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During embryogenesis, exocrine and endocrine pancreatic tissues are formed in distinct regions within the branched ductal structure in mice. We previously reported that exocrine-specific inactivation of Pdx1 by Elastase-Cre caused not only hypoplastic exocrine formation but also substantial endocrine defects resulting in diabetic phenotype, indicating the existence of an exocrine-driven factor(s) that regulates proper endocrine development. In this study, we identified Trefoil Factor 2 (TFF2) as an exocrine gene expressed from embryonic day 16.5 to adulthood in normal mice but significantly less in our Pdx1 mutants. Using in vitro explant culture of embryonic pancreatic tissue, we demonstrated that TFF2 prevented the apoptosis of insulin-producing cells but that antagonizing CXCR4, a known TFF2 receptor, suppressed this anti-apoptotic effect in the mutants. Furthermore, the antagonist in normal pancreatic tissue accelerated the apoptosis of insulin-producing cells, indicating that the TFF2/CXCR4 axis maintains embryonic insulin-producing cells in normal development. TFF2 also suppressed the apoptosis of Nkx6.1+ endocrine precursors in mutant pancreata, but this effect was unperturbed by the CXCR4 antagonist, suggesting the existence of an unknown receptor for TFF2. These findings suggest TFF2 is a novel exocrine factor that supports the survival of endocrine cells in the multiple stages of organogenesis through distinct receptors.

Previous reports have revealed that Prospero-related homeobox 1 (Prox1) is required for the migration and differentiation of hepatoblasts during embryonic liver formation. However, the role of Prox1 in adults remains to be elucidated. We created liver-specific Prox1 knockout mice to verify the role of Prox1 in adult hepatocytes. The mutant mice exhibit hepatic injury and a nonobese, insulin-resistant diabetic phenotype in vivo. Hepatocyte injury is observed predominantly in the perivenous region and is characterized by the formation of vacuoles and emergence of round-shaped mitochondria, suggesting that the effect of Prox1 on the maintenance of adult hepatocytes is region dependent. Furthermore, glycolysis is suppressed, and both oxidative phosphorylation and autophagy are upregulated in the livers of Prox1 knockout mice, indicating that Prox1 has a role in regulating energy homeostasis in hepatocytes.

Pancreas transcription factor 1 subunit alpha (PTF1A) is one of the key regulators in pancreatogenesis. In adults, it transcribes digestive enzymes, but its other functions remain largely unknown. Recent conditional knockout studies using Ptf1aCreER/floxed heterozygous mouse models have found PTF1A contributes to the identity maintenance of acinar cells and prevents tumorigenesis caused by the oncogenic gene Kras. However, Ptf1a heterozygote is known to behave differently from homozygote. To elucidate the effects of Ptf1a homozygous loss, we prepared Elastase-CreERTM; Ptf1afloxed/floxed mice and found that homozygous Ptf1a deletion in adult acinar cells causes severe apoptosis. Electron microscopy revealed endoplasmic reticulum (ER) stress, a known cause of unfolded protein responses (UPR). We confirmed that UPR was upregulated by the activating transcription factor 6 (ATF6) and protein kinase RNA (PKR)-like endoplasmic reticulum kinase (PERK) pathways, but not the inositol requiring enzyme 1 (IRE1) pathway. Furthermore, we detected the expression of CCAAT-enhancer-binding protein (C/EBP) homologous protein (CHOP), a pro-apoptotic factor, indicating the apoptosis was induced through UPR. Our homozygous model helps clarify the role PTF1A has on the homeostasis and pathogenesis of exocrine pancreas in mice.

Crohn病（以下CD）に併発し穿孔性腹膜炎で発症した回腸癌の1例を報告する．症例は50歳代男性．11年前より小腸型CDと診断されていた．腹痛・発熱あり受診，腹腔内膿瘍と診断された．保存的治療にて軽快していたが約2カ月後腹痛・発熱が再燃し，小腸穿孔・汎発性腹膜炎と診断し開腹手術を施行した．膿性腹水および回腸の穿孔を認めたが明らかな腫瘤性病変は認めず，穿孔部および狭窄部を切除した．切除標本の精査にて，穿孔部の回腸に漿膜下に達する中分化管状腺癌を認めた．補助化学療法につき患者と相談し，術後は経過観察としたところ，再発のため術後21カ月目に死亡した．CDに併発した小腸癌は本邦では20例あまりの報告しかないが，CD患者の増加に伴って今後増加する可能性がある．CDの癌化リスクの疫学的評価，また有効な早期診断法の確立，また小腸癌の併発の可能性を念頭に置いたCDの経過観察・急性腹症の加療が必要と考えられる．

In the adult pancreas, there has been a long-standing dispute as to whether stem/precursor populations that retain plasticity to differentiate into endocrine or acinar cell types exist in ducts. We previously reported that adult Sox9-expressing duct cells are sufficiently plastic to supply new acinar cells in Sox9-IRES-CreERT2 knock-in mice. In the present study, using Sox9-IRES-CreERT2 knock-in mice as a model, we aimed to analyze how plasticity is controlled in adult ducts. Adult duct cells in these mice express less Sox9 than do wild-type mice but Hes1 equally. Acinar cell differentiation was accelerated by Hes1 inactivation, but suppressed by NICD induction in adult Sox9-expressing cells. Quantitative analyses showed that Sox9 expression increased with the induction of NICD but did not change with Hes1 inactivation, suggesting that Notch regulates Hes1 and Sox9 in parallel. Taken together, these findings suggest that Hes1-mediated Notch activity determines the plasticity of adult pancreatic duct cells and that there may exist a dosage requirement of Sox9 for keeping the duct cell identity in the adult pancreas. In contrast to the extended capability of acinar cell differentiation by Hes1 inactivation, we obtained no evidence of islet neogenesis from Hes1-depleted duct cells in physiological or PDL-induced injured conditions.

Click-evoked otoacoustic emissions were recorded from 28 ears of 20 patients with Meniere's disease. Evoked otoacoustic emissions (EOAEs) were present in 27 ears, although ears with hearing loss exceeding 40 dB HL were included. EOAEs recorded were examined by 100 Hz narrow-band EOAE analysis. This analysis permits easy detection of weak echoes in patients with severe hearing loss and aids in the analysis of characteristics of EOAEs which are composed mainly of fast and slow components. In general, the duration of EOAEs tended to be shorter in the ears of patients with Meniere's disease. There-fore, slow component with longer latency were diminished in amplitude even in patients with slight deafness. In ears with advanced deafness, the slow component disappeared and only the fast component with shorter latency persisted ; ultimately the fast component also disappeared if the hearing was severely impaired. These results suggest the possibility of the clinical application of EOAEs in the diagnosis of Meniere's disease.