Tomoo Watanabe

Interleukin-6 (IL-6) is one of the major mediators of inflammation, and its expression is inducible by the other inflammatory lymphokines, interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha). We demonstrate that a common IL-6 promoter element, termed inflammatory lymphokine-responsive element (ILRE), is important for induction of IL-6 gene expression by IL-1 and TNF-alpha despite possible differences in the mechanisms of action of these lymphokines. Remarkably, the ILRE sequence, located between -73 to -63 relative to the mRNA cap site, is highly homologous to NF-kappa B transcription factor-binding motifs and binds an IL-1-TNF-alpha-inducible nuclear factor; the sequence specificities, binding characteristics, and subcellular localizations of this factor are indistinguishable from those of NF-kappa B. In addition, mutations of the ILRE sequence which impair the binding of this nuclear factor abolished the induction of IL-6 gene expression by IL-1 and TNF-alpha in vivo. These results indicate that a nuclear factor indistinguishable from NF-kappa B is involved in the transcriptional activation of the IL-6 gene by IL-1 and TNF-alpha.

HES-1 is a mammalian helix-loop-helix factor structurally related to the Drosophila hairy and Enhancer of split proteins. It binds more preferentially to the N box (CACNAG) than to the E box (CANNTG) and acts as a negative regulator. In this study, we have isolated and characterized the mouse HES-1 gene. This gene consists of four exons, and the positions of introns are well conserved when compared with those of the Drosophila hairy gene, except for the third intron. Southern blot and interspecies backcross analyses suggest that the mouse HES-1 gene is a single-copy gene and is located around position 26 on chromosome 16. The transcription initiation site, determined by the S1 nuclease and primer extension experiments, is located 31 nucleotides downstream of a TATA box. In the 5'-regulatory region, there are four N box sequences, and the DNase I foot-printing and gel mobility shift analyses show that HES-1 binds to these sequences. Transient transfection assays using C3H10T1/2 cells suggest that there are several positive regulatory regions in the HES-1 gene. However, cotransfection of the HES-1 expression vector leads to approximately 40-fold repression in promoter activity. Furthermore, when the N box sequences are disrupted, this negative regulation is severely impaired. These results raise the possibility that HES-1 gene expression may be negatively autoregulated through the N box sequences.

We have encountered cases of unusual intraductal pancreatic neoplasms with predominant tubulopapillary growth. We collected data on 10 similar cases of "intraductal tubulopapillary neoplasms (ITPNs)" and analyzed their clinicopathologic and molecular features. Tumor specimens were obtained from 5 men and 5 women with a mean age of 58 years. ITPNs were solid and nodular tumors obstructing dilated pancreatic ducts and did not contain any visible mucin. The tumor cells formed tubulopapillae and contained little cytoplasmic mucin. The tumors exhibited uniform high-grade atypia. Necrotic foci were frequently observed, and invasion was observed in some cases. The ITPNs were immunohistochemically positive for cytokeratin 7 and/or cytokeratin 19 and negative for trypsin, MUC2, MUC5AC, and fascin. Molecular studies revealed abnormal expressions of TP53 and SMAD4 in 1 case, but aberrant expression of beta-catenin was not observed. No mutations in KRAS and BRAF were observed in the 8 cases that were examined. Eight patients are alive without recurrence, 1 patient died of liver metastases, and 1 patient is alive but had a recurrence and underwent additional pancreatectomy. The mitotic count and Ki-67 labeling index were significantly associated with invasion. All the features of ITPN were distinct from those of other known intraductal pancreatic neoplasms, including pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, and the intraductal variant of acinar cell carcinoma. Intraductal tubular carcinomas showed several features that were similar to those of ITPN, except for the tubulopapillary growth pattern. In conclusion, ITPNs can be considered to represent a new disease entity encompassing intraductal tubular carcinoma as a morphologic variant.

OBJECTIVE: When performing transcanal myringoplasty under a microscope, the total circumference of the perforation can be difficult to confirm in patients where the external ear canal is narrow and/or protruded. In such patients, a retroauricular incision approach is usually used. However, we have developed a transcanal endoscopic myringoplasty procedure, and the microscopic and endoscopic views are compared herein for the first time. The feasibility and advantages of transcanal endoscopic myringoplasty were examined. STUDY DESIGN: A prospective case series. SETTING: Tertiary referral center. PATIENTS: Transcanal endoscopic myringoplasty was performed on 25 ears in 21 patients with chronic otitis media between September 2011 and December 2012. INTERVENTION: Microscopic and endoscopic views were compared for each patient. The 2 fields of views were both recorded and evaluated to determine the advantages and disadvantages of microscopes and endoscopes. Myringoplasty was performed using an endoscopic technique while comparing views as necessary. RESULTS: Endoscopic views revealed the entire tympanic membrane in a single field with clear visualization of the perforation edges even when the ear canal was curved. This clear visualization facilitated reliable refreshing of the perforation edges and grafting. The anterior edge of the perforation was not visible under microscopy in 5 of 25 ears. Under an endoscopic wide view, the tympanic cavity was observable through the perforation, and the orifice of the tube, ossicular chain, and tympanic isthmus were visible especially with large perforations. Transcanal endoscopic myringoplasty was successfully performed with a simple underlay technique or with an intracanal incision in cases of marginal perforation. CONCLUSION: Comparison of microscopic and endoscopic views revealed superior visualization and operability of the endoscopic approach as opposed to transcanal simple underlay myringoplasty. Transcanal endoscopic myringoplasty does not require surgical exposure such as a retroauricular skin incision to get an anterior view. Our results demonstrated that transcanal endoscopic myringoplasty can be performed, regardless of the perforation size and the narrowness and/or protrusion of external ear canal.