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Difficulty in multi-component self-assembly under thermodynamic control arises from increasing the number of possible isomers with similar thermodynamic stabilities. Past efforts on multi-component self-assembly of metal-organic cages have mainly focused on finding a suitable combination of building blocks to lead to a single multi-component self-assembly as the thermodynamically most stable product. Here, we present another approach to selectively produce multi-component Pd(II)-based self-assemblies under kinetic control based on the selective ligand exchanges of weak Pd–L coordination bonds retaining the original orientation of the metal centers in a kinetically stabilized cyclic structure and on local reversibility given in a certain area of the energy landscape in the presence of the assist molecule that facilitates error correction of coordination bonds. The kinetic approach enabled us to build all six types of Pd2L4 cages and heteroleptic tetranuclear cages composed of three kinds of ditopic ligands. Though the cage complexes thus obtained are metastable, they are stable for 1 month or more at room temperature.

IntroductionThe purpose of this study is to examine the worker’s motivation effect on intellectual concentration by an experiment and a cognitive process simulation. By utilizing the Adaptive Control of Thought-Rational (ACT-R) concept, it helps to understand the cognitive models of the different motivational condition. ACT-R is one of the prevalent cognitive architectures that mainly differ the cognitive process into production modules and declarative modules.Several studies have been investigating the human cognitive performance in respect of others factors such as working environments. Inspirited by previous studies, this study has explored the human motivational factors that might influence intellectual concentration. Additionally, exploring the differences in workers’ individual problem-solving strategy is one of the alluring factors in this study given the differences in motivational conditions.MethodsFive participants were recruited for the experiment the range of their ages between 18-22 years old as a pilot study. The simple summation mathematical task was given during the experiments and shows two numbers on the left side and right side of the monitor screen. They were asked to answer the problem by pressing the numerical keyboard and the answering time was automatically recorded on the experiment program. The eye gaze movements were recorded and analyzed during the experiments. In this study, the participants performed the task under two different motivational conditions. The first condition was set to create the urge to finish the task immediately which generates high motivation to finish the task as fast as they can. The other condition was set in a neutral condition which the participants could perform at their own pace without a rush. From this experiment, approximately 3000 answering time data and 900.000 frames of the eye gaze movement were gathered and analyzed.ResultsThe different motivational conditions influenced the user’s task performance, showing a statistical difference in the user’s answering time in a high motivational and neutral conditions (p < 0.01). The distribution of the answering time follows the log-normal distribution shapes shown by both conditions.The participants performed different strategies in the cognitive task. Following the ACT-R modules, in general, the identified eye gaze patterns are divided into 2 patterns. The first pattern follows the production rules: (1)find-left-number, (2)attend-left-number, (3)encode-left-number, (4)retrieve-left-number, (5)find-right-number, (6)attend-right-number, (7)encode-right-number, (8)waiting-for-start-back, (9)attend-start-back, summation, and (10)keyboard-click. On the other hand, the second pattern follows the production rules: (1)find-left-number, (2)attend-left-number, (3)encode-left-number, (4)retrieve-left-number, (5)find-right-number, (6)encode-right-number, (7)summation, keyboard-click, (8)waiting-for-start-back, and (9)attend-start-back.In the different motivational conditions, the pattern’s appearance is altered. For participants 1, 3, and 5 the second patterns were dominant during the high motivational condition. Some irregular patterns arouse in the last 5 minutes of the task. This condition might due to the degradation of the user’s cognitive performance when the user feels tired and it might be the time duration that affected their cognitive performance. The results of this study might enlighten future research on cognitive performance by proposing a new method of eye gaze pattern identification on ACT-R cognitive models.

Residual strains in a punched electrical steel sheet increase the iron loss in the steel sheet. To accurately estimate the effect of residual strain on iron loss, the residual strain distribution in a punched electrical steel sheet should be evaluated. In this study, we demonstrated the two-dimensional imaging of the residual strain distribution in a punched electrical steel sheet using the neutron Bragg-edge transmission imaging method. To improve the accuracy of strain measurement with minimal deterioration of spatial resolution, we applied a process of superposing many specimen images. The tensile strain near the punched edge and the compressive strain inside the core were experimentally confirmed using this method. Finally, the neutron Bragg-edge imaging results and those obtained from kernel average misorientation map using electron backscattered diffraction were compared to verify the validity of the proposed method.

Aim To evaluate the clinical and molecular characteristics of hepatitis E virus (HEV) infection in Mie Prefecture, Japan, from 2004 through 2018. Methods The clinical information of hepatitis E cases was collected from 21 medical institutions in Mie Prefecture. The nucleotide sequences of infecting HEV strains were determined for cases with available serum samples. The origins or transmission routes were inferred from phylogenetic analyses of the nucleotide sequences. Results Fifty-three patients were diagnosed with HEV infection. The number of cases increased each year through 2012 and then decreased. Analyses of the clinical characteristics of the cases indicated that even mild cases were detected in the latter 10 years of the study. Nucleotide sequence analyses were undertaken on 38 of the 53 cases. The HEV subtype 3e (HEV-3e) strains identified for 13 cases were closely related to a swine HEV-3e strain that was isolated from the liver of a pig bred in Mie Prefecture. The number of cases infected with the indigenous Mie HEV-3e strains increased until 2012 but have not been reported since 2014. In the latter half of the study, cases involving various HEV strains of different genotypes and subtypes emerged. Conclusions The disappearance of indigenous Mie HEV-3e strains appeared to be the primary cause for the decrease in hepatitis E cases in Mie Prefecture. The disappearance might have been associated with improved hygienic conditions on pig farms or the closure of contaminated farms. The results suggest that indigenous HEV strains can be eradicated by appropriate management.

Aim Mutations in lipoprotein-associated phospholipase A2 (Lp-PLA2) are related to atherosclerosis. However, the molecular effects of Lp-PLA2 on atherosclerosis have not been fully investigated. Therefore, this study attempted to elucidate this issue. Methods Monocytes were isolated from randomly selected healthy male volunteers according to each Lp-PLA2 genotype (wild-type Lp-PLA2 [Lp-PLA2 (V/V)], the heterozygous V279F mutation [LpPLA2 (V/F)] and the homozygous V279F mutation [Lp-PLA2 (F/F)]) and differentiated into macrophages. The level of apoptosis in the macrophages following incubation without serum was measured using the annexin V/propidium iodide double staining method, and the underlying mechanisms were further examined using a culture cell line. Results The average plasma Lp-PLA2 concentration [Lp-PLA2 (V/V): 129.4 ng/mL, Lp-PLA2 (V/F): 70.7 ng/mL, Lp-PLA2 (F/F): 0.4 ng/mL] and activity [Lp-PLA2 (V/V): 164.3 nmol/min/mL, LpPLA2 (V/F): 100.9 nmol/min/mL, Lp-PLA2 (F/F): 11.6 nmol/min/mL] were significantly different between each genotype, although the basic clinical characteristics were similar. The percentage of apoptotic cells was significantly higher among the Lp-PLA2 (F/F) macrophages compared with that observed in the Lp-PLA2 (V/V) macrophages. This induction of apoptosis was independent of the actions of acetylated low-density lipoproteins. In addition, the transfection of the expression plasmid of V279F mutant Lp-PLA2 into Cos-7 cells or monocyte/macrophage-like U937 cells promoted apoptosis. The knockdown of Lp-PLA2 also increased the number of apoptotic cells. Among the cells expressing mutant Lp-PLA2, the caspase-7 activity was increased, while the activated Akt level was decreased. Conclusions The V279F mutation of Lp-PLA2 positively regulates the induction of apoptosis in macrophages and Cos-7 cells. An increase in the caspase-7 activity and a reduction in the activated Akt level are likely to be involved in this phenomenon.

Legumain (EC 3.4.22.34) is an asparaginyl endopeptidase. Strong legumain activity was observed in the mouse kidney, and legumain was found to be highly expressed in tumors. We previously reported that bovine kidney annexin A2 was co-purified with legumain and that legumain cleaved the N-terminal region of annexin A2 at an Asn residue in vitro and in vivo. In this study, we found a p53-binding site in intron 1 of the human legumain gene using computational analysis. To determine whether transcription of the legumain gene is regulated by p53, HCT116 cells were transfected with p53 siRNA and the effect of knockdown of p53 expression on legumain expression was examined. The results showed that expression levels of both legumain mRNA and protein were decreased in the siRNA-treated cells. Furthermore, enzyme activity of legumain was also increased by doxorubicin and its activity was reduced by knockdown of p53 in HCT116 cells. These results suggest that legumain expression and its enzyme activity are regulated by p53.

Legumain (EC 3.4.22.34) is an asparaginyl endopeptidase. Strong legumain activity was observed in the mouse kidney, and legumain was highly expressed in tumors. We previously reported that bovine kidney annexin A2 was co-purified with legumain and that legumain cleaved the N-terminal region of annexin A2 at an Asn residue in vitro. In this study, to determine whether annexin A2 is cleaved by legumain in vivo, siRNA-lipoplex targeting mouse legumain was injected into mouse tail veins. Mouse kidneys were then isolated and the effect of knockdown of legumain expression on annexin A2 cleavage was examined. The results showed that both legumain mRNA and protein expression levels were decreased in the siRNA-treated mouse kidneys and that legumain activity toward a synthetic substrate, Z-Ala-Ala-Asn-MCA, was decreased by about 40% in the kidney but not in the liver or spleen. Furthermore, cleavage of annexin A2 at the N-terminal region was decreased in the mouse kidney that had been treated with the legumain siRNA-lipoplex. These results suggest that legumain siRNA was delivered to the kidney by using LipoTrust and that the reduced legumain expression inhibited legumain-induced degradation of annexin A2 in vivo. (C) 2012 Elsevier Inc. All rights reserved.

Noninvasive vascular function measurement plays an important role in detecting early stages of atherosclerosis and in evaluating therapeutic responses. In this regard, recently, new vascular function measurements have been developed. These new measurements have been used to evaluate vascular function in coronary arteries, large aortic arteries, or peripheral arteries. Increasing vascular diameter represents vascular remodeling related to atherosclerosis. Attenuated vascular elasticity may be a reliable marker for atherosclerotic risk assessment. However, previous measurements for vascular diameter and vascular elasticity have been complex, operator-dependent, or invasive. Therefore, simple and reliable approaches have been sought. We recently developed a new automated oscillometric method to measure the estimated area (eA) of a brachial artery and its volume elastic modulus (VE). In this review, we further report on this new measurement and other vascular measurements. We report on the reliability of the new automated oscillometric measurement of eA and VE. Based on our findings, this measurement technique should be a reliable approach, and this modality may have practical application to automatically assess muscular artery diameter and elasticity in clinical or epidemiological settings. In this review, we report the characteristics of our new oscillometric measurements and other related vascular function measurements.

Dipeptidyl peptidase III (DPP III) cleaves dipeptide residues from the N terminus of polypeptides ranging from 3 to 10 amino acids in length and is implicated in pathophysiological processes through the breakdown of certain oligopeptides or their fragments. In this study, we newly identified the biochemical properties of DPP III for angiotensin II (Ang II), which consists of 8 amino acids. DPP III quickly and effectively digested Ang II with K m = 3.7×10 −6 mol/L. In the in vivo experiments, DPP III remarkably reduced blood pressure in Ang II–infused hypertensive mice without alteration of heart rate. DPP III did not affect hemodynamics in noradrenalin-induced hypertensive mice or normotensive mice, suggesting specificity for Ang II. When DPP III was intravenously injected every other day for 4 weeks after Ang II osmotic minipump implantation in mice, Ang II–induced cardiac fibrosis and hypertrophy were significantly attenuated. This DPP III effect was at least similar to that caused by an angiotensin receptor blocker candesartan. Furthermore, administration of DPP III dramatically reduced the increase in urine albumin excretion and kidney injury and inflammation markers caused by Ang II infusion. Both DPP III and candesartan administration showed slight additive inhibition in the albumin excretion. These results reveal a novel potential use of DPP III in the treatment of hypertension and its protective effects on hypertension-sensitive organs, such as the heart and kidneys.

Management of α-sexithiophene (6T) molecular orientation is a key issue to improve the performance of organic photovoltaic (OPV) devices based on 6T thin films, which act as p-type semiconductor layers; however, it is difficult to produce 6T layers with the molecules lying on smooth surfaces, including oxide covered substrates. We have succeeded in orienting the 6T molecules on oriented conductive polythiophene (PT) films, parallel to the oriented PT molecular axis; i.e. parallel to the substrate, by evaporating 6T in vacuum. Here, we reported planar heterojunction (PHJ) OPV devices consisting of 6T films with molecular orientation parallel to the substrate. The orientation of 6T led to improvement of the power conversion efficiency (PCE) in these PHJ OPVs. The average PCE of PHJ OPVs with oriented PT was 2.8 times higher than that without PT. The PCE and the maximum value of the short-circuit photocurrent action spectra of the OPV with the PT was larger under irradiation of polarized light parallel to the 6T molecular axis than that orthogonal to the axis. On the other hand, the PCE and the action spectra of the OPV without the PT did not show the response to polarized light.

High molecular weight kininogen (HK) is a plasma glycoprotein with multiple functions, including the regulation of coagulation. We previously demonstrated that domain 5 (D5 H ), a functional domain of HK, and its derived peptides played an important role in the vitronectin-mediated suppression of cancer cell adhesion and invasion. However, the underlying mechanisms of the D5 H -mediated suppressive effects remain to be elucidated. Here, we showed that D5 H and its derivatives inhibited the collagen-mediated cell adhesion and invasion of human osteosarcoma MG63 cells. Using purified D5 H fused to glutathione- S -transferase (GST) and D5 H -derived peptides for column chromatography, an actin-binding protein, α-actinin-4, was identified as a binding protein of D5 H with high-affinity for P-5m, a core octapeptide of D5 H . Immunofluorescence microscopy demonstrated that D5 H co-localized with α-actinin-4 inside MG63 cells. In addition, exogenous GST-D5 H added to the culture media was transported into MG63 cells, although GST alone as a control was not. As α-actinin-4 regulates actin polymerization necessary for cell adhesion and is related to the integrin-dependent attachment of cells to the extracellular matrix, our results suggest that D5 H may modulate cell adhesion and invasion together with actinin-4.

Background and Aim: Proton pump inhibitor (PPI) monotherapy cannot cure all cases of gastroesophageal reflux disease (GERD), and combination therapy with prokinetics and PPI achieves symptomatic improvement for some GERD patients. Few studies have been performed to predict the need for prokinetics. Methods: Subjects were 163 patients (64 male, mean age 53.1 ± 16.6 years) with GERD symptoms. They were evaluated using the frequency scale for the symptoms of GERD (FSSG), a GERD-specific questionnaire developed in Japan1 and endoscopy. They were administered with rabeprazole 10 mg daily. At 12 and 24 weeks of treatment, subjects were offered a choice of four treatment regimens according to their degree of satisfaction (1, no need for further treatment; 2, opt for continued PPI treatment; 3, step-down to H2RA; 4, dissatisfied with present treatment, so opt for combination treatment with prokinetics, mosapride 5 mg tid). Results: The choice of treatment after 12 weeks of treatment placed 79.1% of subjects in the satisfied group (1, 21; 2, 98; 3, 10). After 24 weeks, 98.2% of subjects were in the satisfied group. Pretreatment FSSG scores were significantly higher in the dissatisfied group (4, 17.4 ± 1.4) than in the satisfied group (1, 12.3 ± 1.3; 2, 12.8 ± 0.8; 3, 10.2 ± 1.8) (P

Legumain/asparaginyl endopeptidase (EC 3.4.22.34) is a novel cysteine protease that is abundantly expressed in the late endosomes and lysosomes of renal proximal tubular cells. Recently, emerging evidence has indicated that legumain might play an important role in control of extracellular matrix turnover in various pathological conditions such as tumor growth/metastasis and progression of atherosclerosis. We initially found that purified legumain can directly degrade fibronectin, one of the main components of the extracellular matrix, in vitro. Therefore, we examined the effect of legumain on fibronectin degradation in cultured mouse renal proximal tubular cells. Fibronectin processing can be inhibited by chloroquine, an inhibitor of lysosomal degradation, and can be enhanced by the overexpression of legumain, indicating that fibronectin degradation occurs in the presence of legumain in lysosomes from renal proximal tubular cells. Furthermore, in legumain-deficient mice, unilateral ureteral obstruction (UUO)-induced renal interstitial protein accumulation of fibronectin and renal interstitial fibrosis were markedly enhanced. These findings indicate that legumain might have an important role in extracellular matrix remodeling via the degradation of fibronectin in renal proximal tubular cells.

Introduction: Simple vascular function measurements are desirable for atherosclerosis risk assessments. Recently, we developed a novel modality of automated oscillometric method to measure a brachial artery’s vascular elastic modulus (V E ) and reported that V E is uninfluenced by blood pressure. Galectin-3 (Gal-3) expressed in endothelial cells regulates vascular fibrosis and is a molecular determinant of vascular stiffness. Hypothesis: We aimed to clarify whether V E selectively correlates with marker of vascular stiffness in chronic kidney disease (CKD). Methods: 12 moderate-to-severe CKD pts (mean eGFR 25.9±23.5 mL/min/1.73m 2 ) and 15 controls were studied. Rest V E in brachial artery was measured by new automated oscillometric detector. V E was defined as follows [VE =ΔPressure/ (100XΔarea/Area) mmHg/%]. Using ultrasound, the brachial artery diameter at rest and during reactive hyperemia [flow mediated dilatation (FMD) with endothelial-dependent dilatation] was measured. Gal-3 and interleukin-6 (IL-6), a representative inflammatory marker, were measured by enzyme-linked immune assay. Results: CKD had lower FMD (4.86±3.37 vs 9.05±2.98 %, P=0.003) and had attenuated V E than control (1.08±0.26 vs 0.83±0.17 mmHg/%, P=0.002). CKD had higher IL-6 (0.67±0.29 vs 0.29±0.33 pg/mL, P=0.003) and higher Gal-3 (20.0±12.4 vs. 5.84±2.83 pg/mL, PE was negatively correlated with %FMD (r=-0.46, P=0.015) and correlated with Gal-3 (r=0.40, P=0.036) but not in IL-6 (r=0.21, P=0.28). Conclusions: Attenuated vascular elasticity detected by this novel approach closely correlated with increase in Gal-3 and reduced FMD in CKD. This may indicate that the attenuated vascular elasticity selectively reflects vascular fibrosis as evidenced by Gal-3 and subsequent endothelial responses to vascular stiffness. Thus, this oscillometric measurement may be useful for detecting vascular fibrosis information and dysfunction in endothelium level.

Objectives: Whether traffic remoteness from health care service in rural areas influences usage of ambulance service has not been well investigated. This study aimed to evaluate the relation between remoteness to health care facilities and incidence of ambulance calls in rural areas of Japan. Methods: We analyzed 155 rural communities of Hiroshima. Data were obtained on all ambulance dispatches from 2010 to 2012. Driving time was calculated from each community to the closest primary/secondary and tertiary health care facility (equivalent to tertiary emergency care centers). We estimated the incidence rate and the incidence rate ratio (IRR) of ambulance calls for each 10-minute increase in the driving time, using generalized log-linear regression models, and evaluated the effect among each specific subgroup of emergency level and season. Results: During the study period, the median incidence rate was 436 per 10 000 people in targeted communities. When driving time to the closest primary/secondary facility increased by an increment of 10 minutes, there was a significant increase in the IRR of ambulance calls, especially during colder seasons (IRR: 1.29 [95% confidence interval: 1.11-1.49]), and this relation was also obtained for most emergency levels. In comparison, there was no such increase in IRRs observed for driving time to a tertiary facility. Conclusion: This study indicated a positive association between remoteness to primary/secondary medical facilities and the frequency of ambulance calls. The remoteness to a primary/secondary health care may induce an increase in ambulance calls, particularly during cold seasons.

Apical ballooning syndrome, the so-called takotsubo cardiomyopathy (TTC), is characterized by wall-motion abnormality. The wall-motion abnormality includes hypokinesis in the mid and apical segments of the left ventricle (LV) with hyperkinesis in the mid LV segment. The LV dysfunction is reversible. TTC has been reportedly been found in 1 to 2 % of patients suspected of having acute coronary syndrome (ACS). Although the wall-motion abnormality of TTC is a significant feature, clinical presentation involving chest pain or ECG abnormalities is similar to that for ACS. Therefore, the diagnosis of TTC is still a challenge in emergency settings. Cardiovascular imaging may assist in the diagnosis and understanding of the pathophysiology of TTC.

Although spliced leader (SL) trans-splicing in the chordates was discovered in the tunicate Ciona intestinalis there has been no genomic overview analysis of the extent of trans-splicing or the make-up of the trans-spliced and non-trans-spliced gene populations of this model organism. Here we report such an analysis for Ciona based on the oligo-capping full-length cDNA approach. We randomly sampled 2078 5'-full-length ESTs representing 668 genes, or 4.2% of the entire genome. Our results indicate that Ciona contains a single major SL, which is efficiently trans-spliced to mRNAs transcribed from a specific set of genes representing approximately 50% of the total number of expressed genes, and that individual trans-spliced mRNA species are, on average, 2-3-fold less abundant than non-trans-spliced mRNA species. Our results also identify a relationship between trans-splicing status and gene functional classification; ribosomal protein genes fall predominantly into the non-trans-spliced category. In addition, our data provide the first evidence for the occurrence of polycistronic transcription in Ciona. An interesting feature of the Ciona polycistronic transcription units is that the great majority entirely lack intercistronic sequences.

Platelet-activating factor acetylhydrolase (PAF-AH) is an enzyme that catalyzes hydrolysis of PAF and is important for regulation of serum PAF concentration. Twenty-seven patients with hyperbililubinemic hepatobiliary diseases (eight patients with liver cirrhosis, five with acute hepatitis and 14 with obstructive cholestasis) were studied. Serum PAF-AH activity was elevated in hyperbilirubinemic condition associated with liver cirrhosis, obstructive cholestasis or acute hepatitis. There was a significant correlation of serum PAF-AH activity with serum cholesterol (r=0.891, P=0.014 in liver cirrhosis, r=0.813, P=0.002 in obstructive cholestasis) or low density lipoprotein (LDL) cholesterol (r=0.771, P=0.007 in obstructive cholestasis). Serum PAF-AH activity/cholesterol ratio and PAF-AH activity/LDL cholesterol ratio were elevated in the three types of hyperbilirubinemic liver disease. LDL cholesterol increased and PAF-AH/LDL cholesterol ratio decreased in acute hepatitis after remission. On the other hand, LDL cholesterol decreased and PAF-AH/LDL cholesterol ratio did not change after treatment in obstructive cholestasis. These findings suggest that, though serum LDL is a factor influencing serum PAF-AH activity in obstructive jaundice, other factors, i.e. reduced biliary PAF-AH excretion, may also influence serum PAF-AH activity in hyperbilirubinemic hepatobiliary diseases.

Legumain (asparaginyl endopeptidase) was purified to homogeneity from bovine kidneys. The molecular mass of the purified enzyme was calculated to be 34000 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis in the presence of beta-mercaptoethanol. The enzyme rapidly hydrolyzed the substrate Z-Ala-Ala-Asn-MCA and was strongly inhibited by N-ethylmaleimide, p-chloromercuribenzene-sulfonic acid, Hg(2+) and Cu(2+). The amino acid sequence of the first 26 residues of the enzyme was Gly-Gly-Lys-His-Trp-Val-Val-Ile-Val-Ala-Gly-Ser-Asn-Gly-Gln-Tyr-Asn-Tyr-Arg-His-Gln-Ala-Phe-Ala-Asp-His-. This sequence is highly homologous to the sequences in the N-terminal of pig kidney legumain. We screened a bovine kidney cortex cDNA library using a DNA probe that originated from rat legumain, and we determined the bovine kidney cDNA structure and deduced the amino acid sequence. The cDNA is composed 1934 bp and encodes 433 amino acids in the coding region. The enzyme was strongly stained in the proximal tubules of the rat kidney in an immunohistochemical study. Vitamin D-binding protein which is known to be a ligand to megalin existing in the proximal tubules, was cleaved in a limited proteolytic manner by bovine kidney legumain. These results suggested that legumain contributes to the processing of macromolecules absorbed by proximal tubule cells. The enzyme also cleaved an N-terminal synthetic peptide of bovine annexin II (Gly(24)-Ser-Val-Lys-Ala-Tyr-Thr(30)-Asn-Phe-Asp-Ala-Glu(35)-Arg-Asp(37)) at a position between Asn(31) and Phe(32). The amino-terminal domain of annexin II has p11 subunit binding sites and phosphorylation sites for both pp60(src) and protein kinase C. This suggests that legumain plays an important role in inactivation and degradation of annexin II, which is abundant in the receptor-recycling compartments of endosomes/lysosomes.

Objectives Responding to the serious shortage of physicians in rural areas, the Japanese government has aggressively increased the number of entrants to medical schools since 2008, mostly as a chiikiwaku, entrants filling a regional quota. The quota has spread to most medical schools, and these entrants occupied 16% of all medical school seats in 2016. Most of these entrants were admitted to medical school with a scholarship with the understanding that after graduation they will practise in designated areas of their home prefectures for several years. The quota and scholarship programmes will be revised by the government starting in 2018. This study evaluates the intermediate outcomes of these programmes. Design Cross-sectional survey to all prefectural governments and medical schools every year from 2014 to 2017 to obtain data on medical graduates. Settings Nationwide. Participants All quota and non-quota graduates with prefecture scholarship in each prefecture, and all the quota graduates without scholarship in each medical school. Primary outcome measures Passing rate of the National License Examination for Physicians and the percentage of graduates who have not bought out the scholarship contract after graduation. Results Most prefectures and medical schools in Japan participated in this study (97.8%–100%). Quota graduates with scholarship were significantly more likely to pass the National License Examination for Physicians than the other medical graduates in Japan at all the years (97.9%, 96.7%, 97.4% and 94.7% vs 93.9%, 94.5%, 94.3% and 91.8%, respectively). The percentage of quota graduates with scholarship who remained in the scholarship contract 3 years after graduation was 92.2% and 89.9% for non-quota graduates with scholarship. Conclusions Quota entrants showed better academic performance than their peers. Most of the quota graduates remained in the contractual workforce. The imminent revision of the national policy regarding quota and scholarship programmes needs to be based on this evidence., This study is funded by the Ministry of Education, Culture, Sports, Science and Technology KAKENHI Grant-in-Aid for Scientific Research (C), Grant Number (25460803).

In the field of computer graphics and 3-D visual communication, ray-based representation of 3-D scenes/objects has been studied. The most popular way to acquire light ray data is to take perspective projection images from multiple viewpoints, however, light rays are equivalent to orthogonal projections. This difference in projection causes errors in images synthesized from light rays. To solve this problem, we have developed a capturing system using telecentric optics, which provides orthogonal projections of objects. This system captures light rays with an angular resolution of 0.09° by rotating object (s) and taking orthogonal projection images automatically. In this paper, we discuss the implementation of the telecentric capturing system. In particular, we focus on the errors caused by disarrangement of the system's components or lens distortion, and show some methods for measuring and correcting errors. Furthermore, experimental results show the applicability of the system for acquiring light ray data as orthogonal projections and synthesizing arbitrary views.

INTRODUCTION Non-physician community' (NPC) is a policy term that indicates a medically underserved area in Japan. Designated NPCs are politically targeted as the foci of medical resource allocation. NPC is defined as a specified district where 50 or more persons dwell within a geographic diameter of 4 km and medical care is not easily accessible. The definition of NPC was first introduced in 1960 and has been unchanged for more than half a century despite radical social changes in rural Japan. This study examines whether designated NPCs are still more disadvantaged in terms of geographical access to healthcare in comparison to other communities. METHODS Hiroshima prefecture, which has the largest number of NPCs in terms of tertiary healthcare areas of Japan, was used as the study area. Targeted communities were all the NPCs in the prefecture, and, as controls, two community groups were selected: non-NPC adjacent to NPC, and municipal center. We measured driving time from NPCs and control communities to the nearest healthcare facilities, which were classified into the following two types: primary or secondary care facilities (n=2636) and tertiary care facilities (equal to tertiary emergency care centers; n=6). We further calculated the driving time to the nearest facilities for secondary emergency care (n=246) extracted from the 2636 primary or secondary care facilities. RESULTS The median driving times to the nearest primary or secondary healthcare facility for NPC, non-NPC, and municipal center were 11 minutes, 11 minutes, and 1 minute, respectively; the times to a tertiary healthcare facility (equal to an accident and emergency care center) were 80 minutes, 84 minutes, and 68 minutes, respectively; and the times to a secondary emergency care facility were 24 minutes, 18 minutes, and 15 minutes, respectively. Although a municipal center was significantly more advantageous in driving time compared to a primary or secondary care facility, the disadvantage of a NPC in access was no more obvious than an adjacent non-NPC for any type of healthcare facility. CONCLUSIONS NPCs had a disadvantage in access time to primary, secondary and tertiary medical care compared with a municipal center. NPCs, however, did not have a greater access disadvantage in comparison to adjacent rural communities for any type of medical facility. As such, future resource allocation policies in Japan need to redefine medically underserved communities.

Fluorescence spectroscopy has been applied in the investigation of water content in micelles of polyethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) triblock copolymers at 20 and 50 °C. The triblock copolymers examined consist of Pluronic F68® (F68) and Pluronic L64® (L64), which are known to form micelles with cores of PPO and shells of PEO in aqueous solutions. 2- p-Toluidinylnaphthalene-6-sulfonic acid (TNS) is used as a fluorescence probe. Several fluorescence parameters of TNS are employed as tools to evaluate the water content in the micelles: (1) the wavelength at maximal intensity, which strongly depends on the polarity and viscosity of the surrounding media; and (2) the degree of polarization (P) and lifetime, which give the microviscosity of the media through the Perrin-Weber equation. Aqueous solutions of PEO of various compositions are used as standard solutions. It is found that the water content in F68 and L64 micelles ranges from 10 to 70 wt %, depending on the size of the PEO block, concentration of the polymer, and temperature. The usefulness of fluorescence spectroscopy in the studies of block copolymer micelles is demonstrated along with some comments on the interpretation of P of the TNS probe.

Background and aim Low-grade fasting hyperbilirubinemia is a common observation in healthy subjects (HS), whereas high-grade fasting hyperbilirubinemia is believed to be a characteristic finding of Gilbert's syndrome. This study was undertaken to assess the role of mutation in bilirubin UDP- glycosyltransferase gene (UGT1A1) on fasting hyperbilirubinemia. Methods Analysis of UGT1A1 and a caloric restriction test (400 kcal for 24 h) were performed in 56 healthy subjects (25 males, 31 females), and 28 patients with Gilbert's syndrome (18 males, 10 females). There were 29 healthy subjects with no mutation in UGT1A1, and 27 healthy subjects and 26 Gilbert's syndrome patients with mutations in the coding and/or promoter (TATA box) regions of UGT1A1. Results The mean increment of serum bilirubin (DeltaSB) was 7.6 micromol/L [corrected] (males) and 4.1 micromol/L (females) in subjects with no UGT1A1 mutation. Subjects with mutation in UGT1A1 showed higher levels of DeltaSB than individuals without mutation. Among healthy subjects, gender difference in DeltaSB values was observed only in individuals with the wild type of UGT1A1, but not in those with mutations in this gene. Conclusion The results of the present study suggest that UGT1A1 mutation has a role in the development of high-grade fasting hyperbilirubinemia after caloric restriction.

Bilirubin is taken up from blood into hepatocytes by sinosuidal membrane transporters and then excreted into bile through the bile canalicular membrane mainly as bilirubin glucuronides. (1) Mechanism of bilirubin uptake into hepatocytes: many organic anions are incorporated into hepatocytes by organic anion transporting polypeptides (rat, oatp 1, oatp2, oatp3; human, OATP), liver-specific transporter (rlst/HLST), and/or by organic anion transporters (OAT2, OAT3). Oatp1 and HLST transport bilirubin monoglucuronide. However, a transporter of unconjugated bilirubin in the sinusoidal membrane has not as yet been identified. Unconjugated bilirubin may also go across the hepatocyte sinusoidal membrane by a diffusion process. (2) Intrahepatic transport and conjugation of bilirubin: ligandin carries bilirubin to the endoplasmic reticulum (ER) of hepatocytes. In the ER, bilirubin is conjugated by bilirubin uridine diphosphate (UDP)-glycosyltransferase (bilirubin UGT; UGT1A1) to form mono- and diglucuronides of bilirubin. (3) Transport mechanism of bilirubin glucuronides across the hepatocyte canalicular membrane: at the canalicular membrane, bilirubin glucuronides are excreted into bile by multidrug resistance-associated protein 2 (MRP2), a member of the ATP-binding cassette transporter family. (4) Regurgitation of bilirubin glucuronides into blood: MRP3, which is located in the lateral membrane, transports bilirubin glucuronides into blood under conditions of impaired biliary bilirubin excretion.

A ray-based method has been proposed as a neutral description method for various kinds of 3-D images. In this paper, we propose a new method for converting a set of range and color data of 3-D objects obtained by a range finder into ray data. This method enables us to handle range data in the same manner as other kinds of 3-D images and to use conventional image processing techniques to improve the quality of reconstructed images. Furthermore, to compensate for the missing of range data caused by some restrictions inherent to a range finder, we examine the ray-based merging method of multiple sets of range and color data of the same object, which are obtained under different conditions. Experimental results show the usefulness of the proposed method to facilitate a range finder as an input device of 3-D information in an integrated 3-D communication system.

People's engagement in community activities is reportedly stronger in rural areas than in urban areas. However, it is unknown whether this affects the health-seeking behaviour of residents in rural communities. We examined whether the rurality-related index of a community was associated with the participation rate of residents in community-based preventive health services. Based on the national census data on all the 1816 municipalities in Japan in 2007, the correlation was evaluated between the participation rate in cancer screening (stomach cancer, colorectal cancer) or influenza vaccination programmes among those older than 65, and each of the municipality-level variables. The correlations were examined by simple correlation and multiple regression analyses. The correlations were also evaluated between voting rate (a parameter of people's engagement in community activities) and each municipality-level variable with multiple regression analysis. Simple correlation analysis showed that the population density was negatively correlated with the participation rate of all (stomach cancer, colorectal cancer, and influenza) preventive programmes (r = -0.367, -0.171 and -0.188, respectively; each p0.001). The significant correlations were maintained even after adjustment for other socioeconomic factors in multiple regression analysis in stomach cancer screening and influenza vaccination (beta = -0.279 and -0.133, respectively: each p0.05). Population density was negatively correlated with voting rate (beta = -0.488: p0.001). Residents in rural communities were more likely to participate in community-based mass preventive services and were more actively engaged in political activities than their urban counterparts. These results suggest that rural residents have a stronger sense of community, and this could potentially facilitate residents' engagement in mass preventive services.

Introduction For an equitable distribution of health resources, resource-allocation policies focus on rural and also remote areas, assuming that these areas are underserved. However, definitions of 'rural' and 'remote' vary, and are not necessarily synonymous with 'underserved'. This Japanese study evaluated the association between the rurality/remoteness of the community in which a patient lives and his/her geographic accessibility to dialysis facilities. Methods Based on 1867 communities (census blocks) in Hiroshima Prefecture, Japan, predictive powers of five community-level rural/remote parameters (population size, population density, elderly rate, agriculture rate, and distance to the nearest city) were evaluated to identify communities where dialysis patients had a longer commute time to dialysis facilities. The proportion of low-access communities was examined when those communities were merged to form larger geographic units (four-level stepwise merger). One-way driving times of dialysis patients were used as the access parameter of a community and were calculated using geographic information systems based on the addresses of all the 7374 patients certified by municipalities as having renal disability, and on the addresses and capacities of all 98 dialysis facilities in Hiroshima. Results The average driving time was negatively correlated with population and population density, and positively correlated with elderly rate, agriculture rate, and distance to nearest city. When low-access was defined as >20, >30 & >40 min driving time, all rural/remote parameters showed better sensitivities (range 63.5-94.9%) than specificities (55.2-77.9%) to identify low-access communities, and positive predictive values were less than 50% for most parameters. When low-access was defined as >30 min driving time, the proportion of low-access communities substantially decreased when the geographic unit was expanded. In the administrative 'rural' area, the largest geographic unit, the percentage of low-access communities was 30%. Conclusions In any definition of 'rural/remote', and in any definition of 'low-access', the rural/remote areas contain a substantial proportion of high-access communities. In addition, a substantial proportion of low-access communities was excluded from rural/remote areas. The accuracy of the term 'low-access' deteriorated when the geographic unit of analysis was expanded. In order to identify underserved areas precisely, it is necessary to set the geographic unit of analysis as small as possible and measure the geographic accessibility itself, rather than designate some areas as 'rural' or 'remote', based on conventional geographic/demographic/distance parameters.

Introduction : Japan has the highest elderly rate of population in the world. In 2012, the government implemented the community-based integrated care system, which integrates various health-related resources within the community through cooperation among formal, long-term care facilities, welfare and medical care specialists, and informal voluntary activities by the residents. The system was first born in a rural town in Hiroshima. Description of the policy : This presentation shows how a trial in a typical rural town achieved the community-based integrated care system, influenced the governmental policies, and became the first model for the subsequent nationwide reform of healthcare system. In 1970s, the aging population has been prominent in Mitsugi. At that time, care for the elderly was fragmented into various service sections. An integrated care system marshaling all services and providing an integrated delivery system, which was later called the community-based integrated care system, has been gradually constructed in Mitsugi as follows. Firstly, in 1970s, the hospital started providing home-visit services; doctors, nurses, long-term care workers and the like would visit patients’ houses, support their life at home instead of patients coming to the hospital. It promoted linkage between care services in the hospital and at home. Secondly, the Health Management Center was opened as an annex of the hospital in 1984. This center involved some departments of the municipal government, which had been responsible for the preventive, welfare and long-term care services in those days. It enabled the hospital to play a role in not only medical but also preventive, welfare and long-term care services, which facilitated providing these services seamlessly. Thirdly, long-term care facilities such as a nursing home and a group home for demented elderly patients were established. These facilities made long-term care possible for the elderly people that cannot be cared for at home. Lastly, Mitsugi launched volunteers’ action by community citizens to help the elderly with the cooperation of the hospital. This volunteer system has formed the connection between residents and the hospital, which has made more seamless community-cooperative comprehensive care possible. Results : After the system, the proportion of bedridden people decreased remarkably from 3.5 to 1% in this town. In addition, this system realized slowing growth of healthcare costs, while they were then rapidly increasing throughout the rest of Japan. Although healthcare costs for elderly in Mitsugi were above average in Hiroshima prefecture until about 1985, the status has since been reversed, maintaining a lower level than the prefectural mean. After its success, the first community-based integrated care system case in Mitsugi became the model for the national policy implemented in 2012. Highlights : Success in a small rural town can influence the entire country. This is the first case of diffusion of a healthcare system from rural to urban areas, which is unusual. The reasons why the first community-based integrated care system arose in Mitsugi are the aging of the population, easy integration of services due to its small size, the economic support from the prefecture, and existence of a leader that coordinated different sectors of healthcare. Conclusion : There are three future tasks to sustain the community-based integrated care system. Firstly, the system suitable for each community should be constructed. Secondly, vigorous resident participation is needed in this system so that they can find and introduce neighbors that need medical or long-term care services to the system. Finally, finding ways to reduce the costs for medical and long-term care services at a nationwide level.

Introduction: Given the shortage of physicians, particularly in rural areas, the Japanese government has rapidly expanded the number of medical school students by adding chiikiwaku (regional quotas) since 2008. Quota entrants now account for 17% of all medical school entrants. Quota entrants are usually local high school graduates who receive a scholarship from the prefecture government. In exchange, they temporarily practise in that prefecture, including its rural areas, after graduation. Many prefectures also have scholarship programmes for non-quota students in exchange for postgraduate in-prefecture practice. The objective of this cohort study, conducted by the Japanese Council for Community-based Medical Education, is to evaluate the outcomes of the quota admission system and prefecture scholarship programmes nationwide. Methods and analysis: There are 3 groups of study participants: quota without scholarship, quota with scholarship and non-quota with scholarship. Under the support of government ministries and the Association of Japan Medical Colleges, and participation of all prefectures and medical schools, passing rate of the National Physician License Examination, scholarship buy-out rate, geographic distribution and specialties distribution of each group are analysed. Participants who voluntarily participated are followed by linking their baseline information to data in the government’s biennial Physician Census. Results to date have shown that, despite medical schools’ concerns about academic quality, the passing rate of the National Physician License Examination in each group was higher than that of all medical school graduates. Ethics and dissemination: The Ethics Committee for Epidemiological Research of Hiroshima University and the Research Ethics Committee of Nagasaki University Graduate School of Biomedical Sciences permitted this study. No individually identifiable results will be presented in conferences or published in journals. The aggregated results will be reported to concerned government ministries, associations, prefectures and medical schools as data for future policy planning., This study is funded by the Ministry of Education, Culture, Sports, Science and Technology KAKENHI Grant-in-Aid for Scientific Research (C), grant number (25460803).

A case of epithelioid hemangioma of the duodenum causing bleeding was encountered. A 32-year-old man was admitted because of anemia. Endoscopic examination revealed a submucosal tumor with central depression in the 2nd portion of the duodenum. It was considered to be the bleeding focus of anemia. A partial resection of the duodenum was performed. The macro- and microscopic examination of the specimen revealed an epithelioid hemangioma. Hemangiomas of the intestinal tract are rare, representing only 0.3% of all tumors of the intestinal tract, and among them, hemangiomas of the duodenum are extremely rare, representing only 3.4% of those of the intestinal tract. Most hemangiomas of the duodenum are cavernous hemangiomas or capillary hemangiomas. We report the first case of epithelioid hemangioma of the duodenum.

Backgrounds The geographic disparity of prevalence rates among dialysis patients is unclear. We evaluate the association between travel time to dialysis facilities and prevalence rates of dialysis patients living in 1,867 census areas of Hiroshima, Japan. Furthermore, we study the effects of geographic features (mainland or island) on the prevalence rates and assess if these effects modify the association between travel time and prevalence. Methods The study subjects were all 7,374 people that were certified as the “renal disabled” by local governments in 2011. The travel time from each patient to the nearest available dialysis facility was calculated by incorporating both travel time and the capacity of all 98 facilities. The effect of travel time on the age- and sex-adjusted standard prevalence rate (SPR) and 95% confidence intervals (CIs) at each census area was evaluated in two-level Poisson regression models with 1,867 census areas (level 1) nested within 35 towns or cities (level 2). The results were adjusted for area-based parameters of socioeconomic status, urbanity, and land type. Furthermore, the SPR of dialysis patients was calculated in each specific subgroup of population for travel time, land type, and combination of land type and travel time. Results In the regression analysis, SPR decreased by 5.2% (95% CI: −7.9–−2.3) per 10-min increase in travel time even after adjusting for potential confounders. The effect of travel time on prevalence was different in the mainland and island groups. There was no travel time-dependent SPR disparity on the islands. The SPR among remote residents (>30 min from facilities) in the mainland was lower (0.77, 95% CI: 0.71–0.85) than that of closer residents (≤30 min; 0.95, 95% CI: 0.92–0.97). Conclusions The prevalence of dialysis patients was lower among remote residents. Geographic difficulties for commuting seem to decrease the prevalence rate.

Phosphatidylethanolamine-binding proteins (PEBPs) are found in various species and have multiple functions. In this study, we purified the swine homolog of human PEBP4 (sPEBP4) from swine seminal plasma, cloned the sPEBP4 cDNA and functionally characterized this protein. The molecular mass of the purified protein was calculated to be 25 kDa by SDS-polyacrylamide gel electrophoresis under reducing conditions. The full-length cDNA of sPEBP4 contains 815 bp with an open reading frame of 669 bp that encodes a protein 222 residues in length. sPEBP4 contains a putative phosphatidylethanolamine-binding domain between residues 79 and 195; however, this domain did not show lipid binding activity. The overall amino acid sequence identity of PEBP4s from swine, human, mouse, bovine and canine ranges between 56.1% and 82.4%. Immunohistochemical staining and western blotting analysis showed that sPEBP4 is secreted from epithelial cells in the epididymis to the seminal plasma. To explore the role of sPEBP4 in the seminal plasma, we tested the effect of sPEBP4 on swine sperm motility. Sperms suspended in phosphate-buffered saline began to swim after the addition of purified sPEBP4, but not when swine serum albumin was added, indicating that sPEBP4 promotes sperm motility.

e17 www.thelancet.com Vol 378 December 3, 2011 2 Flouri E, Buchanan A. Early father’s and mother’s involvement and child’s later educational outcomes. Br J Educ Psychol 2004; 74: 141–53. 3 United Nations Division of Economic and Social Aff airs (DESA), Division for Social Policy and Development (DSPD). Men in families and family policy in a changing world. http://www. un.org/esa/socdev/family/docs/men-infamilies.pdf (accessed Nov 16, 2011). 4 Buchanan A, Flouri E. Father involvement and outcomes in adolescence and adulthood. Swindon: Economic and Social Research Council, 2001. http://www.esrc.ac.uk/my-esrc/grants/ R000223309/read (accessed Nov 22, 2011). 5 Lorber MF, Engeland B. Parenting and infant diffi culty: testing a mutual exacerbation hypothesis to predict early onset conduct problems. Child Dev 2011; published online Oct 25. DOI:10.1111/j.1467-8624.2011.01652.x. action requires training. Furthermore, eff ective advocacy eff orts require mindfulness of certain skills such as eff ective education, community engagement and organisation, and policy development. Incorporation of advocacy into our work and in the training of our future physicians will allow us to become better doctors for our patients. Only if words are followed by action can universities produce professionals capable of addressing the everchanging health needs of our society.

Context In post-war Japan, a number of factors lead to a general shortage of physicians by the 1950s, which became acute in rural areas and has continued until recent times. Issue Teamwork among national, prefectural, municipal governments and public medical schools has addressed this shortage of physicians. The national government doubled the number of medical schools in the 1960s and 1970s; each of the country's 47 prefectures, whether rural or not, has at least one medical school. In rural areas where private hospitals are not profitable, municipal governments have funded public hospitals and physician recruitment from their own budgets. A cooperative project among Japan's 47 prefectural governments and the national government established Jichi Medical University (JMU), which conducts a bound medical education program followed by obligatory rural service. As a result, the number of 'non-physician communities' (muichiku) nationwide has decreased by 73%; however, the gap between physician concentrations in urban and rural areas has not changed. Therefore, the government has recently implemented a JMU-like contractual program as a form of 'rural quota' at other medical schools in all 47 prefectures. If all the replicated programs work as successfully as JMU, the impact on the geographic distribution of physicians will be substantial. Lessons learned The Japanese public-sector-led rural physician securing system could also be effective in countries where rural healthcare provision is the responsibility of the public sector and close cooperation among levels of government is possible.

We found that factor H (FH) exists in porcine seminal plasma. Purified FH strongly inhibited serum alternative pathway complement activation against lipopolysaccharide. The molecular weight, pI, and heparin-binding activity of the purified protein were different from those of purified FH from porcine serum. The complement regulatory activity of seminal plasma FH was approximately 2-fold stronger than that of serum FH. Treatment of purified serum FH with sialidase and N-glycosidase F gave almost the same results as those of seminal plasma FH. The deletion of sialic acid from the carbohydrate chains of both FHs contributed to heparin-binding and complement regulatory activities. Results of reverse transcriptase-PCR, Western blot analysis, and immunohistochemistry showed that seminal plasma FH is mainly secreted from epithelial cells of the seminal vesicle in male genital tracts. FH was also detected in the outer acrosomal region of ejaculated sperm by immunofluorescence staining, and found that the purified FH from the sperm membrane has the same complement regulatory activity as that of seminal plasma FH. The ejaculated sperm possessing FH in the outer acrosomal region considerably evaded complement attack. We also found that there is strong complement activity in fluids from female genital tract ducts. These findings indicate that FH bound to the outer acrosomal region and soluble FH play important roles in protecting sperm against complement attack in male and female genital tracts.