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.

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 a (TNF-a). 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-a 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-KB transcription factor-binding motifs and binds an IL-1-TNF-a-inducible nuclear factor; the sequence specificities, binding characteristics, and subcellular vocalizations of this factor are indistinguishable from those of NF-KB. 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-a in vivo. These results indicate that a nuclear factor indistinguishable from NF-KB is involved in the transcriptional activation of the IL-6 gene by IL-1 and TNF-a.

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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.

Intraductal tubulopapillary neoplasm (ITPN) is a recently recognized rare variant of intraductal neoplasms of the pancreas. Molecular aberrations underlying the neoplasm remain unknown. We investigated somatic mutations in PIK3CA, PTEN, AKT1, KRAS, and BRAF. We also investigated aberrant expressions of phosphorylated AKT, phosphatase and tensin homolog (PTEN), tumor protein 53 (TP53), SMAD4, and CTNNB1 in 11 cases of ITPNs and compared these data with those of 50 cases of intraductal papillary mucinous neoplasm (IPMN), another distinct variant of pancreatic intraductal neoplasms. Mutations in PIK3CA were found in 3 of 11 ITPNs but not in IPMNs (P = 0.005; Fisher exact test). In contrast, mutations in KRAS were found in none of the ITPNs but were found in 26 of the 50 IPMNs (P = 0.001; Fisher exact test). PIK3CA mutations were associated with strong expression of phosphorylated AKT (P < 0.001; the Mann-Whitney U test). Moreover, the expression of phosphorylated AKT was apparent in most ITPNs but only in a few IPMNs (P < 0.001; the Mann-Whitney U test). Aberrant expressions of TP53, SMAD4, and CTNNB1 were not statistically different between these neoplasms. Mutations in PIK3CA and the expression of phosphorylated AKT were not associated with age, sex, tissue invasion, and patients' prognosis in ITPNs. These results indicate that activation of the phosphatidylinositol 3-kinase pathway may play a crucial role in ITPNs but not in IPMNs. In contrast, the mutation in KRAS seems to play a major role in IPMNs but not in ITPNs. The activated phosphatidylinositol 3-kinase pathway may be a potential target for molecular diagnosis and therapy of ITPNs.

To clarify the contribution of the skull contents to the transmission of bone vibratory stimuli, and to examine the characteristics of such stimuli, we compared auditory thresholds and distortion-product otoacoustic emission (DPOAE) levels with a bone vibrator placed on various sites of the head, including the eye. The best audiometric thresholds and the highest DPOAE levels were obtained with the vibrator placed on the mastoid of the measuring side, or on the "ultrasound-window" of the temple. The audiometric thresholds obtained with the bone vibrator on the eye were similar to those of the forehead, and about 10 dB higher than at the best sites. DPOAEs were clearly present when elicited by a combination of air-conducted stimuli presented through an insert earphone and with the bone vibrator placed on the eye. These results indicate that vibratory sounds can be transmitted through the skull contents to the inner ear. The intracranial transmission pathway of the vibratory stimuli may play a significant role, particularly at low frequencies, and possibly also when the vibratory stimuli are applied on the skull bone.

TEES is associated with lower postoperative pain and lower use of NSAIDs compared with MES patients.

1 The e ects of endothelin-1 (ET-1) on intracellular Ca 2+ ion level and cell contraction were simultaneously investigated in rabbit ventricular cardiac myocytes loaded with indo-1/AM. The role of Na + /Ca 2+ exchange in ET-1-induced positive inotropic e ect (PIE) was examined by using phenyl]ethyl]isothiourea methanesulphonate), a selective inhibitor of reverse mode Na + /Ca 2+ exchange. 2 ET-1 at 0.3 pM ± 1 nM increased cell contraction and Ca 2+ transient (CaT) with EC 50 values of 2.9 pM and 1.2 pM, respectively, and the increase in amplitude of CaT was much smaller relative to the PIE: ET-1 at 1 nM increased peak cell shortening by 237%, while it increased peak CaT by 167%. For a given level of PIE, ET-1-induced increase in CaT was much smaller than that induced by elevation of [Ca 2+ ] o and by isoprenaline. Therefore, ET-1 shifted the relationship between peak CaT and cell shortening to the left relative to the relationship for increase in [Ca 2+ ] o , an indication that ET-1 increased myo®brillar Ca 2+ sensitivity. 3 KB-R7943 at 0.1 mM and higher inhibited contraction and CaT induced by 0.1 nM ET-1 and at 0.3 mM it abolished the increase in CaT while inhibiting the PIE by 48.1%. Over concentration range of 0.1 ± 0.3 mM, KB-R7943 neither inhibited baseline contraction and CaT nor the isoprenalineinduced response, although at 1 mM and higher it had a signi®cant inhibitory action on these responses. 4 These results indicate that in rabbit ventricular myocytes both increases in CaT and myo®brillar Ca 2+ sensitivity contribute to the ET-induced PIE, and the activation of reverse mode Na + /Ca 2+ exchange may play a crucial role in increase in CaT induced by ET-1 in rabbit ventricular cardiac myocytes.