-compatible PC cases were associated with germline deleterious or likely deleterious variants. These findings showed that these guidelines could be useful for identifying PC patients with DNA damage repair genes as well as MMR genes.

Taste compounds detected by G protein-coupled receptors on the apical surface of Type 2 taste cells initiate an intracellular molecular cascade culminating in the release of ATP. It has been suggested that this ATP release is accomplished by pannexin 1 (PANX1). However, we report here that PANX1 knockout mice do not differ from wild-type controls in response to representative taste solutions, measured using 5-s brief-access tests or 48-h two-bottle choice tests. This implies that PANX1 is unnecessary for taste detection and consequently that ATP release from Type 2 taste cells does not require PANX1.

OBJECTIVE The aim of this study was to clarify the indications for oral glucose tolerance tests (OGTT) in non-alcoholic fatty liver disease (NAFLD) subjects with a HbA1c level of ≤6.4%, fasting plasma glucose (FPG) level of

A highly potent and well-balanced dual agonist for the EP

We investigated differences between the pathological features of gastric signet-ring cell carcinoma (sig) and poorly differentiated adenocarcinoma (por) by examining the expressions of the trefoil factor family peptides (TFFs) and mucin core proteins (MUCs). Ninety-seven tissues of 97 gastric cancer patients were selected for this study. After gastrectomy, the major histopathologic types were determined to be sig, solid-type poorly differentiated adenocarcinoma (por1), non-solid type poorly differentiated adenocarcinoma (por2), and well-differentiated tubular adenocarcinoma (tub1). We evaluated the prevalence of positive staining for MUCs (MUC5AC and MUC2) and TFFs (TFF1 and TFF3) and assessed the correlation between MUCs and TFFs in each histopathological type. The rate of MUC2 expression significantly differed between sig and por2 (50.0% vs 11.7%, P = 0.011). TFF3 expression in sig significantly differed from TFF3 expression in both por2 (100% vs 17.6%, P 0.0001) and por1 (100% vs 33.3%, P = 0.0004). MUC5AC and TFF1 expressions were significantly correlated in por1 (r = 0.705, P = 0.002), por2 (r = 0.535, P = 0.0009), and tub1 (r = 0.470, P = 0.0034), while MUC2 and TFF3 expressions were significantly correlated only in sig (r = 0.593, P = 0.040). The expression and correlation patterns of the TFFs and MUCs suggest that the histopathologic features of gastric sig differ from those of por.

Dietary inorganic phosphate (Pi) is the most important factor in the regulation of renal Pi excretion. Recent studies suggest the presence of an enteric-renal signaling axis for dietary Pi as well as the existence of a mechanism by which the intestine detects changes in luminal Pi concentrations. The mechanisms of intestinal Pi sensing, however, are unknown. In the present study, we focused on Pi depletion signals and investigated the effects of dietary components on intestinal Pi sensing. After feeding rats experimental diets for 3 days, we investigated urinary Pi excretion and plasma biochemical parameters. Renal Pi excretion was suppressed in rats fed a low-Pi diet (0.02% Pi). Elimination of dietary calcium (Ca) completely blocked the suppression of Pi excretion, suggesting that the presence of Ca is essential for the Pi depletion signal. Furthermore, a minimum Ca content of more than 0.02% was necessary for the Pi depletion signal. Magnesium, lanthanum, and strontium, which are agonists of calcium sensing receptor, instead of Ca, reduced Pi excretion. Therefore, dietary Ca appears to be important for the Pi depletion-sensing mechanism in the gastrointestinal tract. In addition, the calcium sensing receptor may be involved in the Pi depletion signal.

Objective We reported previously that serum arginase I increased in asthmatic patients and was associated with oxidative stress in a small healthy population. However, the exact association of arginase I with oxidative stress is not known. The present study aimed to analyze the association of arginase I with oxidative stress in a larger healthy population by a newly established ELISA. Design and methods The new ELISA for the measurement of human arginase I was established by generating recombinant arginase I protein in human arginase I gene-transfected Escherichia coli via an ARG1 cDNA fragment-inserted vector and -specific antibody in rabbits. Serum arginase I was evaluated in a cross-sectional study on a healthy population (n = 721) by comparing a commercial ELISA kit with the new ELISA. Results The mean levels of serum arginase I were 20.3 ± 0.7 ng/mL and 4.7 ± 0.2 ng/mL using the commercial ELISA kit and the new ELISA, respectively. Arginase I was correlated with WBC, RBC, hs-CRP, 8-OHdG, HDL-c, ALT, and BMI. Logistic regression analysis showed independent positive associations of arginase I with WBC, RBC, and urinary 8-OHdG and inverse independent associations with serum insulin and age. The association of arginase I with hs-CRP was not independent. Conclusion The independent associations of arginase I with urinary 8-OHdG and serum insulin may reflect its involvement in oxidative stress and diabetes mellitus.

The voltage-gated ion channel CALHM1 is vital to taste-stimuli-evoked ATP release from sweet-, bitter- and umami-sensing taste bud cells in mice, but does not seem relevant to the recognition of sour and salty tastes. Perception of sweet, bitter and umami tastes relies on the non-vesicular release from taste bud cells of ATP, which acts as a neurotransmitter to activate the nerves sending gustatory signals to the brain. Now teams led by Kevin Foskett and Philippe Marambaud have used gene-knockout mice to show that the voltage-gated ion channel CALHM1 (calcium homeostasis modulator 1) acts as a voltage-gated ATP-release channel required for sweet, bitter and umami taste perception. CALHM1 deficiency affected taste perception without interfering with taste cell development or integrity, implying that it is a key functional component of the peripheral taste system. Recognition of sweet, bitter and umami tastes requires the non-vesicular release from taste bud cells of ATP, which acts as a neurotransmitter to activate afferent neural gustatory pathways1. However, how ATP is released to fulfil this function is not fully understood. Here we show that calcium homeostasis modulator 1 (CALHM1), a voltage-gated ion channel2,3, is indispensable for taste-stimuli-evoked ATP release from sweet-, bitter- and umami-sensing taste bud cells. Calhm1 knockout mice have severely impaired perceptions of sweet, bitter and umami compounds, whereas their recognition of sour and salty tastes remains mostly normal. Calhm1 deficiency affects taste perception without interfering with taste cell development or integrity. CALHM1 is expressed specifically in sweet/bitter/umami-sensing type II taste bud cells. Its heterologous expression induces a novel ATP permeability that releases ATP from cells in response to manipulations that activate the CALHM1 ion channel. Knockout of Calhm1 strongly reduces voltage-gated currents in type II cells and taste-evoked ATP release from taste buds without affecting the excitability of taste cells by taste stimuli. Thus, CALHM1 is a voltage-gated ATP-release channel required for sweet, bitter and umami taste perception.

Recent investigations revealed that lysophosphatidic acid (LPA), a phospholipid with a growth factor-like activity, plays an important role in the integrity of the gastrointestinal tract epithelium.This paper attempts to clarify the effect of orally administered phosphatidic acid (PA) and LPA on aspirin-induced gastric lesions in mice.Phospholipids, a free fatty acid, a diacylglycerol and a triglyceride at 1 mM (5.7 μmol/kg body weight) or 0.1 mM were orally administered to mice 0.5 h before oral administration of aspirin (1.7 mmol/kg). The total length of lesions formed on the stomach wall was measured as a lesion index. Formation of LPA from PA in the mouse stomach was examined by in vitro (in stomach lavage fluid), ex vivo (in an isolated stomach) and in vivo (in the stomach of a living mouse) examinations of phospholipase activity.Palmitic acid, dioleoyl-glycerol, olive oil and lysophosphatidylcholine did not affect the aspirin-induced lesions. In contrast, phosphatidylcholine (1 mM), LPA (1 mM) and PA (0.1, 1 mM) significantly reduced the lesion index. Evidence for formation of LPA from PA in the stomach by gastric phospholipase A2 was obtained by in vitro, ex vivo and in vivo experiments. An LPA-specific receptor, LPA2, was found to be localized on the gastric surface-lining cells of mice.Pretreatment with PA-rich diets may prevent nonsteroidal anti-inflammatory drug-induced stomach ulcers.

International audience; Helminth parasitic infections are a major global health and social burden. The host defence against helminths such as Nippostrongylus brasiliensis is orchestrated by type 2 cell-mediated immunity. Induction of type 2 cytokines, including interleukins (IL) IL-4 and IL-13, induce goblet cell hyperplasia with mucus production, ultimately resulting in worm expulsion. However, the mechanisms underlying the initiation of type 2 responses remain incompletely understood. Here we show that tuft cells, a rare epithelial cell type in the steady-state intestinal epithelium, are responsible for initiating type 2 responses to parasites by a cytokine-mediated cellular relay. Tuft cells have a Th2-related gene expression signature and we demonstrate that they undergo a rapid and extensive IL-4Ralpha-dependent amplification following infection with helminth parasites, owing to direct differentiation of epithelial crypt progenitor cells. We find that the Pou2f3 gene is essential for tuft cell specification. Pou2f3(-/-) mice lack intestinal tuft cells and have defective mucosal type 2 responses to helminth infection; goblet cell hyperplasia is abrogated and worm expulsion is compromised. Notably, IL-4Ralpha signalling is sufficient to induce expansion of the tuft cell lineage, and ectopic stimulation of this signalling cascade obviates the need for tuft cells in the epithelial cell remodelling of the intestine. Moreover, tuft cells secrete IL-25, thereby regulating type 2 immune responses. Our data reveal a novel function of intestinal epithelial tuft cells and demonstrate a cellular relay required for initiating mucosal type 2 immunity to helminth infection.

Introduction The relationship between dopamine receptor D2 (DRD2) gene TaqIA polymorphisms and smoking behavior remains controversial. The aim of this review was to update a previous meta-analysis on the effect of DRD2 polymorphisms on smoking behavior by considering the influence of ethnicity. Methods This review presents analyses stratified by ancestry, as the samples included individuals of different ethnicities. Pooled effect sizes were calculated using fixed- and random-effects models to verify heterogeneity. We investigated the association for the proportion of men and Caucasians by regression analysis using the effect sizes calculated by each meta-analysis. Results Analysis of smoking cessation revealed a significant effect, which suggested that ethnic differences between Caucasians and Asians moderate the effect of DRD2 polymorphisms. Smoking initiation and rate exhibited no relationship with DRD2 polymorphisms; furthermore, we detected heterogeneity. Although the analysis of smoking persistence indicated significant effects, heterogeneity was detected. The finding of heterogeneity for smoking persistence and rate suggests the possibility of gene-gene interactions arising from ethnic differences between the samples. We found a significant inverse relationship between the proportion of men and effect sizes among Caucasians for smoking persistence and rate. Gender differences between Caucasian samples may moderate the effect of DRD2 polymorphisms on smoking persistence and rate. Conclusions Our findings indicate that the ethnicity of the participants alters the effect of DRD2 polymorphisms on smoking behavior. The observed heterogeneity may be associated with participant gender as a moderating factor, and the association may be specific to Caucasians.

INTRODUCTION The aim of this review was to report an update of a previous meta-analysis (by another group) of a possible relationship between serotonin transporter (5-HTTLPR) genotype and smoking behavior, and extend previous work by factoring in some demographic parameters (age, gender, and ethnicity) in a multiple regression model to examine the relationship between these demographic factors and the effect of 5-HTTLPR polymorphism on smoking behavior. METHODS Effect sizes were calculated for each study selected for meta-analysis and were pooled using the random-effects model, which assumes within-study sampling and between-study variance and provides wider confidence intervals. Effect sizes calculated in each study were used to evaluate the correlations with participant data for age, gender, and ethnicity (moderating variable) by multiple regression analysis. RESULTS Meta-analysis indicated a relationship between smoking rate and the 5-HTTLPR genotype, but not smoking initiation and persistence, which was consistent with that of the previous review. Publication bias was not indicated for smoking initiation or persistence. Multiple regression analysis revealed that mean participant age significantly affected effect sizes for smoking initiation and persistence of each study. The proportion of Caucasians may have been partially influenced by the difference in effect sizes for smoking persistence among the studies. CONCLUSION A significant relationship stratified by ancestry was observed between the 5-HTTLPR genotype and smoking rate, but not between the 5-HTTLPR genotype and smoking initiation and persistence. Regression analysis detected effects of age and/or ethnicity as moderating factors on smoking initiation and persistence.

Emerging data indicate that serum trefoil factors (TFFs), especially TFF3, could be potential biomarkers for gastric cancer risk. We aimed to evaluate the influence of Helicobacter pylori (H. pylori) status and eradication on serum TFFs and the pepsinogen test. Healthy individuals who underwent a thorough medical checkup were enrolled in study 1, and gastric ulcer patients who undertook H. pylori eradication therapy were enrolled in studies 2 and 3. Serum levels of the TFFs (TFF1, TFF2 and TFF3), H. pylori antibody and pepsinogen test were examined in all studies. In study 3, TFF expressions in biopsy samples of the gastric mucosa were additionally examined before and 2 months after eradication. In 1,260 healthy individuals enrolled in study 1, serum TFF1 and TFF2 levels were markedly different between H. pylori antibody-positive and -negative participants (P

The aim of this study was to determine the incidence and risk factors of hepatocellular carcinoma (HCC), and to elucidate the utility of two non-invasive predictive procedures for liver fibrosis: the aspartate aminotransferase (AST) to platelet ratio index (APRI) and the BARD score (which includes the following three variables: body mass index, AST/alanine aminotransferase ratio, and diabetes) in the prediction of HCC in a large population of Japanese patients with non-alcoholic fatty liver disease (NAFLD).This was a retrospective cohort study conducted at a public hospital. Study subjects included 6,508 patients with NAFLD diagnosed by ultrasonography. The median follow-up period was 5.6 years. The primary end point was the onset of HCC. Evaluation was performed using Kaplan-Meier methodology and Cox's proportional hazards analysis.In all, 16 (0.25%) new cases with HCC were diagnosed during the study. The cumulative rates of NAFLD-related HCC were 0.02% at year 4, 0.19% at year 8, and 0.51% at year 12. The annual rate of new HCC was 0.043%. Multivariate analysis identified serum AST level ≥40 IU/L (hazard ratio (HR): 8.20; 95% confidence interval (95% CI): 2.56-26.26; P0.001), platelet count150 × 10(3)/μl (HR: 7.19; 95% CI: 2.26-23.26; P=0.001), age ≥60 years (HR: 4.27; 95% CI: 1.30-14.01; P=0.017), and diabetes (HR: 3.21; 95% CI: 1.09-9.50; P=0.035) as independent risk factors for HCC. With regard to the APRI, 184 patients (2.83%) were considered to have significant fibrosis (equivalent to non-alcoholic steatohepatitis (NASH) stage 3-4). The cumulative rate of HCC was significantly higher in this group (HR: 25.03; 95% CI: 9.02-69.52; P0.001). In contrast, regarding the BARD score, 3,841 (59%) patients were considered to have advanced fibrosis (NASH stage 3-4). However, no significant associations between the BARD score and the incidence of HCC were observed (HR: 1.16; 95% CI: 0.40-3.37; P=0.780).This retrospective study indicates that the annual incidence rate of HCC among Japanese NAFLD patients is low. Elderly NAFLD patients with diabetes, elevated serum AST, and especially thrombocytopenia (suggested to be associated with advanced liver fibrosis) should be monitored carefully during follow-up that includes using the APRI to ensure early diagnosis and treatment of HCC.

The objective of this study was to evaluate whether hyperuricemia, acidic urine, or their combination predicts metabolic syndrome (MetS). In study 1, 69,094 subjects who received a general health checkup between 1985 and 2005 were included in a cross-sectional study of serum uric acid (SUA) and urine pH in relation to MetS. In study 2, the association of SUA and urine pH with MetS development over a 5-year period was evaluated in 5617 subjects with body mass index less than 25 kg/m(2) at the first examination. In study 1, higher SUA and lower urine pH were both positively correlated to MetS status (P < .001). The combination of high SUA and low urine pH was significantly associated with higher MetS prevalence compared with the combination of low SUA and high urine pH (odds ratio, 3.383; 95% confidence interval [CI], 3.034-3.784 in men; odds ratio, 4.000; 95% CI, 2.992-5.452 in women). In study 2, the top quartile of SUA levels was associated with higher MetS development compared with the bottom quartile during the 5-year period in men (hazard ratio [HR], 1.793; 95% CI, 1.084-2.966; P = .023). In women, the HR was 3.732 (95% CI, 0.391-35.62; P = .252) for the upper vs the lower half of SUA levels. For urine pH, the HR was 1.955 (95% CI, 1.089-3.509; P = .025) for the bottom vs the top quartile in men. A likelihood ratio test confirmed that high SUA and low urine pH act synergistically in the development of MetS. High SUA, low urine pH, and their combination are predictive risk factors for MetS development.

Taste cells release neurotransmitters to gustatory neurons to transmit chemical information they received. Sweet, umami, and bitter taste cells use ATP as a neurotransmitter. However, ATP release from sour taste cells has not been observed so far. Instead, they release serotonin when they are activated by sour/acid stimuli. Thus it is still controversial whether sour taste cells use ATP, serotonin, or both. By reverse transcription-polymerase chain reaction and subsequent in situ hybridization (ISH) analyses, we revealed that of 14 serotonin receptor genes only 5-HT3A and 5-HT3B showed significant/clear signals in a subset of neurons of cranial sensory ganglia in which gustatory neurons reside. Double-fluorescent labeling analyses of ISH for serotonin receptor genes with wheat germ agglutinin (WGA) in cranial sensory ganglia of pkd1l3-WGA mice whose sour neural pathway is visualized by the distribution of WGA originating from sour taste cells in the posterior region of the tongue revealed that WGA-positive cranial sensory neurons rarely express either of serotonin receptor gene. These results suggest that serotonin receptors expressed in cranial sensory neurons do not play any role as neurotransmitter receptor from sour taste cells.

Background The trefoil factor family (TFF) 2 protein is produced by gastric gland mucous cells (GMCs), and the secreted TFF2 shares a mucosal barrier function with GMC-type mucin. Recently, we presented an enzyme-linked immunosorbent assay (ELISA) method for measurement of GMC-type mucin in the gastric juice. Aims We aimed to develop an ELISA for TFF2 and to assess pathophysiological changes in the gastric surface mucous gel layer (SMGL) of patients with Helicobacter pylori infection. Methods The distribution of TFF2 and GMC-type mucin in the SMGL was immunohistochemically determined. The ELISA for TFF2 was based on a polyclonal goat antibody. Recombinant TFF2 was employed to prepare the calibrators. TFF2 and GMC-type mucin in the gastric juice in healthy individuals (n = 33) and patients with gastritis (n = 37), gastric ulcer (n = 16), and duodenal ulcer (n = 10) were assayed using ELISA. Results TFF2 and GMC-type mucin were immunohistochemically co-localized in the gastric SMGL and GMCs. The TFF2 levels in the patients were significantly higher than those in the healthy individuals. Further, the TFF2 levels in the H. pylori-positive patients were significantly higher than those in the H. pylori-negative patients, and decreased after the eradication of the infection. GMC-type mucin levels showed a tendency similar to that of TFF2 levels. Conclusions The upregulation of TFF2 and GMC-type mucin secretion may reflect the response of the gastric mucosa to H. pylori-induced injuries. TFF2 and GMC-type mucin secreted into the SMGL may protect the gastric mucosa against H. pylori., Article, DIGESTIVE DISEASES AND SCIENCES. 56(12):3498-3506 (2011)

The aim of this study was to evaluate the therapeutic efficacy of tolvaptan, a vasopressin V(2) receptor antagonist, on edema in two rat models: 1) histamine-induced vascular hyperpermeability of the dorsal skin and 2) carrageenan-induced paw edema.In the skin vascular hyperpermeability model, 3 h after oral administration of tolvaptan or the natriuretic agent furosemide, rats were intravenously injected with Evans Blue (EB), followed by intradermal injection of 10 μg of histamine into the dorsal skin. One hour later, blood was collected to measure serum parameters. EB leakage area into the dorsal skin was also measured. Urine was collected for 4 h to determine urine parameters. In the paw edema model, edema was induced by injecting 1% w/v carrageenan into the right hind paw. Paw volume was measured hourly for 5 h. Tolvaptan or furosemide was orally administered 1 h before carrageenan injection.A single oral dose of tolvaptan (1-10 mg/kg) elicited marked and dose-dependent aquaresis, and improvements in edema. Similar effects were observed with furosemide (30 mg/kg). Tolvaptan tended to elevate the serum sodium level while furosemide caused a significant decrease.Tolvaptan had anti-edematous effects in two different rat models. By increasing free water excretion, tolvaptan may be more advantageous for certain patients than loop diuretics because it does not cause electrolyte loss, and may prevent electrolyte abnormities, such as hyponatremia. These results suggest that tolvaptan has potential clinical benefits for the treatment of edema.

A few reports suggest that the emergence of double balloon endoscopy (DBE) has likely changed the clinical picture of small bowel tumors (SBTs).To further clarify the characteristics of SBTs detected by DBE.A retrospective chart review was conducted in 227 patients who had undergone DBE.The SBT group contained more symptomatic patients than the non-SBT group (90% vs. 49%, P0.0005) with a significantly higher rate of gastrointestinal symptoms at presentation (72% vs. 33%, P0.005). Twenty patients (8.8%) were eventually diagnosed with SBT, and their indications for DBE were obscure gastrointestinal bleeding (n=5), abdominal pain (n=5), abdominal fullness (n=5), vomiting (n=2), and diarrhea (n=1). Tumors were located in the jejunum in 14 patients (70%) and in the ileum in 6 (30%). A final histological diagnosis was assigned to all 20 patients: primary adenocarcinoma (n=8, 40%), malignant lymphoma (n=5, 25%), metastatic cancer (n=4, 20%), gastrointestinal stromal tumor (n=1, 5%), carcinoid tumor (n=1, 5%) and inflammatory fibroid polyp (n=1, 5%). Stenosis or ulceration were the most frequently observed endoscopic findings (n=13, 65%). All primary adenocarcinomas and three of four (75%) metastatic cancers showed stenosis or ulceration. Three of five (60%) malignant lymphomas showed multiple lymphomatous polyps. All patients but one underwent surgical resection or chemotherapy or both.DBE is a safe and useful procedure that enables a precise diagnosis of SBTs.

Purpose To determine whether alterations in architecture cause corneal biomechanical changes after simultaneous cataract surgery and limbal relaxing incisions (LRIs). Setting Department of Ophthalmology, Kitasato University, Kanagawa, Japan. Design Observational case series. Methods This study longitudinally assessed corneal hysteresis (CH) and the corneal resistance factor (CRF) using the Ocular Response Analyzer in eyes having cataract surgery with LRIs. The relationship between these biomechanical parameters and central corneal thickness (CCT), measured using an ultrasound pachymeter, was also assessed. Results The mean CH was 10.0 mm Hg ± 1.2 (SD) preoperatively, 9.0 ± 1.6 mm Hg 1 day postoperatively, 9.7 ± 1.4 mm Hg at 1 week, 9.6 ± 1.4 mm Hg at 1 month, and 10.2 ± 1.3 mm Hg at 3 months. The mean CRF was 10.0 ± 1.5 mm Hg, 8.9 ± 1.6 mm Hg, 9.5 ± 1.5 mm Hg, 9.5 ± 1.4 mm Hg, and 9.5 ± 1.4 mm Hg, respectively. There were significant differences between preoperative and 1-day postoperative measurements (P=.005, CH; P=.004, CRF). The CH and CRF were significantly correlated with CCT (r = 0.33, P=.04 and r = 0.40, P=.01, respectively) 3 months postoperatively. Conclusions The CH and CRF values decreased 1 day after simultaneous cataract surgery with LRIs but soon recovered to preoperative levels, suggesting there were no significant changes in corneal biomechanical factors after 1 day. Corneal thickness may play a role in biomechanical factors even in such eyes. Financial Disclosure No author has a financial or proprietary interest in any material or method mentioned.

Purpose To assess the time course of corneal biomechanical parameters after phacoemulsification with intraocular lens implantation. Methods We examined 54 eyes of 33 consecutive patients undergoing cataract surgery. We quantitatively assessed the values of corneal biomechanics characterized by corneal hysteresis (CH) and corneal resistance factor (CRF) using an Ocular Response Analyzer before and 1 day, 1 week, 1 month, and 3 months after surgery. We also investigated the relationship between these biomechanical parameters and central corneal thickness 3 months after surgery. Results The CH was 9.7 ± 1.1 (mean ± SD) mm Hg preoperatively, and 9.0 ± 1.4, 9.7 ± 1.1, 9.7 ± 1.1, and 9.7 ± 1.3 mm Hg 1 day, 1 week, 1 month, and 3 months postoperatively, respectively. The CRF was 9.5 ± 1.1 mm Hg preoperatively, and 8.8 ± 1.2, 9.2 ± 1.3, 9.1 ± 0.9, and 9.2 ± 1.2 mm Hg 1 day, 1 week, 1 month, and 3 months postoperatively, respectively. Multiple comparisons demonstrated significant differences between measurements made before and 1 day after surgery (P = 0.01 for CH and CRF, Dunnett test). Both CH and CRF were significantly correlated with central corneal thickness (Pearson correlation coefficient r = 0.29; P = 0.03 for CH and r = 0.42; P = 0.002 for CRF). Conclusions Both CH and CRF decreased briefly at 1 day after cataract surgery but soon recovered to the preoperative levels, suggesting that cataract surgery does not induce a significant change in corneal biomechanics, except for 1 day postoperatively. The corneal thickness may play some role in corneal biomechanics even in postcataract eyes.

Transient receptor potential channel M5 (Trpm5)-expressing cells, such as sweet, umami, and bitter taste cells in the oropharyngeal epithelium, solitary chemosensory cells in the nasal respiratory epithelium, and tuft cells in the small intestine, that express taste-related genes function as chemosensory cells. Previous studies demonstrated that Skn-1a/Pou2f3, a POU homeodomain transcription factor is expressed in these Trpm5-expressing chemosensory cells, and is necessary for their generation. Trpm5-expressing cells have recently been found in trachea, auditory tube, urethra, thymus, pancreatic duct, stomach, and large intestine. They are considered to be involved in protective responses to potential hazardous compounds as Skn-1a-dependent bitter taste cells, respiratory solitary chemosensory cells, and intestinal tuft cells are. In this study, we examined the expression and function of Skn-1a/Pou2f3 in Trpm5-expressing cells in trachea, auditory tube, urethra, thymus, pancreatic duct, stomach, and large intestine. Skn-1a/Pou2f3 is expressed in a majority of Trpm5-expressing cells in all tissues examined. In Skn-1a/Pou2f3-deficient mice, the expression of Trpm5 as well as marker genes for Trpm5-expressing cells were absent in all tested tissues. Immunohistochemical analyses demonstrated that two types of microvillous cells exist in trachea, urethra, and thymus, Trpm5-positive and Trpm5-negative cells. In Skn-1a/Pou2f3-deficient mice, a considerable proportion of Trpm5-negative and villin-positive microvillous cells remained present in these tissues. Thus, we propose that Skn-1a/Pou2f3 is the master regulator for the generation of the Trpm5-expressing microvillous cells in multiple tissues.

Purpose: To assess the effect of aging on corneal biomechanical parameters in a normal population. Methods: We prospectively examined 204 normal eyes of 204 healthy Japanese volunteers (68 men, 136 women; mean age 46.7±19.4 years [range: 19 to 89 years]). Corneal hysteresis, corneal resistance factor, corneal-compensated intraocular pressure (IOP cc ), and Goldmann-correlated intraocular pressure (IOP G ) were qualitatively assessed using a Reichert Ocular Response Analyzer. Central corneal thickness was measured using an ultrasound pachymeter. This measurement was performed 3 times, and the mean value obtained was used for statistical analysis. The relationships between patient age and corneal biomechanical parameters, or age and intraocular pressure (IOP), were investigated. Results: Mean corneal hysteresis and corneal resistance factor were 10.1±1.5 mmHg and 10.1±1.6 mmHg, respectively. Mean central corneal thickness was 539.1±30.9 µm. A weak, but significant, negative correlation was found between age and corneal hysteresis (Pearson's correlation coefficient r=−0.17, P =.02) and corneal resistance factor (r=−0.18 P =.01). On the other hand, no significant correlation was found between age and central corneal thickness (r=−0.06, P =.41), age and IOP cc (r=−0.02, P =.82), or age and IOP G (r=−0.11, P =.11). Conclusions: Corneal biomechanical parameters are significantly decreased by aging without significant changes in central corneal thickness or IOP, suggesting that age-related structural changes resulting from collagen cross-linking may lead to a reduction of corneal biomechanical variables independent of central corneal thickness or IOP. [ J Refract Surg . 2009;25:888–893.]

Neurons in the pontine parabrachial nucleus (PBN) transduce signals for the general visceral sensory, somatic sensory, gustatory, and autonomic nervous systems, and the various PBN neurons that perform these functions are intermingled. In this study, we analyzed PBN gene expression profiles in male Wistar rats and obtained data on gene expression in the PBN and the principal sensory nucleus of the trigeminal nerve (Pr5). Using these data in combination with in situ hybridization analyses, we identified genes that showed higher expression in the PBN than in Pr5. Our findings indicate that expression patterns in the PBN were different for different genes: Fxyd6, syt5, and plxnc1 were expressed in many neuron populations in the PBN, while the expression patterns of calcr and asb4 were restricted to the central lateral subnucleus and waist area. Furthermore, calcr and asb4 expression patterns were distinct from those of neurotransmitters/neuropeptides such as neurotensin and calcitonin gene-related peptides. Satb2 was specifically expressed in the waist area, which is essential for gustation. In-depth analysis of spatial distribution in the PBN enabled classification of the genes into seven characteristic spatial expression patterns. Expression signatures differed significantly in the subnuclei of the rostral half, mediodorsal half, and ventrolateral third of the PBN, indicating a correlation between the spatial arrangement of the subnuclei and the molecular characteristics of the corresponding neurons. Thus, our results provide valuable information regarding the molecular features and neurotransmission mechanisms of PBN neurons that transmit specific types of information.

Background It is unknown whether AQP5 and lipid rafts are released into human unstimulated (resting) saliva and saliva in response to secretagogues. Methods In order to quantitate the salivary concentration of AQP5, we produced a polyclonal antibody for human AQP5 and developed an enzyme-like immunosorbent assay (ELISA). Results AQP5 and lipid rafts were identified in human resting saliva. The amount of AQP5 in resting saliva showed a diurnal variation with high levels during waking hours, and an age-related decrease in AQP5 was coincident with the volume of resting saliva. Cevimeline, a muscarinic acetylcholine receptor (mAChR) agonist, induced the release of AQP5 with lipid rafts, amylase, mucin, and lysozyme. Changes in saliva AQP5 levels after cevimeline administration occurred simultaneously with changes in saliva flow rates. Confocal microscopy revealed that AQP5 was located in the apical plasma membrane and showed a diffuse pattern in parotid glands under resting conditions. Following cevimeline administration, AQP5 was predominantly associated with the APM and was localized in the lumen. General significance AQP5 and lipid rafts were released with salivary proteins from human salivary glands by the stimulation of M 3 mAChRs, and that changes in saliva AQP5 levels can be used as an indicator of salivary flow rate and also as a useful index of M 3 mAChR agonist's action on human salivary glands.

Purpose: To assess the time course of corneal biomechanics after laser in situ keratomileusis (LASIK). Methods: We examined 36 eyes of 20 consecutive patients undergoing LASIK for low to moderate myopia. We quantitatively assessed the values of corneal biomechanics characterized by corneal hysteresis (CH) and corneal resistance factor (CRF) using an Ocular Response Analyzer™ (Reichert Ophthalmic Instruments) before and 1 week, 1, 3, and 6 months after surgery. We carried out this measurement 3 times, and the average value was used for statistical analysis. Results: The CH was 10.6 ± 1.7 (mean ± SD) mm Hg preoperatively, and 8.6 ± 1.2, 9.0 ± 1.7, 9.0 ± 1.4, and 8.9 ± 1.5 mm Hg 1 week, 1, 3, and 6 months postoperatively, respectively. The CRF was 10.0 ± 1.7 mm Hg preoperatively, and 7.3 ± 1.5, 7.6 ± 2.0, 7.8 ± 1.6, and 7.7 ± 1.6 mm Hg 1 week, 1, 3, and 6 months postoperatively, respectively. The variances of the data were statistically significant (p < 0.001 for both CH and CRF). Multiple comparisons demonstrated significant differences between measurements made before surgery and at all postoperative times (at 1 week and 1, 3, and 6 months; p < 0.001 for CH and CRF, Fisher’s least significant difference test). Conclusions: Over the study period, the largest changes in corneal biomechanical parameters occurred within 1 week after surgery, and these then became nearly stable. No progressive deterioration of the corneal biomechanics was observed at any time during the 6-month follow-up period.

Purpose: Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) is a recently developed liver-specific contrast agent for magnetic resonance (MR) imaging that is excreted equally via the kidneys and the biliary system. To our knowledge, its effects on T2-weighted MR cholangiopancreatography (MRCP) images have not been explored. Acquisition of the hepatobiliary phase is recommended 20 min after administration of Gd-EOB-DTPA. Examination time cannot be extended if the contrast does not take effect on T2-weighted MRCP within 20 min after administration. We attempted to assess the change in signal of T2-weighted MRCP by excretion of Gd-EOB-DTPA. Methods: Between March and July 2008, 40 patients (15 women, 25 men; mean age 70.8 years) were examined with abdominal MR imaging. T2-weighted MRCP was performed before and 10 and 20 min after administration of Gd-EOB-DTPA. We analyzed signal intensity of the bile duct, gallbladder, cystic duct, and pancreatic duct on MRCP for changes in intensity. Results: T2-weighted MRCP 20 min after contrast administration showed loss of signal of the bile duct (intrahepatic bile duct in all cases, upper extrahepatic duct in 36 [90%], middle extrahepatic duct in 33 [85%], and lower extrahepatic duct in 26 [67%]), the gallbladder in 23 cases (72%), and the cystic duct in 25 (64%). This signal change increased with time. We observed no change in signal of the pancreatic duct. Conclusion: T2-weighted MRCP sequences should not be obtained after administration of Gd-EOB-DTPA because this contrast agent decreases signal intensity of the biliary structure on these images.

Despite male predominance in the prevalence of hypertrophic cardiomyopathy (HCM), repeated diagnosis at our institute indicates a possible higher prevalence of deep Q waves with HCM in women.The current study examined gender similarities and differences in the prevalence of deep Q waves in HCM and in the morphologic and electrocardiographic features of HCM with deep Q waves.Patients with HCM underwent cardiac magnetic resonance (CMR) imaging to identify the prevalence of deep Q waves in electrocardiographic limb leads, and to analyze the relationship between distribution patterns of deep Q waves and those of the localization of maximum amplitude of left ventricular (LV) hypertrophy. Contiguous LV short-axis images were obtained from the base toward the apex.Of the 200 consecutive patients (172 males, aged 20-78 years; 28 females, aged 16-79 years) with HCM who underwent CMR imaging, 10 male and 8 female patients had deep Q waves. Deep Q waves were more prevalent in females with HCM than in their male counterparts (28.6% vs 5.8%, respectively; P0.001). Of the 18 patients with deep Q waves, maximum wall thickness was localized at either the basal anterior wall or the midventricular septum in 9 (90%) of the 10 male patients and 6 (75%) of the 8 female patients. In both sexes, the Q wave distribution pattern of I and aVL and of II and aVF indicated localization of maximum hypertrophy at the midventricular septum in 6 (75%) of the 8 patients with the former pattern, and at the basal anterior wall in 9 (90%) of the 10 patients with the latter pattern.Diagnostic deep Q waves were detected more frequently in female patients with HCM than in their male counterparts. In HCM with deep Q waves in limb leads, morphologic and electrocardiographic analysis showed similar features in both sexes.

We report a case of hepatocellular carcinoma located just below the right hemidiaphragm that was diagnosed as having hepatitis C virus–related cirrhosis 12 years ago. Although the lesion was not clear on conventional sonography, it was clearly defined on CO2-enhanced sonography, allowing safe and accurate radiofrequency ablation. By combining radiofrequency ablation with transcatheter arterial chemoembolization, extensive cauterization and complete tumor necrosis were obtained with only 1 session of treatment. The patient had no serious adverse effects and has shown no recurrence during 35 months of follow-up. © 2006 Wiley Periodicals, Inc. J Clin Ultrasound, 2007.

Accumulating evidence has shown the pathophysiological significance of the translocator protein 18 kDa (TSPO) in the central nervous system. In this study, we evaluated the beneficial effects of ONO-2952, a novel TSPO antagonist in rat stress models. ONO-2952 potently bound both rat and human TSPO (Ki=0.330-9.30 nmol/L) with high selectivity over other receptors, transporters, ion channels and enzymes. ONO-2952 inhibited both neurosteroid accumulation and noradrenaline release in the brain of rats exposed to acute stress. The inhibitory effect of ONO-2952 on stress-induced noradrenaline release was attenuated by co-treatment with the TSPO agonist CB34 in a dose-dependent manner. ONO-2952, at 0.3 mg/kg or higher, dose-dependently suppressed restraint stress-induced defecation in rats with brain TSPO occupancy of more than 50%. In addition, ONO-2952, at 1 mg/kg or higher, suppressed conditioned fear stress-induced freezing behavior in rats with an efficacy equivalent to that of diazepam, given orally at 3 mg/kg. Results of the passive avoidance learning test revealed that ONO-2952, unlike diazepam, did not affect learning and memory even at doses 10 times higher than its effective doses in the stress models. The present findings indicate that ONO-2952 is a promising candidate for the treatment of stress-related disorders.

We compared the results ten years after an inverted V-shaped high tibial osteotomy with those of a historical series of conventional closing-wedge osteotomies. The closing-wedge series consisted of 56 knees in 51 patients with a mean follow-up of 11 years (10 to 15). The inverted V-shaped osteotomy was evaluated in 48 knees in 43 patients at a mean follow-up of 14 years (10 to 19). All the patients were scored using the Japanese Orthopaedic Association rating scale for osteoarthritis of the knee and radiological assessment. The pre-operative grade of osteoarthritis was similar in both groups. Post-operatively, the knee function score was graded as satisfactory in 63% (35) of the closing-wedge group but in 89% (43) of the inverted V-shaped osteotomy group. Post-operative radiological examination showed that delayed union and loss of correction occurred more often after a closing-wedge osteotomy than after an inverted V-shaped procedure. Our study suggests that the inverted V-shaped osteotomy may offer more dependable long-term results than traditional closing-wedge osteotomy.

The aim of this study was to assess the efficacy of the combination of endoscopic variceal ligation (EVL) and partial splenic embolization (PSE) compared with EVL alone in cirrhosis patients with thrombocytopenia. In a prospective study, 84 cirrhosis patients with esophageal varices and thrombocytopenia (platelet count < 50,000/mm(3)) underwent EVL plus PSE (N = 42) or EVL alone (N = 42). Primary end points assessed during the follow-up period included the recurrence of varices, progression to variceal bleeding, and death. Comparison between combined treatment and variceal ligation alone by multivariate analysis showed a hazard ratio of 0.44 for the recurrence of varices (P = 0.02), 0.19 for progression to variceal bleeding (P = 0.01), and 0.31 for death (P = 0.04). These results suggest that the combination of EVL plus PSE can prevent the recurrence of varices, progression to variceal bleeding, and death in cirrhosis patients with esophageal varices and thrombocytopenia.

Background This study investigated whether polymorphisms of the ankyrin repeat and kinase domain containing 1 gene (ANKK1), which is adjacent to the dopamine D2 receptor gene (DRD2), and the dopamine transporter (SLC6A3) and cytochrome P450 2A6 (CYP2A6) genes influence smoking cessation and nicotine dependence in a Japanese population. In 96 current and former smokers, genotyping frequencies for the ANKK1/DRD2 TaqIA, SLC6A3 VNTR, and CYP2A6 polymorphisms were subjected to chi-square analysis, and regression analyses were used to determine the association of the genotypes of current smokers with a Heavy Smoking Index, in addition to evaluating the effect of the subjects’ smoking history on the association. Results Genotyping results suggested that nicotine dependence among current smokers homozygous for the SLC6A3 10r allele was lower than that of smokers carrying the minor alleles, and that the CYP2A6 polymorphism might mediate this association. Furthermore, the age at which current smokers began smoking might moderate the association between their genetic polymorphisms and nicotine dependence. Conclusions This study provides preliminary findings on the influence of genetic variants on the smoking phenotypes in a Japanese population.

We documented an interesting case of adult "unilateral (probable)" moyamoya disease displaying familial occurrence in two "definite" cases. A 55-year-old female presented with motor aphasia, involuntary movement of the right hand and right homonymous hemianopia due to cerebral infarction. Cerebral angiography revealed typical angiographic findings on the left side and normal findings on the right side; consequently, the patient was diagnosed with probable moyamoya disease. Previously, her mother and nephew had been diagnosed with definite moyamoya disease with bilateral involvement. The patient continued to exhibit unilateral involvement on angiography for more than 4 years. Clinical features such as absence of familial occurrence suggest that most cases of probable moyamoya disease are distinct from definite cases, especially in adults. To the best of our knowledge, this report appears to be the first involving an adult probable case characterized by familial occurrence. The literature pertaining to adult probable moyamoya disease was reviewed and the etiology of this disease was discussed.