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In Japan, older people are expected to comprise 30% of the population as early as 2025. We hypothesized that visiting a zoo or aquarium might be good for their health, compared with visiting a near...

Background There are many obvious health benefits to riding, including developing a strong core and legs, but there are also many less obvious benefits, such as increased confidence and introspection. Few studies have addressed the effects of horseback riding on children and the mechanisms underlying how riding affects humans. We examined the effects of horseback riding on the ability to distinguish Go/No-go tasks and solve arithmetic problems in children. Methods The subjects were 34 boys and 72 girls, aged 10–12 years old, which were divided into three groups (horse riding, walking, and resting). They were healthy typical children, who performed the Go/No-go tasks and solved the arithmetic problems. The heart rate and heart rate variability of the children, and the three-dimensional acceleration of the children while walking horses, were examined. Results Riding on a half-breed horse or a pony improved the ability to perform Go/No-go tasks and solve arithmetic problems, possibly through sympathetic activity. Some horses, like the Kiso, might provide a healing effect to children through parasympathetic activity. Statistically significant differences in the three-dimensional acceleration and the autonomic activities were observed among the three horses. The acceleration in the Kiso horse group during walking in hand was significantly different from those involving the other two horses, indicating that the vibrations produced by these horses might modify the autonomic activities. Conclusion The most important beneficial factor of horseback riding for children and for human health appears to be associated with the horse’s vibrations, which may differ among horses. Riding some horses may improve the ability of children to respond with an appropriate action depending on the situation (Go reaction) or use self-control appropriately (No-go reaction), possibly through the activation of the sympathetic nervous system.

Notch signaling plays an essential role in the proliferation and differentiation of intestinal epithelial cells (IECs). We have previously shown that Notch signaling is up-regulated in the inflamed mucosa of ulcerative colitis (UC) and thereby plays an indispensable role in tissue regeneration. Here we show that in addition to Notch signaling, STAT3 signaling is highly activated in the inflamed mucosa of UC. Forced expression of the Notch target gene Hes1 dramatically enhanced the IL-22-mediated STAT3-dependent transcription in human IECs. This enhancement of STAT3-dependent transcription was achieved by the extended phosphorylation of STAT3 by Hes1. Microarray analysis revealed that Hes1-mediated enhancement of IL-22-STAT3 signaling significantly increased the induction of genes encoding antimicrobial peptides, such as REG1A, REG3A and REG3G, in human IECs. Conversely, the reduction of Hes1 protein levels with a γ-secretase inhibitor significantly down-regulated the induction of those genes in IECs, resulting in a markedly poor response to IL-22. Our present findings identify a new role for the molecular function of Hes1 in which the protein can interact with cytokine signals and regulate the immune response of IECs.

Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract that is frequently accompanied by systemic complications. Neuropathologies have not been well investigated as extraintestinal manifestations of CD. We herein report the case of a 36-year-old man with CD who presented with progressive weakness and numbness. A neurological examination and the results of a nerve conduction study and a sural nerve biopsy led to a diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Plasma exchanges were initially effective; however, the effects gradually declined starting 10 days after the plasma exchange (PE). These results suggest that humoral factors may play an important role in CIDP associated with CD.

Previously reported propellane derivative KNT-42 preferred the κ receptor and functioned as a message part in the message-address concept, but its affinity for the κ receptor was not high. To improve affinity, we synthesized five pentacyclic propellane derivatives designed for the purpose of fixing the conformation of KNT-42. The etheno- and ethano-bridged derivatives SYK-347 and SYK-393 exhibited high affinity and selectivity for the κ receptor, whereas the other derivatives did not. These results would be due to the different ranges of movement of the basic nitrogens and less basicity of the nitrogens due to the electron withdrawing effect of the introduced hydroxy or keto group. SYK-347 and SYK-393 preferring the κ receptor were expected to be useful for designing selective ligands for opioid receptor types, especially the κ receptor.

Notch signaling has previously been implicated in the regulation of the cell fate of intestinal epithelial cells. However, the expression and function of Notch ligands in the human intestine remain largely unknown. In the present study, we showed that Notch ligands Delta-like 1 (Dll1) and Delta-like 4 (Dll4) are expressed in a goblet cell-specific manner in human colonic tissue. Additionally, we found that Dll1 and Dll4 expression was regulated in-parallel with Atoh1 and MUC2, which are both under the control of the Notch-Hes1 signaling pathway. Because knockdown of Dll1 expression completely abrogated the acquisition of the goblet cell phenotype in Notch-inactivated colonic epithelial cells, we postulate that Dll1 might function as a cis-acting regulatory element that induces undifferentiated cells to become goblet cells. Our results suggest a link between Dll1 expression and human goblet cell differentiation that might be mediated by a function that is distinct from its role as a Notch receptor ligand.

The aim of this study was to confirm the effect of dithiothreitol (DTT)-treated spermatozoa on oocyte activation following intracytoplasmic sperm injection (ICSI). Boar spermatozoa with or without DTT treatment (5 mM, 30 min) were injected into in vitro matured porcine oocytes, and the nuclear phase in presumptive zygotes was observed at 3 h intervals up to 12 h after ICSI. Furthermore, developmental competence of embryos produced by DTT-treated or non-treated spermatozoa was monitored after cultivation in vitro for 144 h. Male and female pronuclear formation rates in the oocytes injected with DTT-treated spermatozoa were significantly (P < 0.05) higher than those in the oocytes injected with non-treated spermatozoa. Additionally, we observed that female pronuclear formation was linked to male pronuclear formation. Sperm treatment with DTT improved (P < 0.05) subsequent development up to the blastocyst stage. These findings confirm the efficiency of DTT in in vitro porcine embryo production medi...

The acoustic mode is the most reasonable means for social animals such as dolphins to maintain contact in the underwater habitat, and has been developed since they moved to the sea. This study investigates variations in dolphin vocalizations under the following conditions in a captive environment: 1) before feeding (Pre-feeding), 2) during feeding (Feeding), 3) during free time without the presence of people (Free), 4) during interaction with people located upon a float (Float), 5) during interaction with people in the water (Water). During the experiments, a total of 2642 whistles were extracted from sonogram data using a spectrogram. About 44% of the total whistles were observed during Pre-feeding (1171/2642), and the number recorded during Free, when people were absent, was the smallest. The acoustic contours of dolphin whistles differed in different situations: convex, wave, and trill whistles were made repeatedly during Pre-feeding, thereby being more common at this time than at other times. The situation of Feeding saw an increased number of Upsweeps, which might be related to the use of echolocation. The lower frequencies were recorded during Pre-feeding, reflecting the emotion related to the dolphin's hunger. The results of this study indicate that dolphins increase their vocalization during interaction with people, suggesting that interactions with dolphins provide an effective treatment for human health problems, which is discussed with a reference article in this study. Vocal data obtained during contact with humans might serve as an important index for the dolphin-assisted therapy.

The effects of animal-assisted therapy (AAT) on the physical and physiological health of old people have been well known. In general, dogs, cats and small animals have been used at the AAT for seniors. In this study we tried to clarify physical and mental effects of the interactions of old people and dolphins, with ten people aged from 50 to 60. The blood pressure and the heart rate were measured with a hemodynamometer before and after the activity with the dolphins. The psychological test was performed at the same time, using the Multiple Mood Scale. The results show that the positive emotions of the subjects were increased significantly, with concomitant decreases in the negative emotions. The means of the blood pressures were increased before approaching to dolphins and decreased gradually after the interaction with dolphins. These findings indicate that interactions with dolphins have a relaxed effect upon both mental and physical states of the participants in a short time.

目的:不同視症例において異なるコントラストを持つ視標を用い,コントラスト視力を測定しその視機能を検討する。方法および対象:Wangらにより開発されたWang-Katsumiマルチプルコントラスト視力チャートを使用し,コントラスト視力を測定した。この視力表は90%,15%,3.5%の3つの異なるコントラスト視標とコントラスト90%の逆位相視標(背景が黒で視標が白)の4つのチャートからからなっていて,その配列は幾何学的配列になっている。コントラスト視力は各チャートの合計スコアポイントで表記した。対象は年齢5～11歳の遠視性不同視を有する11症例である。そのうち高コントラスト視標による視力検査により分類した弱視(+)の群が5例,弱視(-)の群が6例であった。結果:弱視(+)の群5例では,屈折異常のより強い眼のコントラスト視力はより弱い眼と比較して4つのチャートすべてにおいて低下が見られた。その平均は屈折異常のより強い眼が20.5ポイントであるのに対し,より少ない眼は30.5ポイントであり,32.8%の低下が見られた。また弱視(-)の群6例では高コントラスト視力による視力結果は良好であるにもかかわらず,屈折異常の強い眼のコントラスト視力は他眼と比較して低下を示した。その平均は屈折異常のより強い眼が26.3ポイントであるのに対し,より少ない眼は31.3ポイントであり,16.0%の低下が見られた。結論:不同視症例の視機能評価,特に弱視の診断には現在使われている高コントラスト視標による視力検査に加えて,中～低コントラスト視標による測定結果を考慮に入れることは有用であると考える。

Bacillus circulans strain YUS-2 was isolated as the strongest antioxidant-producer in fermentation of sesame oil cake (SOC, defatted residue yielded from sesame seed oil production). Two major strong antioxidants from fermented SOC were purified and identified as known sesaminol triglucoside and sesaminol diglucoside, however, our results demonstrated that the fermentation process with B. circulans YUS-2 was highly effective to gain the extraction efficiency of the sesaminol glucosides.

Introduction Inverted Meckel’s diverticulum has usually been misdiagnosed in the cases based on computed tomography images presented in the literature. The final diagnosis was made intra-operatively or by pathology reports after surgery. Despite this, preoperative diagnosis could be made successfully by using endoscopic ultrasound with double-balloon endoscopy prior to surgery. Case presentation A 60-year-old Japanese woman with severe anemia complained of several episodes of black stool over the preceding 2 years. Abdominal computed tomography showed a 3.0-cm low-density tumor in the ileum, suggesting a diagnosis of intestinal lipoma. Examination of the tumor by endoscopic ultrasound with double-balloon endoscopy revealed a hypo-echoic layer corresponding to the muscularis propria, and a hyper-echoic layer corresponding to the fat tissue. These findings, which suggested that the tumor included areas outside the intestinal serosa, are not typical for a lipoma, despite the existence of a hyper-echoic layer corresponding to fatty tissue. We then considered a diagnosis of inverted Meckel’s diverticulum. Conclusion Lipoma and inverted Meckel’s diverticulum are difficult to differentially diagnose by computed tomography. Polypectomy is the preferred therapeutic approach when a lipoma is present; however, polypectomy in a patient with Meckel’s diverticulum requires full-thickness resection. Situations where polypectomy is performed without preparing for full-thickness resection can be avoided by first making a precise diagnosis using double-balloon endoscopy and endoscopic ultrasound.

We designed and synthesized propellane derivatives with a 6- or 7-amide side chain on the basis of the active conformation of the κ selective agonist nalfurafine. The 6-amides showed high affinities for the κ receptor, and one of the 6β-amides showed higher κ selectivity than nalfurafine. On the other hand, although the affinities of the 7-amides decreased compared to the 6-amides, some 7α-amides showed the highest selectivities for the κ receptor among the tested compounds. The affinities of 7β-isomers were extremely low, which was postulated to result from the shielding effect of the 7β-amide side chain against the lone electron pair on the 17-nitrogen. This is the first conformational information about the 7-amide side chain in propellane derivatives.

Notch signaling regulates cell differentiation and proliferation, contributing to the maintenance of diverse tissues including the intestinal epithelia. However, its role in tissue regeneration is less understood. Here, we show that Notch signaling is activated in a greater number of intestinal epithelial cells in the inflamed mucosa of colitis. Inhibition of Notch activation in vivo using a γ-secretase inhibitor resulted in a severe exacerbation of the colitis attributable to the loss of the regenerative response within the epithelial layer. Activation of Notch supported epithelial regeneration by suppressing goblet cell differentiation, but it also promoted cell proliferation, as shown in in vivo and in vitro studies. By utilizing tetracycline-dependent gene expression and microarray analysis, we identified a novel group of genes that are regulated downstream of Notch1 within intestinal epithelial cells, including PLA2G2A, an antimicrobial peptide secreted by Paneth cells. Finally, we show that these functions of activated Notch1 are present in the mucosa of ulcerative colitis, mediating cell proliferation, goblet cell depletion, and ectopic expression of PLA2G2A, thereby contributing to the regeneration of the damaged epithelia. This study showed the critical involvement of Notch signaling during intestinal tissue regeneration, regulating differentiation, proliferation, and antimicrobial response of the epithelial cells. Thus Notch signaling is a key intracellular molecular pathway for the proper reconstruction of the intestinal epithelia.

Musashi-1 (Msi-1) is a RNA-binding protein, known as a putative marker of intestinal stem cells (ISCs). However, little is known about the function of Msi-1 within human intestinal epithelial cells (IECs). Thus, the present study aimed to clarify the role of Msi-1 in differentiation and proliferation of IECs.A human intestinal epithelial cell line stably expressing Msi-1 was established. Proliferation of the established cell lines was measured by bromodeoxyuridine incorporation, whereas differentiation were assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of lineage-specific genes. Activities of the Notch and Wnt pathways were examined either by reporter assays or expression of downstream target genes. The distribution of Msi-1 and PLA2G2A expression in vivo was determined by immunohistochemistry.Constitutive expression of Msi-1 in IECs had no significant effect on cell proliferation, but suppressed expression of Paneth cell-specific genes, including PLA2G2A. Msi-1 appeared to suppress expression of the PLA2G2A gene at the mRNA level. Analysis of Notch and Wnt pathway activity, however, revealed no significant change upon Msi-1 expression. The expression of Msi-1 and PLA2G2A in vivo was restricted to IECs residing at the lowest part of the human intestinal crypt, but was clearly separated to within basal columnar cells or mature Paneth cells, respectively.Msi-1 suppresses expression of Paneth cell-specific genes in IECs, presumably through a pathway independent from Notch or Wnt. These findings suggest Msi-1 is a negative regulator of Paneth cell differentiation, an may contribute to maintain the undifferentiated phenotype of ISCs.

IL-7 is a cytokine, which regulates development, maintenance and proliferation of T lymphocytes within the human immune system. Production of IL-7 is observed in a sterile environment such as thymus or bone marrow. However, it is also known that intestinal epithelial cells (IECs) residing in close contact with numerous bacterial stimuli also produce IL-7. Here we show that secretion of IL-7 by IECs is significantly suppressed upon stimulation by various bacterial components, including flagellin. Analysis of the intracellular mechanism by which flagellin regulates IL-7 production revealed that flagellin down-regulates expression of the two major transcripts encoding IL-7. Surprisingly, such function of flagellin was independent from the known transcriptional regulation of the IL-7 gene, as no significant change was observed in the transcriptional activity regulated by the previously identified promoter region. As the stability of IL-7 mRNA also remained unchanged upon flagellin stimulation, results suggested the possible involvement of a yet unknown transcriptional regulation of the IL-7 gene. These results describe a novel regulation of IL-7 production by bacterial stimuli, presumably mediated via Toll-like receptors. The present system might contribute to regulate the local lymphocyte pool, in response to the gut luminal or sub-mucosal bacterial abundance.

N-Trifluoroacetyl-L-acosamine 20 and N-trifluoroacetyl-L-daunosamine 21 were formally synthesized from an achiral precursor, methyl sorbate 4, based on enzymatic chiral induction and diastereoselective 1, 4-conjugated addition of benzylamine to the olefinic moiety of the α, β-unsaturated ester 12.

Intestinal epithelial cells (IECs) regulate the absorption and secretion of anions, such as HCO3(-) or Cl(-). Bestrophin genes represent a newly identified group of calcium-activated Cl(-) channels (CaCCs). Studies have suggested that, among the four human bestrophin-family genes, bestrophin-2 (BEST2) and bestrophin-4 (BEST4) might be expressed within the intestinal tissue. Consistently, a study showed that BEST2 is expressed by human colonic goblet cells. However, their precise expression pattern along the gastrointestinal tract, or the lineage specificity of the cells expressing these genes, remains largely unknown. Here, we show that BEST2 and BEST4 are expressed in vivo, each in a distinct, lineage-specific manner, in human IECs. While BEST2 was expressed exclusively in colonic goblet cells, BEST4 was expressed in the absorptive cells of both the small intestine and the colon. In addition, we found that BEST2 expression is significantly down-regulated in the active lesions of ulcerative colitis, where goblet cells were depleted, suggesting that BEST2 expression is restricted to goblet cells under both normal and pathologic conditions. Consistently, the induction of goblet cell differentiation by a Notch inhibitor, LY411575, significantly up-regulated the expression of not BEST4 but BEST2 in MUC2-positive HT-29 cells. Conversely, the induction of absorptive cell differentiation up-regulated the expression of BEST4 in villin-positive Caco-2 cells. In addition, we found that the up- or down-regulation of Notch activity leads to the preferential expression of either BEST4 or BEST2, respectively, in LS174T cells. These results collectively confirmed that BEST2 and BEST4 could be added to the lineage-specific genes of humans IECs due to their abilities to clearly identify goblet cells of colonic origin and a distinct subset of absorptive cells, respectively.

Background & Aims: Recent studies have shown that OLFM4 is a robust marker for intestinal epithelial stem cells. However, the precise distribution of OLFM4-expressing cells within the inflamed human intestinal mucosa has never been described. Also, the molecular mechanism regulating its expression within intestinal epithelial cells (IECs), with regard to the inflammatory environment, remains largely unknown. Our previous studies have shown that NotchHes1 pathway is constitutively activated in IECs of the inflamed intestinal mucosa, and function as a key pathway for lineage-specific gene expression. Thus, we planned the present study to identify the distribution of OLFM4-expressing IECs, and also to reveal the underlying molecular mechanism regulating expression of OLFM4, under such an inflammatory environment. Methods: Immunostaining using human intestinal tissues were performed to determine the distribution of OLFM4-expressing cells. The expression level of OLFM4 by IECs in response to various inflammatory cytokines was analyzed by RT-PCR or western blot. Also, tetracycline inducible over-expression of Notch1 intracellular domain (NICD1), or Hes1, was employed to examine the involvement of Notch-Hes1 pathway upon OLFM4 expression. Finally, a series of promoter assay was performed to analyze the transcriptional regulation of the human OLFM4 gene. Results: Immunostaining of normal small intestinal and colonic tissues clearly showed the distribution of OLFM4-positive IECs at the lowest part of the crypt, including the crypt base columnar cells. However, in inflamed intestinal tissues of inflammatory bowel disease patients, increased number of OLFM4-expressing IECs was observed, expanding its distribution to the upper part of the crypt. In LS174T cells, stimulation by TNF-α, but not by IL1-β and IFN-γ, significantly up-regulated the mRNA expression of OLFM4. Also, forced expression of both NICD1 and Hes1 significantly up-regulated mRNA and protein expression of OLFM4. Surprisingly, combination of NICD1 or Hes1 over-expression with TNF-α stimulation had synergistic effect upon up-regulation of OLFM4 mRNA expression, reaching up to 2500 fold increase in LS174T cells. Promoter assays using 5' flanking region of the human OLFM4 gene revealed that such a synergistic effect of TNF-α and Notch-Hes1 pathway is mediated through transcriptional regulation, depending on the proximal NF-κB binding site. Consistently, TNF-αmediated up-regulation of NF-κB-dependent transcriptional activity was significantly enhanced by both NICD1 and Hes1 over-expression in LS174T cells. Conclusion: In the inflamed human intestinal mucosa, TNF-α and Notch-Hes1 pathway synergistically up-regulate expression of OLFM4 in IECs. Such an up-regulation of a stem-cell specific genemight be required to promote the regenerative response of the inflamed intestinal environment.

Background: Transcription factor pancreatic and duodenal homeobox 1 (Pdx1) is essential for pancreatic development and maintaining proper islet function. Null mutant mice lacking Pdx1 are apancreatic and survive only a few days after birth. The role of Pdx1 in modulating intestinal gene expression has therefore yet to be determined in viable mice with normal pancreatic development. Objective: We aimed to identify genes differentially regulated by Pdx1 in response to Pdx1 inactivation restricted to intestinal epithelium. Methods: To conditionally inactivate Pdx1 in the intestine of Pdx1;VilCremice, mutant mice homozygous for loxP site-flanked Pdx1 alleles were crossed with transgenic mice expressing Cre recombinase under the control of mouse villin 1 gene promoter. Total RNA was isolated from the first five centimeters of the small intestine from adult Pdx1;VilCre and littermate control mice. Microarray analysis was then performed to compare genome-wide transcriptional profiles of the proximal small intestine between Pdx1;VilCre and littermate control mice. Differentially expressed genes identified by the microarray analysis were validated by real-time RT-PCR. Results: Among more than thirty-nine thousand mouse transcripts screened by microarray analysis, expression of twenty genes decreased while that of six genes increased more than 2-fold in the proximal small intestine of Pdx1;VilCre mice, as compared to that of control mice (p

Summary With an avidin-biotin-peroxidase (or glucose oxidase) complex method using anti-epidermal growth factor receptor monoclonal antibody (528 IgG), the tissue and cellular distribution of the receptors for epidermal growth factor (EGF) in normal human placental villi, from 6 to 42 weeks of gestation, were studied. EGF receptors were mainly localized on the free surface of the syncytiotrophoblast that directly faced to intervillous space of the maternal circulation. The cell surface of cytotrophoblasts, except for the region that was adjacent to the basal lamina, was also positive for EGF receptors. The receptors were in close contact to the fetal vessels in the villous stroma. The EGF receptors on the syncytiotrophoblast were thought to be involved in the production and secretion of human chorionic gonadotropin and placental lactogen, probably under the control of maternal EGF. The receptors on cytotrophoblasts may play a role in trophoblastic proliferation, possibly mediated by EGF in the fertal circulatory system.