Akira Fukui

Peptic ulcer is prevalent among shift workers.

To elucidate sleep disturbances in the etiology of peptic ulcers, the prevalence of peptic ulcer disease was compared among shift workers and daytime workers. The subjects (N=11,657) were employees of various institutions, such as factories, banks, or schools, and had undergone a mass x-ray examination of the upper gastrointestinal tract. With present shift workers (N=2269), the prevalence of gastric ulcers was 2.38% (N=54) and that of duodenal ulcers, 1.37% (N=31). With the past shift workers (N=2111), the prevalence of gastric ulcers was 1.52% (N=32) and that of duodenal ulcers, 0.62% (N=13). On the contrary, with the daytime workers (N=6525) the prevalence of gastric ulcer was 1.03% (N=67) and that of duodenal ulcer, 0.69% (N=45). The working schedule for 752 examinees was unknown. The prevalence of gastric and duodenal ulcers was higher with shift workers than daytime workers. Thus, shift work involving sleep disturbances may play an important role in the development of peptic ulcers.

Xenobiotic Kidney Organogenesis from Human Mesenchymal Stem Cells Using a Growing Rodent Embryo

Given the limits of allogenic organ transplantation, an ultimate therapeutic solution is to establish a self-organ from autologous stem cells and transplant them as syngrafts back into donor patients. It was reported previously that human mesenchymal stem cells (hMSC) that are cultivated in growing rodent embryos can differentiate within a spatially and temporally appropriate developmental milieu, facilitating the first step of nephrogenesis. As another step toward clinical application, the system was modified for progression to complete functional organogenesis. Rat embryos (E11.5) were isolated from uteri, and bone marrow-derived hMSC, which were transfected adenovirally with glial cell line-derived neurotrophic factor and retrovirally with LacZ, were implanted into the nephrogenic site. Forty-eight hours later, ureteric buds were elongated and initial branching was completed. The metanephroi were dissected out, developed further using in vitro organ culture for 24 h, transplanted into the omentum of a uninephrectomized rat, and grown for 2 wk. They enlarged and exhibited normal kidney structure and ultrastructure. hMSC-derived LacZ-positive cells were identified throughout the regenerated kidney and were morphologically identical to resident renal cells. Transplantation of developing metanephroi into the LacZ transgenic rat revealed that neo-kidney vasculature originated from the host circulation. Finally, fluid was collected from expanded ureters, and urea nitrogen and creatinine were measured. Levels were much higher in these fluids compared with transplanted rat sera (840.3 +/- 184.6 versus 30.4 +/- 10.8 and 10.1 +/- 3.1 versus 0.3 +/- 0.2 mg, respectively), suggesting that the neo-kidney may produce urine. Taken together, these findings suggest that hMSC can differentiate into a mature renal structure with the potential to replace lost kidney function.

Coemergence of Insomnia and a Shift in the Th1/Th2 Balance toward Th2 Dominance

Objectives: Insomnia is associated with physical and mental disorders. We examined the effect of insomnia on immune functions, focusing on the T helper 1 (Th1)/ T helper 2 (Th2) balance, by a cross-sectional design. Methods: We provided a self-administered questionnaire to evaluate sleep habits, smoking and medical disorders to 578 men without any toxic exposure (20–64 years old), and measured natural killer (NK) cell activity in 324 men and production of interferon-gamma (IFN-γ) and interleukin-4 (IL-4) after stimulation with phytohemagglutinin in 254 men. According to the criteria of DSM-IV, in which insomnia is classified into primary and secondary insomnia, we assessed the effect of insomnia on immune functions, controlling for age and smoking in groups with and without medical disorders. Results: The prevalence of insomnia in the present study was 9.2%. In the absence of medical disorders, insomniac men had a significantly lower IFN-γ and ratio of IFN-γ to IL-4 than noninsomniac men. Men with insufficient sleep or difficulty initiating sleep (DIS) had a significantly lower IFN-γ to IL-4 ratio than those not suffering from insufficient sleep or DIS. In the presence of medical disorders, insomniac men had significantly higher IL-4 than noninsomniac men. Men with difficulty maintaining sleep (DMS) had a significantly lower IFN-γ to IL-4 ratio than men without DMS. NK cell activity was independent of insomnia. Conclusions: The present results showed a link between insomnia unrelated to medical disorders and a shift in the Th1/Th2 balance toward Th2 dominance, indicating that the relationship between sleep quality and the etiology of immune-related diseases should be reconsidered.

Generation of a transplantable erythropoietin-producer derived from human mesenchymal stem cells.

Differentiation of autologous stem cells into functional transplantable tissue for organ regeneration is a promising regenerative therapeutic approach for cancer, diabetes, and many human diseases. Yet to be established, however, is differentiation into tissue capable of producing erythropoietin (EPO), which has a critical function in anemia. We report a novel EPO-producing organ-like structure (organoid) derived from human mesenchymal stem cells. Using our previously established relay culture system, a human mesenchymal stem cell-derived, human EPO-competent organoid was established in rat omentum. The organoid-derived levels of human EPO increased in response to anemia induced by rapid blood withdrawal. In addition, the presence of an organoid in rats suppressed for native (rat) EPO production enhanced recovery from anemia when compared with control animals lacking the organoid. Together these results confirmed the generation of a stem cell-derived organoid that is capable of producing EPO and sensitive to physiological regulation.

Integration of human mesenchymal stem cells into the Wolffian duct in chicken embryos

Developing animal embryos have been providing human mesenchymal stem cells (hMSCs) with an appropriate environment for their differentiation between species. We previously demonstrated that hMSCs transplanted into the metanephric mesenchyme region of rat embryos differentiate into kidney-specific cells. Here, we assessed whether hMSCs are competent to differentiate into precursors of the collecting duct system when they are transplanted into the ureteric bud progenitor region of chicken embryos that are easier to be manipulated and cultured than mammalian embryos. When chicken Pax2-expressing hMSCs were transplanted into the chicken ureteric bud progenitor region, they migrated caudally with the elongating Wolffian duct and then were integrated into the Wolffian duct epithelia. Also, chicken Pax2-expressing hMSCs started to express human LIM1 after their integration into the Wolffian duct epithelia. These results suggest that chicken Pax2-expressing hMSCs can be competent to differentiate into the Wolffian duct cells by the influence of chicken local signals.

A Thermoreversible Polymer Mediates Controlled Release of Glial Cell Line-Derived Neurotrophic Factor to Enhance Kidney Regeneration

Previously, we reported that human mesenchymal stem cells (hMSCs) that were cultivated in growing embryos differentiated in an appropriate developmental milieu, thereby facilitating the development of a functional renal unit. However, this approach required transfection with an adenovirus that expressed glial cell line-derived neurotrophic factor (GDNF) to enhance the development of hMSC-derived renal tissue, and safety issues restrict the clinical use of such viral vectors. To circumvent this problem, we tested an artificial polymer as a means to diffuse GDNF. This GDNF-polymer, which exists in liquid form at 4 degrees C but becomes a hydrogel upon heating to 37 degrees C, was used as a thermoreversible switch, allowing the injection of hMSCs at low viscosity using a mouth pipette, with subsequent slow diffusion of GDNF as it solidified. The polymer, which was dissolved in a solution of GDNF at 4 degrees C and then maintained at 37 degrees C, acted as a diffuser of GDNF for more than 48 h. LacZ-transfected hMSCs and the GDNF-polymer (at 4 degrees C) were placed in the nephrogenic sites of growing rat embryos that were maintained at 37 degrees C. Forty-eight hours later, the resultant kidney anlagen were dissected out and allowed to continue developing for 6 days in vitro. Whole-organ X-Gal staining and fluorescence activated cell sorter analysis showed that the number of hMSC-derived cells was significantly increased in developed anlagen that have been generated from hMSCs plus GDNF-polymer compared with those from hMSCs plus GDNF-containing medium and was comparable to those from adenovirus-transfected hMSCs. These findings suggest that the GDNF-polymer can be used as a diffuser of GDNF for kidney organogenesis.

Stem cells and kidney organogenesis.

The discovery of tissue stem cells has launched the current boom in the field of regenerative research, which is tremendously exciting and holds enormous therapeutic potential. Despite such optimism, recent findings have tempered the potential for medical practice. Anatomically complicated organs, such as the kidney, have proved refractory to stem cell-based regenerative techniques. As the kidney has the capacity to regenerate after renal injury, investigations into the mechanisms underlying kidney organogenesis may provide the clues to solving the puzzle of complex organ regeneration. This article reviews the current understanding of kidney organogenesis and kidney stem cells, and discusses the potential of kidney organogenesis as a therapeutic strategy for renal failure.

The Role of H2 Receptors in Gastric Mucosal Blood Flow

To determine the relation between H2 receptors and gastric mucosal blood flow, we measured the latter in rats by the electrolytically generated hydrogen gas clearance technique. The blood flow increased significantly after intravenous injection of 0.1 mg/kg of impromidine, a very potent and specific agonist of H2 receptors. On the other hand, gastric mucosal blood flow decreased significantly after intravenous administration of 5 or 20 mg/kg of cimetidine or 2 mg/kg of famotidine. However, 2 or 20 rng/kg of omeprazole, whose anti-secretory effect is as strong as that of H2 blockers such as cimetidine and famotidine, caused no significant change in the gastric rnucosal blood flow. This indicates that H2 receptors regulate gastric mucosal blood flow in rats.

EFFECTS OF PROSTAGLANDIN D2 AND OMEPRAZOLE ON INDOMETHACIN-INDUCED GASTRIC ULCERS IN RATS

1. The mechanism of indomethacin‐induced gastric ulcers was investigated by measuring tissue prostaglandins (PG) levels.

Renal histopathological findings in relation to ambulatory blood pressure in chronic kidney disease patients

Recent studies have demonstrated that ambulatory blood pressure monitoring is useful for predicting the long-term renal prognosis and future cardiovascular events in chronic kidney disease patients. Currently, however, information is limited regarding the relationships between individual renal histopathological findings and abnormalities in ambulatory blood pressure. This retrospective cross-sectional study included a total of 138 patients, in whom both renal biopsies and ambulatory blood pressure monitoring were performed during the same admission period. Renal histopathological findings, including global glomerulosclerosis, interstitial fibrosis/tubular atrophy and the presence of arterial lesions and arteriole lesions, were scored and analyzed in relation to the ambulatory blood pressure values. Among these histopathological characteristics, only the severity of interstitial fibrosis/tubular atrophy exhibited a significant association with an increased mean value of daytime and nighttime blood pressure. However, the remaining histopathological features showed only trends or weak relationships with these values. In addition, a moderately advanced grade of interstitial fibrosis/tubular atrophy was found to be significantly associated with both daytime and nighttime hypertension, independent of the kidney function, overt proteinuria and the use of antihypertensive medications, according to multivariate analyses. Furthermore, the night-to-day ratio of the mean blood pressure displayed a significant increasing trend according to the grade of interstitial fibrosis/tubular atrophy. These results suggest that interstitial fibrosis/tubular atrophy is the most relevant renal histopathological parameter associated with abnormalities in ambulatory blood pressure, including nocturnal hypertension, in this population.