Prediction of nodal metastasis based on intraoral sonographic findings of the primary lesion in early-stage tongue cancer.

The aim of this study was to clarify the correlation between imaging findings obtained using intraoral ultrasonography (US) and pathological findings of tongue cancers, and to examine the predictive value of intraoral US findings with respect to occult nodal metastasis. This was a retrospective study based on the medical records of 123 patients with T1-2N0 tongue cancer. The depth of invasion (DOI) on intraoral US was positively correlated with the pathological invasion depth (PID) (ρ = 0.7080, P < 0.0001). Receiver operating characteristic analyses revealed an optimal DOI cut-off value of 4.1 mm and optimal PID cut-off value of 3.9 mm to detect nodal metastasis. Regarding the margin shape of the primary tumour on intraoral US, the incidence of nodal metastasis was significantly higher for the permeated type than for the pressure type (P < 0.001) and wedge-shaped type (P = 0.002). Furthermore, tumours with peritumoural vascularity assessed by power Doppler US had a significantly higher incidence of nodal metastasis than tumours without (P = 0.003). The sensitivity, specificity, and accuracy of the permeated type to predict nodal metastasis was 53.6%, 95.8%, and 86.2%, respectively. These results suggest that intraoral US findings closely reflect pathological findings and could be useful to predict occult nodal metastasis in patients with early-stage tongue cancer.

Comparison of postoperative infection after emergency inguinal hernia surgery with enterectomy between mesh repair and non-mesh repair: a national database analysis.

PURPOSE: Synthetic non-absorbable mesh is used for elective inguinal hernia repair but is not commonly used for incarcerated or strangulated inguinal hernia requiring enterectomy to reduce the risk of surgical-site infection. This study aimed to evaluate the safety of synthetic non-absorbable mesh repair in patients with incarcerated or strangulated inguinal hernia requiring enterectomy versus non-mesh repair. METHODS: We analyzed patients with incarcerated or strangulated inguinal hernia with enterectomy from April 2012 to March 2017 using a nationwide inpatient database in Japan. We conducted overlap propensity score-weighted analyses to compare surgical-site infection (SSI), duration of anesthesia, antibiotic use at > 3 days after surgery, postoperative hospital stay, and 30 day readmission. Two sensitivity analyses were performed. First, we compared the proportions of patients requiring wound culture at ≥ 3 days after surgery. Second, we performed overlap propensity score-weighted logistic regression analyses for surgical-site infection. RESULTS: We identified 668 eligible patients, comprising 223 patients with mesh repair and 445 with non-mesh repair. Overlap propensity score-weighted analyses showed no significant differences between the mesh repair and non-mesh repair groups for SSI (2.5 vs. 2.8%, P = 0.79). Secondary outcomes did not differ significantly between the groups. Proportion of wound culture at ≥ 3 days after surgery was similar in the two groups (11.1 vs. 14.6%, P = 0.18). Logistic regression analysis showed no significant association between mesh repair and SSI (odds ratio, 0.93; 95% confidence interval, 0.34-2.57). CONCLUSION: Synthetic non-absorbable mesh use may be safe for incarcerated or strangulated inguinal hernia requiring enterectomy.

Difference in surgical outcomes of rectal cancer by study design: meta-analyses of randomized clinical trials, case-matched studies, and cohort studies.

BACKGROUND: RCTs are considered the standard in surgical research, whereas case-matched studies and propensity score matching studies are conducted as an alternative option. Both study designs have been used to investigate the potential superiority of robotic surgery over laparoscopic surgery for rectal cancer. However, no conclusion has been reached regarding whether there are differences in findings according to study design. This study aimed to examine similarities and differences in findings relating to robotic surgery for rectal cancer by study design. METHODS: A comprehensive literature search was conducted using PubMed, Scopus, and Cochrane CENTRAL to identify RCTs, case-matched studies, and cohort studies that compared robotic versus laparoscopic surgery for rectal cancer. Primary outcomes were incidence of postoperative overall complications, incidence of anastomotic leakage, and postoperative mortality. Meta-analyses were performed for each study design using a random-effects model. RESULTS: Fifty-nine articles were identified and reviewed. No differences were observed in incidence of anastomotic leakage, mortality, rate of positive circumferential resection margins, conversion rate, and duration of operation by study design. With respect to the incidence of postoperative overall complications and duration of hospital stay, the superiority of robotic surgery was most evident in cohort studies (risk ratio (RR) 0.83, 95 per cent c.i. 0.74 to 0.92, P < 0.001; mean difference (MD) -1.11 (95 per cent c.i. -1.86 to -0.36) days, P = 0.004; respectively), and least evident in RCTs (RR 1.12, 0.91 to 1.38, P = 0.27; MD -0.28 (-1.44 to 0.88) days, P = 0.64; respectively). CONCLUSION: Results of case-matched studies were often similar to those of RCTs in terms of outcomes of robotic surgery for rectal cancer. However, case-matched studies occasionally overestimated the effects of interventions compared with RCTs.

Elevated expression of protease-activated receptor 1 via ΔNp63 down-regulation contributes to nodal metastasis in oral squamous cell carcinoma.

Protease-activated receptor 1 (PAR1) is known as a thrombin receptor. Recent studies have reported PAR1 expression in various malignancies; however, its role in oral squamous cell carcinoma (OSCC) requires clarification. A previous study showed that down-regulation of ΔNp63, a homolog of p53, augments PAR1 expression in OSCC. In the present study, the association of PAR1 expression with clinicopathological findings in OSCC was examined retrospectively. Expression of PAR1, thrombin, and ΔNp63 was examined immunohistochemically in OSCC specimens. Patients were divided into three groups based on the expression pattern of PAR1 at the invasive front: group A, PAR1-negative in both cancer and stromal cells; group B, positive in stromal cells but negative in cancer cells; group C, positive in both cancer and stromal cells. Histologically high-grade tumours were significantly more common in group C. Patients in group C had the highest incidence rate of nodal metastasis (P<0.001) and a lower survival rate (P=0.085) than those in the other groups. At the invasive front, in group C, thrombin was expressed but ΔNp63 expression was weak. These results indicate that increased PAR1 expression in both cancer and stromal cells could be a useful predictive marker of nodal metastasis and that ΔNp63 is involved in regulating PAR1 expression.

Stent as a bridge to surgery or immediate colectomy for malignant right colonic obstruction: propensity-scored, national database study.

BACKGROUND: The aim of this study was to compare perioperative outcomes of urgent colectomy and placement of a self-expanding metallic stent followed by colectomy for patients with malignant right colonic obstruction. Right-sided malignant obstruction is less common than left-sided. Stenting for malignant left colonic obstruction has been reported to reduce postoperative complications. However, the impact of stenting for malignant right colonic obstruction remains undefined. METHODS: The study included patients with right-sided malignant obstruction or stenosis undergoing colectomy between April 2012 and March 2017 identified from a nationwide database. Propensity score matching analysis was used to compare mortality and morbidity rates, proportion receiving a stoma and postoperative stay between urgent colectomy and stent groups. RESULTS: From 9572 patients, 1500 pairs were generated by propensity score matching. There was no significant difference in in-hospital mortality between the urgent colostomy and stent groups (1·6 versus 0·9 per cent respectively; P = 0·069). Complications were more common after urgent colectomy than stenting (22·1 versus 19·1 per cent; P = 0·042). Surgical-site infection was more likely with urgent colectomy (7·1 versus 4·4 per cent; P = 0·001). There was no significant difference between the two groups in anastomotic leakage (3·8 versus 2·6 per cent; P = 0·062). The proportion of patients needing a stoma was higher with urgent colectomy than primary treatment with stents (5·1 versus 1·7 per cent; P < 0·001). Postoperative stay was longer after urgent colectomy (15 versus 13 days; P < 0·001). CONCLUSION: Stenting followed by colectomy in patients with malignant right colonic obstruction may provide more favourable perioperative outcomes than urgent colectomy.

ANTECEDENTES: El objetivo de este estudio fue comparar los resultados perioperatorios entre la colectomía urgente y la colocación de una endoprótesis (stent) metálica autoexpandible seguida de colectomía en pacientes con obstrucción maligna del colon derecho. La obstrucción maligna del colon derecho es menos frecuente que la del colon izquierdo. Se ha demostrado que la colocación de una endoprótesis en la obstrucción maligna del colon izquierdo reduce las complicaciones postoperatorias. Sin embargo, el impacto de la colocación de una endoprótesis en la obstrucción maligna del colon derecho no está definido. MÉTODOS: Los pacientes con obstrucción o estenosis maligna del colon derecho sometidos a colectomía desde abril de 2012 hasta marzo de 2017 se analizaron a partir de una base de datos nacional. Se realizó un análisis mediante emparejamiento por puntaje de propensión para comparar la mortalidad, la morbilidad, el porcentaje de pacientes en los que se realizó un estoma y la estancia postoperatoria entre los grupos de colectomía urgente y endoprótesis. RESULTADOS: A partir de 9.572 pacientes, se generaron 1.500 parejas mediante emparejamiento por puntaje de propensión. No hubo diferencias significativas en la mortalidad hospitalaria entre los dos grupos (1,6% versus 0,9%, P = 0,07). Las complicaciones fueron más frecuentes después de la colectomía urgente en comparación con las endoprótesis (22,1% versus 19,1%, P = 0,04). La infección del sitio quirúrgico ocurrió con mayor frecuencia en el grupo de la colectomía urgente en comparación con el grupo de endoprótesis (7,1% versus 4,4%, P = 0,001). No se observaron diferencias significativas en la fuga anastomótica entre los dos grupos (3,8% versus 2,6%, P = 0,06). La proporción de pacientes que precisaron estomas fue mayor con la colectomía urgente en comparación con aquellos tratados inicialmente con endoprótesis (5,1% versus 1,7%, P < 0,001). La estancia postoperatoria fue más larga después de la colectomía urgente que tras la colocación de una endoprótesis (15 días versus 13 días, P < 0,001) CONCLUSIÓN: En pacientes con obstrucción maligna del colon derecho, la colocación de una endoprótesis seguida de colectomía puede proporcionar resultados perioperatorios más favorables en comparación con la colectomía urgente.

Eradication of Helicobacter pylori in a Living Donor Liver Transplant Recipient With Immunosuppressive Therapy of Cyclosporine A: A Case Report.

A 54-year-old woman underwent living donor liver transplantation (LDLT) for primary biliary cholangitis (PBC) three years earlier. She took cyclosporine A (CyA) 150 mg/day as immunosuppression for prevention of rejection and PBC recurrence. Routine upper gastrointestinal endoscopy showed chronic atrophic gastritis and hyperplastic polyp, and rapid urease test was positive. Anti-Helicobacter pylori (H. pylori) serum IgG was elevated to 51 U/ml. We performed H. pylori eradication therapy with amoxicillin, clarithromycin and lansoprazole measuring the blood CyA concentration every day. Although the blood CyA concentration reached a peak (the concentration 2 hours after the administration: 818 ng/ml) on the second day, she did not develop renal dysfunction or other obvious adverse effects. Five weeks after the treatment, we confirmed eradication of H. pylori with the urea breath test. We herein reported a case of successful eradication of H. pylori in a LDLT recipient on immunosuppressive therapy with CyA without adverse effects.

Significant association of increased PD-L1 and PD-1 expression with nodal metastasis and a poor prognosis in oral squamous cell carcinoma.

Programmed cell death ligand 1 (PD-L1) and its receptor PD-1 are immune checkpoint molecules that attenuate the immune response. Blockade of PD-L1 enhances the immune response in a variety of tumours and thus serves as an effective anti-cancer treatment. However, the biological and prognostic roles of PD-L1/PD-1 signalling in oral squamous cell carcinoma (OSCC) remain to be elucidated. The purpose of this study was to examine the correlation of PD-L1/PD-1 signalling with the prognosis of OSCC patients to assess its potential therapeutic relevance. The expression of PD-L1 and of PD-1 was determined immunohistochemically in 97 patients with OSCC and the association of this expression with clinicopathological characteristics was examined. Increased expression of PD-L1 was found in 64.9% of OSCC cases and increased expression of PD-1 was found in 61.9%. Univariate and multivariate analysis revealed that increased expression of PD-L1 and PD-1 positively correlated with cervical lymph node metastasis. The expression of CD25, an activated T-cell marker, was negatively correlated with the labelling index of PD-L1 and PD-1. Moreover, the patient group with PD-L1-positive and PD-1-positive expression showed a more unfavourable prognosis than the group with PD-L1-negative and PD-1-negative expression. These data suggest that increased PD-L1 and PD-1 expression is predictive of nodal metastasis and a poor prognosis and is possibly involved in cancer progression via attenuating the immune response.

Successful Treatment of Stricture of Duct-to-Duct Biliary Anastomosis After Living-Donor Liver Transplantation of the Left Lobe: A Case Report.

Biliary complications, such as stricture or obstruction, after living-donor liver transplantation (LDLT) remain major problems to be solved. Magnetic compression anastomosis (MCA) is a minimally invasive method of biliary anastomosis without surgery in patients with biliary stricture or obstruction. A 66-year-old woman had undergone LDLT for end-stage liver disease for primary biliary cholangitis 20 months previously at another hospital. Computerized tomography showed dilation of the intrahepatic bile duct (B2). Because B2 was invisible with the use of endoscopic retrograde cholangiopancreatography, percutaneous transhepatic biliary drainage (PTBD) was performed for treatment of cholangitis. The rendezvous technique failed because a guidewire could not pass through the biliary stricture. Therefore, we decided to perform MCA. A parent magnet was endoscopically placed distally in the common bile duct of the stricture, and a daughter magnet attached to a guidewire was inserted proximally through the fistula tract of the PTBD. Both magnets were positioned across the stricture, and the 2 magnets were pulled to each other by magnetic power, to sandwich the stricture. By 14 days after MCA, a fistula between B2 and the common bile duct was created. At 28 days after MCA, the magnets were removed distally and a 16-French tube was placed across the fistula. At 7 months after MCA, that tube was removed. In conclusion, when a conventional endoscopic or percutaneous approach including the rendezvous technique fails, MCA is a good technique for biliary stricture after LDLT.

Copy number loss in the region of the ASPN gene in patients with acetabular dysplasia: ASPN CNV in acetabular dysplasia.

OBJECTIVES: We have previously investigated an association between the genome copy number variation (CNV) and acetabular dysplasia (AD). Hip osteoarthritis is associated with a genetic polymorphism in the aspartic acid repeat in the N-terminal region of the asporin (ASPN) gene; therefore, the present study aimed to investigate whether the CNV of ASPN is involved in the pathogenesis of AD. METHODS: Acetabular coverage of all subjects was evaluated using radiological findings (Sharp angle, centre-edge (CE) angle, acetabular roof obliquity (ARO) angle, and minimum joint space width). Genomic DNA was extracted from peripheral blood leukocytes. Agilent's region-targeted high-density oligonucleotide tiling microarray was used to analyse 64 female AD patients and 32 female control subjects. All statistical analyses were performed using EZR software (Fisher's exact probability test, Pearson's correlation test, and Student's t-test). RESULTS: CNV analysis of the ASPN gene revealed a copy number loss in significantly more AD patients (9/64) than control subjects (0/32; p = 0.0212). This loss occurred within a 60 kb region on 9q22.31, which harbours the gene for ASPN. The mean radiological parameters of these AD patients were significantly worse than those of the other subjects (Sharp angle, p = 0.0056; CE angle, p = 0.0076; ARO angle, p = 0.0065), and all nine patients required operative therapy such as total hip arthroplasty or pelvic osteotomy. Moreover, six of these nine patients had a history of operative or conservative therapy for developmental dysplasia of the hip. CONCLUSIONS: Copy number loss within the region harbouring the ASPN gene on 9q22.31 is associated with severe AD. A copy number loss in the ASPN gene region may play a role in the aetiology of severe AD.Cite this article: T. Sekimoto, M. Ishii, M. Emi, S. Kurogi, T. Funamoto, Y. Yonezawa, T. Tajima, T. Sakamoto, H. Hamada, E. Chosa. Copy number loss in the region of the ASPN gene in patients with acetabular dysplasia: ASPN CNV in acetabular dysplasia. Bone Joint Res 2017;6:439-445. DOI: 10.1302/2046-3758.67.BJR-2016-0094.R1.

Mint3-mediated L1CAM expression in fibroblasts promotes cancer cell proliferation via integrin α5ß1 and tumour growth.

Fibroblasts are some of the major cells in tumour tissues that influence tumour progression and drug resistance. However, our understanding on fibroblast-mediated tumour malignancy remains incomplete. Munc18-1-interacting protein 3 (Mint3) is known as an activator of hypoxia-inducible factor-1 (HIF-1) even during normoxia in cancer cells, macrophages and fibroblasts. Although Mint3 promotes ATP production via glycolysis by activating HIF-1 in cancer cells and macrophages, the biological role of Mint3-mediated HIF-1 activation in fibroblasts remains unclear. To address this, we examined whether Mint3 in fibroblasts contributes to tumour growth. Mint3 depletion in mouse embryonic fibroblasts (MEFs) decreased tumour growth of co-injected human breast cancer cells, MDA-MB-231 and epidermoid carcinoma A431 cells in mice. In MEFs, Mint3 also promoted cancer cell proliferation in vitro in a cell-cell contact-dependent manner. Mint3-mediated cancer cell proliferation depended on HIF-1, and further gene expression analysis revealed that the cell adhesion molecule, L1 cell adhesion molecule (L1CAM), was induced by Mint3 and HIF-1 in fibroblasts. Mint3-mediated L1CAM expression in fibroblasts stimulated the ERK signalling pathway via integrin α5ß1 in cancer cells, and promoted cancer cell proliferation in vitro and tumour growth. In cancer-associated fibroblasts (CAFs), knockdown of MT1-MMP, which promotes Mint3-mediated HIF-1 activation, or Mint3 decreased L1CAM expression. As MEFs, CAFs also promoted cancer cell proliferation in vitro, and tumour growth via Mint3 and L1CAM. In human breast cancer specimens, the number of fibroblasts expressing L1CAM, Mint3 and MT1-MMP was higher in cancer regions than in adjacent benign regions. In addition, more phospho-ERK1/2-positive cancer cells existed in the peripheral region surrounded by the stroma than in the central region of solid breast cancer nest. Thus, Mint3 in fibroblasts might be a good target for cancer therapy by regulating cancer cell-stromal cell communication.

Production of three-dimensional tissue-engineered cartilage through mutual fusion of chondrocyte pellets.

In this study, the mutual fusion of chondrocyte pellets was promoted in order to produce large-sized tissue-engineered cartilage with a three-dimensional (3D) shape. Five pellets of human auricular chondrocytes were first prepared, which were then incubated in an agarose mold. After 3 weeks of culture in matrix production-promoting medium under 5.78g/cm(2) compression, the tissue-engineered cartilage showed a sufficient mechanical strength. To confirm the usefulness of these methods, a transplantation experiment was performed using beagles. Tissue-engineered cartilage prepared with 50 pellets of beagle chondrocytes was transplanted subcutaneously into the cell-donor dog for 2 months. The tissue-engineered cartilage of the beagles maintained a rod-like shape, even after harvest. Histology showed fair cartilage regeneration. Furthermore, 20 pellets were made and placed on a beta-tricalcium phosphate prism, and this was then incubated within the agarose mold for 3 weeks. The construct was transplanted into a bone/cartilage defect in the cell-donor beagle. After 2 months, bone and cartilage regeneration was identified on micro-computed tomography and magnetic resonance imaging. This approach involving the fusion of small pellets into a large structure enabled the production of 3D tissue-engineered cartilage that was close to physiological cartilage tissue in property, without conventional polyper scaffolds.

Post-operative swallowing in multiple system atrophy.

BACKGROUND: Some patients with multiple system atrophy (MSA) require surgical interventions such as tracheostomy and aspiration prevention. Few studies have investigated the postoperative clinical course of MSA patients. The aim of this study was to determine a management strategy for dysphagia and respiratory disorder in MSA. METHODS: From 2001 to 2014, 18 MSA patients (13 males and 5 females, 52-76 years) underwent tracheostomy (TR, n = 11) or laryngeal closure (LC, n = 12). Five patients underwent LC following TR. Vocal fold impairment, the degree of dysphagia and pre/post-operative oral ingestion, and postoperative survival time were evaluated retrospectively. Swallowing function was assessed using the penetration aspiration scale (PAS). RESULTS: TR was performed due to respiratory disorder in seven patients and due to dysphagia in four patients. PAS scores ranged 1-8 in TR patients and 7-8 in LC patients. Seven of 11 patients who underwent TR displayed worsened PAS scores, and no patients displayed improved PAS scores following TR. All patients who underwent LC regained complete or partial oral intake after surgery. There were no significant differences in postoperative survival time between the two groups. CONCLUSIONS: Considering the impacts of TR and LC on survival time, postoperative feeding and swallowing, LC is a good option for treating MSA patients with dysphagia.

Comparison of Volumetric and Diametric Analysis in Endovascular Repair of Descending Thoracic Aortic Aneurysm.

OBJECTIVES: The aim was to evaluate computed tomography angiography (CTA) volumetric and diametric analysis after endovascular repair of descending thoracic aortic aneurysms (DTAAs) and its correlation with and applicability for clinical follow up. METHODS: Fifty-four consecutive endovascular repairs for DTAA were retrospectively evaluated from 2008 to 2014. All patients underwent pre-operative CTA and at least one post-operative CTA at 6 months. Fifty-four pre-operative and 137 post-operative CTAs were evaluated (using the Ziosoft 2 software) to analyze the aneurysm and thrombus volume, the maximum aneurysm diameter, and their changes at the last follow up CTA (mean 30.5 months; range 6.5-66.4 months). A statistical analysis was performed to assess the correlation between diameter and volume changes, as well as association with endoleaks. The cut off point to predict endoleaks was determined using a receiver operating characteristic (ROC) curve. The predictive accuracy of volume change versus diameter change for Type I endoleak was analyzed. RESULTS: The mean pre-operative aneurysm diameter, aneurysm volume, and thrombus volume were 56.7 ± 11.7 mm, 145.8 ± 120.0 mL, and 48.8 ± 54.8 mL, respectively. Within the observational period, a mean decrease of -27.9 ± 30.5% in the aortic volume and -15.9 ± 15.4% in diameter was observed. Correlation between aneurysm diameter and volume changes was good (r = 0.854). Volume and diameter changes were significantly different between groups with and without endoleaks (volume change 16.9 ± 38.8% vs. -35.6 ± 23.1%, p < .001; diameter change 8.0 ± 12.1% vs. -18.8 ± 14.3%, p < .001). A pre-operative thrombus volume percentage of <11.3% and increase in aneurysm volume +11.6% were predictive factors for Type II and Type I endoleak, respectively. The accuracy of a >10% volume increase in predicting a Type I endoleak was higher (accuracy 96.3%, sensitivity 75%, and specificity 98%) than a >5 mm diameter increase (accuracy 92.6%, sensitivity 25%, and specificity 98%). CONCLUSIONS: CT volumetric analysis is a more reliable modality for predicting endoleaks after endovascular repair for DTAA than diameter analysis.

Genomewide association study identifies HAS2 as a novel susceptibility gene for adult asthma in a Japanese population.

BACKGROUND: It is increasingly clear that asthma is not a single disease, but a disorder with vast heterogeneity in pathogenesis, severity, and treatment response. To date, 30 genomewide association studies (GWASs) of asthma have been performed, including by our group. However, most gene variants identified so far confer relatively small increments in risk and explain only a small proportion of familial clustering. OBJECTIVE: To identify additional genetic determinants of susceptibility to asthma using a selected Japanese population with reduced tobacco smoking exposure. METHODS: We performed a GWAS by genotyping a total of 480 098 single-nucleotide polymorphisms (SNPs) for a Japanese cohort consisting of 734 healthy controls and 240 patients with asthma who had smoked for no more than 10 pack-years. The SNP with the strongest association was genotyped in two other independent Japanese cohorts consisting of a total of 531 healthy controls and 418 patients with asthma who had smoked for no more than 10 pack-years. For the hyaluronan synthase 2 (HAS2) gene, we investigated SNP-gene associations using an expression quantitative trait loci (eQTL) database and also analysed its gene expression profiles in 13 different normal tissues. RESULTS: In the discovery GWAS, a SNP located upstream of HAS2, rs7846389, showed the strongest statistical significance (P = 1.43 × 10(-7) ). In the two independent replication cohorts, rs7846389 was consistently associated with asthma (nominal P = 0.0152 and 0.0478 in the first and second replication cohorts, respectively). In the meta-analysis, association of rs7846389 with susceptibility to asthma reached the level of genomewide significance (P = 7.92 × 10(-9) ). This variant was strongly correlated with HAS2 mRNA expression. The strongest expression of the gene was detected in the lung. CONCLUSIONS: Our study identified HAS2 as a novel candidate gene for susceptibility to adult asthma.

Viral disruption of olfactory progenitors is exacerbated in allergic mice.

Upper airway viral infection in patients with airway allergy often exacerbates olfactory dysfunction, but the mechanism for this exacerbation remains unclear. Here, we examined the effects of respiratory syncytial virus (RSV) infection, in the presence or absence of airway allergy, on olfactory receptor neurons (ORNs) and their progenitors in mice. Immunohistological analyses revealed that cockroach allergen (CRA)-induced airway allergy alone did not affect the number of OMP(+) mature ORNs and SOX2(+) ORN progenitors. Intranasal RSV line 19 infection in allergy-free mice resulted in a transient decrease in SOX2(+) ORN progenitors without affecting OMP(+) ORNs. In contrast, the RSV-induced decrease in SOX2(+) ORN progenitors was exacerbated and prolonged in allergic mice, which resulted in eventual loss of OMP(+) ORNs. In the allergic mice, reduction of RSV in the olfactory epithelium was delayed as compared with allergy-free mice. These results suggest that ORN progenitors were impaired by RSV infection and that airway allergy exacerbated damage to ORN progenitors by reducing viral clearance.

Upregulation of non-ß cell-derived vascular endothelial growth factor A increases small clusters of insulin-producing cells in the pancreas.

Pancreatic ß cell-derived vascular endothelial growth factor A (VEGF-A) contributes to normal ß cell function. We therefore hypothesized that non-ß cell-derived VEGF-A may affect its properties in adult mice.We generated transgenic mice expressing human VEGF-A (hVEGF-A) in a visceral smooth muscle cell (SMC)-dominant manner under the control of the transgelin (Tagln/SM22α) promoter via a tamoxifen-induced Cre/loxP recombination system (SM-CreER(T2)/hVEGF mice).SM-CreER(T2)/hVEGF mice received tamoxifen orally followed by microscopic examination of their pancreas 4 weeks after the hVEGF-A induction. The number of clusters of insulin-producing cells (IPCs) in islets, pancreatic ducts, and individual IPCs were counted.The number of small IPC clusters (100-215 µm(2)) in the pancreas increased significantly in SM-CreER(T2)/hVEGF mice compared with SM-CreER(T2)(Ki) mice (473 out of 1 992 counts vs. 199 out of 976 counts, p<0.05), although total IPC area and the number of pancreatic duct IPCs, in proportion to exocrine area, were similar between the 2 groups. Although most small IPC clusters observed in SM-CreER(T2)/hVEGF mice were not accompanied by α and/or δ cells, some were attached to a single or a few α cells. An STZ-induced diabetic state in SM-CreER(T2)/hVEGF mice was slightly ameliorated, with only one point of significance 12 weeks after STZ administration, compared with SM-CreER(T2)(Ki) mice.Upregulation of non-ß cell-derived VEGF-A may alter the composition of pancreatic IPCs by increasing the number of small IPC clusters. These findings provide new information on the role of non-ß cell-derived VEGF-A to IPC regeneration and insulin production.

Highly expressed cytoplasmic FcεRIß in human mast cells functions as a negative regulator of the FcRγ-mediated cell activation signal.

BACKGROUND: We recently reported that the interaction between Lyn and FcεRIß is indispensable for FcεRI-mediated human mast cell (MC) activation and that FcεRIß functions as an amplifier of FcεRI-mediated activation signal. Some of FcεRIß in cytoplasm appeared not to be co-localized with FcεRIα. The function of FcεRIß in the cytoplasm remains unknown. METHODS: The localization of FcεRIß and FcεRIα in giant papillae specimens from patients with allergic keratoconjunctivitis and of FcεRIß, FcεRIα, and Lyn in cultured human MCs was examined using confocal microscopy. FcεRIß was overexpressed using an adenovirus vector system. Mediators were measured by enzyme immunoassays or enzyme-linked immunosorbent assays. RESULTS: In the subepithelial region, FcεRIß was mainly localized in the cell membrane of MCs. In the perivascular region, FcεRIß expression was scattered throughout the cytoplasm and in the cell membrane of MCs. Overexpression of FcεRIß in MCs mainly increased its cytoplasmic expression and slightly up-regulated cell surface FcεRI expression. However, overexpression of FcεRIß in MCs resulted in down-regulation of the tyrosine phosphorylation levels of FcεRIß and Syk and down-regulation of the Ca(2+) influx soon after FcεRI aggregation and then resulted in down-regulation of degranulation, PGD2 synthesis, and production of a set of cytokines. This negative regulatory effect may be due to inhibition of the redistribution of Lyn to small patches within the plasma membrane. CONCLUSION: Cytoplasmic FcεRIß, which is not co-localized with FcεRIα, may function as a negative regulator, as it can capture important signalling molecules such as Lyn.

Clinicopathological features of colorectal polyps: evaluation of the 'predict, resect and discard' strategies.

AIM: 'Predict, resect and discard' strategies for diminutive and small colonic polyps are considered to be cost effective for treating colorectal cancers. The aim of this study was to determine, retrospectively, the histological features of colonic polyps resected by endoscopic procedures or surgery using an updated database. METHOD: We retrospectively analysed the clinicopathological features of colorectal polyps, less than 20 mm in size, which were removed by endoscopy from January 2009 to November 2011 at the National Cancer Center Hospital (NCCH) in Tokyo, Japan. RESULTS: Less than 1% of diminutive polyps (≤ 5 mm) were classified as mucosal high-grade neoplasia (Category 4), and no submucosal invasion by carcinoma (Category 5) lesions were noted. However, 3% of small polyps (6-9 mm) were classified as Category 5; of these, 6% were submucosal deep invasive cancers. Morphologically, depressed components were observed more frequently in carcinomas than in adenomas in both small and large polyps (10-20 mm). CONCLUSION: In light of the 'predict, resect and discard' strategies for small polyps, we should pay attention to the possible clinical malignancy of small and large polyps. We recommend that these strategies should be applied selectively and that they should be informed by accurate endoscopic evaluations.