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The methionine addiction of cancer cells is known as the Hoffman effect. While non-cancer cells in culture can utilize homocysteine in place of methionine for cellular growth, most cancer cells require exogenous methionine for proliferation. It has been suggested that a biochemical basis of this effect is the increased utilization of methionine for S-adenosylmethionine, the major methyl donor for a variety of cellular methyltransferases. Recent studies have pointed to the role of S-adenosylmethionine-dependent protein arginine methyltransferases (PRMTs) in cell proliferation and cancer. To further understand the biochemical basis of the methionine addiction of cancer cells, we compared protein arginine methylation in two previously described isogenic cell lines, a methionine-addicted 143B human osteosarcoma cell line and its less methionine-dependent revertant. Previous work showed that the revertant cells were significantly less malignant than the parental cells. In the present study, we utilized antibodies to detect the asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) products of PRMTs in polypeptides from cellular extracts and purified histone preparations of these cell lines fractionated by SDS-PAGE. Importantly, we observed little to no differences in the banding patterns of ADMA- and SDMA-containing species between the osteosarcoma parental and revertant cell lines. Furthermore, enzymatic activity assays using S-adenosyl-ʟ-[methyl-3H] methionine, recombinantly purified PRMT enzymes, cell lysates, and specific PRMT inhibitors revealed no major differences in radiolabeled polypeptides on SDS-PAGE gels. Taken together, these results suggest that changes in protein arginine methylation may not be major contributors to the Hoffman effect and that other consequences of methionine addiction may be more important in the metastasis and malignancy of osteosarcoma and potentially other cancers.

The reaching motion to the back of the head with the hand is an important movement for daily living. The scores of upper limb function tests used in clinical practice alone are difficult to use as a reference when planning exercises for movement improvements. This cross-sectional study aimed to clarify in patients with mild hemiplegia the kinematic characteristics of paralyzed and non-paralyzed upper limbs reaching the occiput. Ten patients with post-stroke hemiplegia who attended the Department of Rehabilitation Medicine of the Jikei University Hospital and met the eligibility criteria were included. Reaching motion to the back of the head by the participants' paralyzed and non-paralyzed upper limbs was measured using three-dimensional motion analysis, and the motor time, joint angles, and angular velocities were calculated. Repeated measures multivariate analysis of covariance was performed on these data. After confirming the fit to the binomial logistic regression model, the cutoff values were calculated using receiver operating characteristic curves. Pattern identification using random forest clustering was performed to analyze the pattern of motor time and joint angles. The cutoff values for the movement until the hand reached the back of the head were 1.6 s for the motor time, 55° for the maximum shoulder joint flexion angle, and 145° for the maximum elbow joint flexion angle. The cutoff values for the movement from the back of the head to the hand being returned to its original position were 1.6 s for the motor time, 145° for the maximum elbow joint flexion angle, 53°/s for the maximum angular velocity of shoulder joint abduction, and 62°/s for the maximum angular velocity of elbow joint flexion. The numbers of clusters were three, four, and four for the outward non-paralyzed side, outward and return paralyzed side, and return non-paralyzed side, respectively. The findings obtained by this study can be used for practice planning in patients with mild hemiplegia who aim to improve the reaching motion to the occiput.

Traumatic spinal cord injury (TSCI) causes an insult to the central nervous system, often resulting in devastating temporary or permanent neurological impairment and disability, which places a substantial financial burden on the health-care system. This study aimed to clarify the up-to-date epidemiology and demographics of patients with TSCI treated at the largest SCI center in Japan. Data on all patients admitted to the Spinal Injuries Center with TSCI between May 2005 and December 2021 were prospectively collected using a customized, locally designed SCI database named the Japan Single Center Study for Spinal Cord Injury Database (JSSCI-DB). A total of 1152 patients were identified from the database. The study period was divided into the four- or five-year periods of 2005-2009, 2010-2013, 2014-2017, and 2018-2021 to facilitate the observation of general trends over time. Our results revealed a statistically significant increasing trend in age at injury. Since 2014, the average age of injury has increased to exceed 60 years. The most frequent spinal level affected by the injury was high cervical (C1-C4: 45.8%), followed by low cervical (C5-C8: 26.4%). Incomplete tetraplegia was the most common cause or etiology category of TSCI, accounting for 48.4% of cases. As the number of injuries among the elderly has increased, the injury mechanisms have shifted from high-fall trauma and traffic accidents to falls on level surfaces and downstairs. Incomplete tetraplegia in the elderly due to upper cervical TSCI has also increased over time. The percentage of injured patients with an etiology linked to alcohol use ranged from 13.2% (2005-2008) to 19% (2014-2017). Given that Japan has one of the highest aging populations in the world, epidemiological studies in this country will be very helpful in determining health insurance and medical costs and deciding strategies for the prevention and treatment of TSCI in future aging populations worldwide.

BackgroundMechanical insufflation-exsufflation (MI-E) facilitates extubation. However, its potential to reduce the duration of ventilator use remains unclear. Therefore, the present study investigated whether the use of MI-E shortened the duration of mechanical ventilation in patients with high sputum retention.MethodsA randomized open-label trial was conducted at a single intensive care unit (ICU) in Japan between November 2017 and June 2019. Ventilated subjects requiring suctioning at least once every hour due to sputum retention were randomly assigned to the MI-E group or conventional care group. The primary endpoint was the number of ventilator-free days on day 28. Secondary endpoints were ventilator days in surviving subjects, the length of ICU stay, and mortality and tracheostomy rates among survivors.ResultsForty-eight subjects (81% males) with a median age of 72 years (interquartile range [IQR], 65-85 years) were enrolled. There were 27 subjects in the MI-E group and 21 in the control group. The median number of ventilator-free days was 21 (IQR, 13-24) and 18, respectively (IQR, 0-23) (P = .38). No significant differences were observed in the ICU length of stay (median, 10 days (IQR, 7-12) vs 12 days (IQR, 6-15); P = .31), mortality rate (19% vs 15%; odds ratio [OR], 1.36 [0.28-6.50]; P = .69), or tracheostomy rate among survivors (14% vs 28%; OR, 0.40 [0.08-1.91]; P = .25).ConclusionIn ventilated subjects in the ICU with high sputum retention, the use of MI-E did not significantly increase the number of ventilator-free days over that with conventional care.

We investigated the wing vein network topology in fruit flies and observed that the posterior cross vein (PCV) disrupts the symmetry of the entire network. The fluidic engineering function of this vein's disposition remains unexplored although the wing vein network is known to transport blood. We examined the fluid mechanical effects of the PCV's disposition on this blood-transporting network through numerical simulations involving the removal and rearrangement of the vein, avoiding impractical physical manipulation. We characterised the geometry of each wing membrane cell, a portion of the wing membrane surrounded by a group of veins, by determining the ratio of its surface area to the contact area with the veins. We considered this ratio in association with the flow velocities of seeping water from the blood within the veins to the membrane and evaporating water from the membrane, based on the mass conservation law. We observed that the division of a membrane cell by the PCV maximises the ratio of the areas in the divided cell on the wing-tip side by virtually shifting this vein's connections in our geometric membrane model. We derived blood flow rate and pressure loss within the venous network from their geometry, using an analogy of the venous network with a circuit consisting of hydraulic resistors based on Kirchhoff and Ohm's laws. The overall pressure loss in the network decreased by 20% with the presence of the PCV functioning as a paralleled hydraulic resistor. By contrast, any other cross-vein computationally arranged on another membrane cell as the PCV's substitution did not exhibit a larger reduction in the pressure loss. Overall, our numerical analyses, leveraging geometry and a circuit analogy, highlighted the effects of the PCV's presence and position on the blood-transporting vein network.

Offshore wind power (OWP) is a promising way to achieve decarbonization and tackle global climate change, but acceptance by residents is an important issue for site location. Information provision could be a more cost-effective intervention than debates or subsidies, assuming that scientifically correct information alone is insufficient and information design to boost the message effects considering realistic human responses is necessary. Thus, we designed nudging messages to increase acceptance of OWP, using a message framework to moderate risk-averse attitudes by reminding readers of familial support based on insights from kin selection theory from evolutionary psychology. A randomized controlled trial based on an internet survey of more than 4000 responses from the general public was performed to investigate the message effects. The messages significantly moderated the risk-averse attitudes toward OWP by 0.228 on average on a five-point Likert scale, which meant that about 5 people out of 100 changed their attitudes to be safer by 1 point. This suggests that disseminating flyers using nudging messages might be an effective way to increase acceptance. We also extracted responses from those who mentioned fisheries in an open-ended question as an alternative to actual fishers. Responses from this segment were more complex and the message effects were limited compared with those who did not mention fisheries; although the attitudes toward OWP before receiving the messages were safer, reading descriptions for potential risks on fisheries may have unexpectedly led them to focus on the risks of which they were unaware at first. Because information provision based on nudging is effective but just one of a wide variety of political interventions available, practitioners should consider a combination of multiple options instead of using only nudging messages.

Cytoplasmic male sterility (CMS) is a mitochondrial-encoded trait that confers reproductive defects in males but not in females or any vegetative function. Why CMS is so often found in plants should be investigated from the viewpoint of mitochondrial phylogeny. Beta vulgaris, including the wild subspecies maritima and cultivated subspecies vulgaris (e.g., sugar beet), is known to be mitochondrially polymorphic, from which multiple CMS mitochondria have been found, but their evolutionary relationship has been obscure. We first refined the B. vulgaris reference mitochondrial genome to conduct a more accurate phylogenetic study. We identified mitochondrial single-nucleotide polymorphic sites from 600 B. vulgaris accessions. Principal component analysis, hierarchical clustering analysis, and creation of a phylogenetic tree consistently suggested that B. vulgaris mitochondria can be classified into several groups whose geographical distribution tends to be biased toward either the Atlantic or Mediterranean coasts. We examined the distribution of CMS-associated mitochondrial genes from Owen, E- and G-type CMS mitochondria. About one-third of cultivated beets had Owen-type CMS, which reflects the prevalence of using Owen-type CMS in hybrid breeding. Occurrence frequencies for each of the three CMS genes in wild beet were less than 4%. CMS genes were tightly associated with specific mitochondrial groups that are phylogenetically distinct, suggesting their independent origin. However, homologous sequences of the Owen type CMS gene occurred in several different mitochondrial groups, for which an intricate explanation is necessary. Whereas the origin of cultivated beet had been presumed to be Greece, we found an absence of Owen-type mitochondria in Greek accessions. [ABSTRACT FROM AUTHOR]

The methionine addiction of cancer cells is known as the Hoffman effect. While non-cancer cells in culture can utilize homocysteine in place of methionine for cellular growth, most cancer cells require exogenous methionine for proliferation. It has been suggested that a biochemical basis of this effect is the increased utilization of methionine for S-adenosylmethionine, the major methyl donor for a variety of cellular methyltransferases. Recent studies have pointed to the role of S-adenosylmethionine-dependent protein arginine methyltransferases (PRMTs) in cell proliferation and cancer. To further understand the biochemical basis of the methionine addiction of cancer cells, we compared protein arginine methylation in two previously described isogenic cell lines, a methionine-addicted 143B human osteosarcoma cell line and its less methionine-dependent revertant. Previous work showed that the revertant cells were significantly less malignant than the parental cells. In the present study, we utilized antibodies to detect the asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) products of PRMTs in polypeptides from cellular extracts and purified histone preparations of these cell lines fractionated by SDS-PAGE. Importantly, we observed little to no differences in the banding patterns of ADMA- and SDMA-containing species between the osteosarcoma parental and revertant cell lines. Furthermore, enzymatic activity assays using S-adenosyl-ʟ-[methyl-3H] methionine, recombinantly purified PRMT enzymes, cell lysates, and specific PRMT inhibitors revealed no major differences in radiolabeled polypeptides on SDS-PAGE gels. Taken together, these results suggest that changes in protein arginine methylation may not be major contributors to the Hoffman effect and that other consequences of methionine addiction may be more important in the metastasis and malignancy of osteosarcoma and potentially other cancers.

BackgroundThe role of antibiotics in the treatment of Shiga toxin-producing Escherichia coli (STEC) infection is controversial.ObjectivesTo evaluate the association between treatment (antibiotics, antidiarrheal agents, and probiotics) for STEC infection and hemolytic uremic syndrome (HUS) development.Patients and methodsWe performed a population-based matched case-control study using the data from the National Epidemiological Surveillance of Infectious Diseases (NESID) between January 1, 2017 and December 31, 2018. We identified all patients with STEC infection and HUS as cases and matched patients with STEC infection without HUS as controls, with a case-control a ratio of 1:5. Further medical information was obtained by a standardized questionnaire. Multivariable conditional logistic regression model was used.Results7760 patients with STEC infection were registered in the NESID. 182 patients with HUS and 910 matched controls without HUS were selected. 90 patients with HUS (68 children and 22 adults) and 371 patients without HUS (266 children and 105 adults) were included in the main analysis. The matched ORs of any antibiotics and fosfomycin for HUS in children were 0.56 (95% CI 0.32-0.98), 0.58 (0.34-1.01). The matched ORs for HUS were 2.07 (1.07-4.03), 0.86 (0.46-1.61) in all ages treated with antidiarrheal agent and probiotics.ConclusionsAntibiotics, especially fosfomycin, may prevent the development of HUS in children, while use of antidiarrheal agents should be avoided.

Traumatic spinal cord injury (TSCI) causes an insult to the central nervous system, often resulting in devastating temporary or permanent neurological impairment and disability, which places a substantial financial burden on the health-care system. This study aimed to clarify the up-to-date epidemiology and demographics of patients with TSCI treated at the largest SCI center in Japan. Data on all patients admitted to the Spinal Injuries Center with TSCI between May 2005 and December 2021 were prospectively collected using a customized, locally designed SCI database named the Japan Single Center Study for Spinal Cord Injury Database (JSSCI-DB). A total of 1152 patients were identified from the database. The study period was divided into the four- or five-year periods of 2005–2009, 2010–2013, 2014–2017, and 2018–2021 to facilitate the observation of general trends over time. Our results revealed a statistically significant increasing trend in age at injury. Since 2014, the average age of injury has increased to exceed 60 years. The most frequent spinal level affected by the injury was high cervical (C1-C4: 45.8%), followed by low cervical (C5-C8: 26.4%). Incomplete tetraplegia was the most common cause or etiology category of TSCI, accounting for 48.4% of cases. As the number of injuries among the elderly has increased, the injury mechanisms have shifted from high-fall trauma and traffic accidents to falls on level surfaces and downstairs. Incomplete tetraplegia in the elderly due to upper cervical TSCI has also increased over time. The percentage of injured patients with an etiology linked to alcohol use ranged from 13.2% (2005–2008) to 19% (2014–2017). Given that Japan has one of the highest aging populations in the world, epidemiological studies in this country will be very helpful in determining health insurance and medical costs and deciding strategies for the prevention and treatment of TSCI in future aging populations worldwide. [ABSTRACT FROM AUTHOR]

Background: Mechanical insufflation-exsufflation (MI-E) facilitates extubation. However, its potential to reduce the duration of ventilator use remains unclear. Therefore, the present study investigated whether the use of MI-E shortened the duration of mechanical ventilation in patients with high sputum retention. Methods: A randomized open-label trial was conducted at a single intensive care unit (ICU) in Japan between November 2017 and June 2019. Ventilated subjects requiring suctioning at least once every hour due to sputum retention were randomly assigned to the MI-E group or conventional care group. The primary endpoint was the number of ventilator-free days on day 28. Secondary endpoints were ventilator days in surviving subjects, the length of ICU stay, and mortality and tracheostomy rates among survivors. Results: Forty-eight subjects (81% males) with a median age of 72 years (interquartile range [IQR], 65–85 years) were enrolled. There were 27 subjects in the MI-E group and 21 in the control group. The median number of ventilator-free days was 21 (IQR, 13–24) and 18, respectively (IQR, 0–23) (P =.38). No significant differences were observed in the ICU length of stay (median, 10 days (IQR, 7–12) vs 12 days (IQR, 6–15); P =.31), mortality rate (19% vs 15%; odds ratio [OR], 1.36 [0.28–6.50]; P =.69), or tracheostomy rate among survivors (14% vs 28%; OR, 0.40 [0.08–1.91]; P =.25). Conclusion: In ventilated subjects in the ICU with high sputum retention, the use of MI-E did not significantly increase the number of ventilator-free days over that with conventional care. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has been affecting the mental health of hospital workers. During the prolonged pandemic, hospital workers may experience much more severe psychological distress, leading to an increased risk of suicide. This study aimed to investigate changes in psychological effects on hospital workers over 12 months from the beginning of the pandemic and clarify factors associated with psychological distress and suicide-related ideation 1-year after the pandemic's beginning. These repeated, cross-sectional surveys collected demographic, mental health, and stress-related data from workers in 2 hospitals in Yokohama, Japan. The first survey, conducted in March-April 2020, contained the 12-item General Health Questionnaire (GHQ-12) assessing general distress and the Impact of Event Scale-Revised (IES-R) assessing event-related distress. In the second survey in March 2021, hospital workers at the same two hospitals were reassessed using the same questionnaire, and Item 9 of the Patient Health Questionnaire (PHQ-9) was added to assess their suicide-related ideation. The findings of the first and second surveys revealed that the average score of GHQ-12 (3.08 and 3.73, respectively), the IES-R total score (6.8 and 12.12, respectively), and the prevalence rates of severe general distress (35.0% and 44.0%, respectively) and severe event-related distress (7.0% and 17.1%, respectively) deteriorated. The second survey showed that 8.6% of the hospital workers were experiencing suicide-related ideation. Both the general and event-related distress were associated with suicide-related ideation. In these surveys, mental health outcomes among the hospital workers deteriorated over one year from the pandemic's beginning, and their severe psychological distress was the risk factor for the suicide-related ideation. Further studies are needed to compare the psychological effects on hospital workers during and after the prolonged pandemic and to explore appropriate measures to support hospital workers' mental health.

Background A large proportion of adults in Japan remain unmarried even though they intend to marry during their lifetime. To provide data for policy makers and those searching for partners in the Japanese marriage market, we estimated the number and characteristics of unmarried women and men with marriage intention and assessed their partner preferences. Based on the findings, we hypothesized regarding potential mismatches between the individuals available in the marriage market and the type of partners they are looking for. Methods We used data from the National Fertility Survey (2015), a nationally representative survey in Japan, and included 20,344 participants aged 18–49 years, of which 6,568 were unmarried with marriage intention. We estimated the total number of unmarried women and men who intend to marry, extrapolated their characteristics to the Japanese population, and assessed their partner preferences, as well as their ideal age of marriage and the ideal age of their partner. Results In 2015, there were 8.48 million unmarried women and 9.83 million unmarried men aged 18–49 years with marriage intention in Japan. Surpluses of around 600,000 men were observed in non-densely inhabited areas (men-to-women ratio: 1.31) and in the Kanto region (1.23). Most of the women and men in the marriage market had annual incomes lower than 3,000,000 JPY (28,000 USD) and only 263,000 women (3%) and 883,000 men (9%) had an income of 5,000,000 JPY (47,000 USD) or more; 167,000 men (2%) had an income of 7,000,000 JPY (66,000 USD) or more, with roughly three-quarters of them having a university degree. When asked about eight items that one may consider in a potential partner, the proportion of women listing an item as “important” tended to be larger than those of men across all items (education, occupation, finances, personality, mutual hobbies, cooperation/understanding regarding one’s work, and attitude towards/skills in housework and childrearing) except appearance. The largest differences were observed for finances (proportion of women vs. men listing the item as “important” or “would consider:” 94.0% vs. 40.5%, pConclusions By providing data on the number, characteristics and partner preferences of individuals in the marriage market, our study could inform decisions for those searching for marriage partners in Japan. Moreover, we hypothesize that mismatches in geographical location, the supply-demand disparity for partners with higher income, and age preferences could partly explain the large number of Japanese women and men who remain unmarried despite intending to get married. Further studies are needed to assess if, and to what extent, the identified mismatches may affect marriage rates.

Immune suppression during pregnancy and parturition is considered a risk factor that is related to the progression of bovine chronic diseases, such as bovine leukosis, which is caused by bovine leukemia virus (BLV). Our previous studies have demonstrated that prostaglandin E2 (PGE2) suppresses BLV-specific Th1 responses and contributes to the disease progression during BLV infection. Although PGE2 reportedly plays important roles in the induction of parturition, PGE2 involvement in immune suppression during parturition is unknown. To investigate its involvement, we analyzed PGE2 kinetics and Th1 responses in BLV-infected pregnant cattle. PGE2 concentrations in sera were increased, whereas IFN-γ responses were decreased before delivery. PGE2 is known to suppress Th1 immune responses in cattle. Thus, these data suggest that PGE2 upregulation inhibits Th1 responses during parturition. We also found that estradiol was important for PGE2 induction in pregnant cattle. In vitro analyses indicated that estradiol suppressed IFN-γ production, at least in part, via PGE2/EP4 signaling. In vivo analyses showed that estradiol administration significantly influenced the induction of PGE2 production and impaired Th1 responses. Our data suggest that estradiol-induced PGE2 is involved in the suppression of Th1 responses during pregnancy and parturition in cattle, which could contribute to the progression of BLV infection.

Antibiotics disrupt normal gut microbiota and cause dysbiosis, leading to a reduction in intestinal epithelial barrier function. Disruption of the intestinal epithelial barrier, which is known as “leaky gut”, results in increased intestinal permeability and contributes to the development or exacerbation of gastrointestinal diseases such as inflammatory bowel disease and irritable bowel syndrome. We have previously reported on a murine model of intestinal epithelial barrier dysfunction associated with dysbiosis induced by the administration of ampicillin and vancomycin. Saireito, a traditional Japanese herbal medicine, is often used to treat autoimmune disorders including ulcerative colitis; the possible mechanism of action and its efficacy, however, remains unclear. In this study, we examined the efficacy of Saireito in our animal model for leaky gut associated with dysbiosis. C57BL/6 mice were fed a Saireito diet for the entirety of the protocol (day1-28). To induce colitis, ampicillin and vancomycin were administered in drinking water for the last seven consecutive days (day22-28). As previously demonstrated, treatment with antibiotics caused fecal occult bleeding, cecum enlargement with black discoloration, colon inflammation with epithelial cell apoptosis, and upregulation of pro-inflammatory cytokines. Oral administration of Saireito significantly improved antibiotics-induced fecal occult bleeding and cecum enlargement by suppressing inflammation in the colon. Furthermore, Saireito treatment ensured the integrity of the intestinal epithelial barrier by suppressing apoptosis and inducing cell adhesion proteins including ZO-1, occludin, and E-cadherin in intestinal epithelial cells, which in turn decreased intestinal epithelial permeability. Moreover, the reduced microbial diversity seen in the gut of mice treated with antibiotics was remarkably improved with the administration of Saireito. In addition, Saireito altered the composition of gut microbiota in these mice. These results suggest that Saireito alleviates leaky gut caused by antibiotic-induced dysbiosis. Our findings provide a potentially new therapeutic strategy for antibiotic-related gastrointestinal disorders.

Leaf mold of tomato is caused by the biotrophic fungus Cladosporium fulvum which complies with the gene-for-gene system. The disease was first reported in Japan in the 1920s and has since been frequently observed. Initially only race 0 isolates were reported, but since the consecutive introduction of resistance genes Cf-2, Cf-4, Cf-5 and Cf-9 new races have evolved. Here we first determined the virulence spectrum of 133 C. fulvum isolates collected from 22 prefectures in Japan, and subsequently sequenced the avirulence (Avr) genes Avr2, Avr4, Avr4E, Avr5 and Avr9 to determine the molecular basis of overcoming Cf genes. Twelve races of C. fulvum with a different virulence spectrum were identified, of which races 9, 2.9, 4.9, 4.5.9 and 4.9.11 occur only in Japan. The Avr genes in many of these races contain unique mutations not observed in races identified elsewhere in the world including (i) frameshift mutations and (ii) transposon insertions in Avr2, (iii) point mutations in Avr4 and Avr4E, and (iv) deletions of Avr4E, Avr5 and Avr9. New races have developed by selection pressure imposed by consecutive introductions of Cf-2, Cf-4, Cf-5 and Cf-9 genes in commercially grown tomato cultivars. Our study shows that molecular variations to adapt to different Cf genes in an isolated C. fulvum population in Japan are novel but overall follow similar patterns as those observed in populations from other parts of the world. Implications for breeding of more durable C. fulvum resistant varieties are discussed.

Increased exposure to blue or visible light, fluctuations in oxygen tension, and the excessive accumulation of toxic retinoid byproducts places a tremendous amount of stress on the retina. Reduction of visual chromophore biosynthesis may be an effective method to reduce the impact of these stressors and preserve retinal integrity. A class of non-retinoid, small molecule compounds that target key proteins of the visual cycle have been developed. The first candidate in this class of compounds, referred to as visual cycle modulators, is emixustat hydrochloride (emixustat). Here, we describe the effects of emixustat, an inhibitor of the visual cycle isomerase (RPE65), on visual cycle function and preservation of retinal integrity in animal models. Emixustat potently inhibited isomerase activity in vitro (IC50 = 4.4 nM) and was found to reduce the production of visual chromophore (11-cis retinal) in wild-type mice following a single oral dose (ED50 = 0.18 mg/kg). Measure of drug effect on the retina by electroretinography revealed a dose-dependent slowing of rod photoreceptor recovery (ED50 = 0.21 mg/kg) that was consistent with the pattern of visual chromophore reduction. In albino mice, emixustat was shown to be effective in preventing photoreceptor cell death caused by intense light exposure. Pre-treatment with a single dose of emixustat (0.3 mg/kg) provided a ~50% protective effect against light-induced photoreceptor cell loss, while higher doses (1-3 mg/kg) were nearly 100% effective. In Abca4-/- mice, an animal model of excessive lipofuscin and retinoid toxin (A2E) accumulation, chronic (3 month) emixustat treatment markedly reduced lipofuscin autofluorescence and reduced A2E levels by ~60% (ED50 = 0.47 mg/kg). Finally, in the retinopathy of prematurity rodent model, treatment with emixustat during the period of ischemia and reperfusion injury produced a ~30% reduction in retinal neovascularization (ED50 = 0.46mg/kg). These data demonstrate the ability of emixustat to modulate visual cycle activity and reduce pathology associated with various biochemical and environmental stressors in animal models. Other attributes of emixustat, such as oral bioavailability and target specificity make it an attractive candidate for clinical development in the treatment of retinal disease.

Massive intraoperative blood loss (IBL) negatively influence outcomes after surgery for pancreatic ductal adenocarcinoma (PDAC). However, few data or predictive models are available for the identification of patients with a high risk for massive IBL. This study aimed to build a model for massive IBL prediction using a decision tree algorithm, which is one machine learning method. One hundred and seventy-five patients undergoing curative surgery for resectable PDAC at our facility between January 2007 and October 2020 were allocated to training (n = 128) and testing (n = 47) sets. Using the preoperatively available data of the patients (34 variables), we built a decision tree classification algorithm. Of the 175 patients, massive IBL occurred in 88 patients (50.3%). Binary logistic regression analysis indicated that alanine aminotransferase and distal pancreatectomy were significant predictors of massive IBL occurrence with an overall correct prediction rate of 70.3%. Decision tree analysis automatically selected 14 predictive variables. The best predictor was the surgical procedure. Though massive IBL was not common, the outcome of patients with distal pancreatectomy was secondarily split by glutamyl transpeptidase. Among patients who underwent PD (n = 83), diabetes mellitus (DM) was selected as the variable in the second split. Of the 21 patients with DM, massive IBL occurred in 85.7%. Decision tree sensitivity was 98.5% in the training data set and 100% in the testing data set. Our findings suggested that a decision tree can provide a new potential approach to predict massive IBL in surgery for resectable PDAC.

The photochemically-induced thrombosis (photothrombosis) method can create focal cerebral infarcts anywhere in the relatively superficial layers of the cerebrum; it is easy to implement and minimally invasive. Taking advantage of this versatility, we aimed to establish a new rat model of urinary frequency with focal cerebral infarction, which was characterized by its simplicity, nonlethal nature, and high reproducibility. The prefrontal cortex and the anterior cingulate cortex, which are involved in lower urinary tract control, were targeted for focal cerebral infarction, and urinary parameters were measured by cystometrogram. Cystometric analysis indicated that micturition intervals significantly shortened in photothrombosis-treated rats compared with those in the sham operative group on Days 1 and 7 (P < 0.01), but prolonged after 14 days, with no difference between the two groups. Immunopathological evaluation showed an accumulation of activated microglia, followed by an increase in reactive astrocytes at the peri-infarct zone after photothrombotic stroke. Throughout this study, all postphotothrombosis rats showed cerebral infarction in the prefrontal cortex and anterior cingulate cortex; there were no cases of rats with fatal cerebral infarction. This model corresponded to the clinical presentation, in that the micturition status changed after stroke. In conclusion, this novel model combining nonlethality and high reproducibility may be a suitable model of urinary frequency after focal cerebral infarction.

Prostaglandin E2 receptor EP4 is involved in inflammation and related tumorigenesis in the colorectum. This study aimed to investigate the chemopreventive ability of RQ-15986, a selective EP4 antagonist, in colitis-related colorectal tumorigenesis. Male Kyoto APC delta rats, which have APC mutations, were treated with azoxymethane and dextran sulfate sodium and subsequently administered RQ-15986 for eight weeks. At the end of the experiment, the development of colorectal tumor was significantly inhibited in the RQ-15986-treated group. The cell proliferation of the crypts and tumors in the colorectum was decreased following RQ-15986 treatment. RQ-15986 also suppressed the expression of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-6, interleukin-18, and monocyte chemotactic protein-1, in the colon mucosa. In addition, the expression levels of indoleamine 2,3-dioxygenase, which is involved in immune tolerance, were decreased in the colorectal epithelium and tumors of the RQ-15986-treated group. These findings indicate that RQ-15986 inhibits colitis-associated colorectal tumorigenesis by attenuating inflammation, suppressing cell proliferation, and modulating the expression of indoleamine 2,3-dioxygenase. Targeting prostaglandin E2/EP4 signaling might be a useful strategy for chemoprevention of inflammation-related colorectal cancer.

Emotion recognition is known to change with age, but associations between the change and brain atrophy are not well understood. In the current study atrophied brain regions associated with emotion recognition were investigated in elderly and younger participants. Group comparison showed no difference in emotion recognition score, while the score was associated with years of education, not age. We measured the gray matter volume of 18 regions of interest including the bilateral precuneus, supramarginal gyrus, orbital gyrus, straight gyrus, superior temporal sulcus, inferior frontal gyrus, insular cortex, amygdala, and hippocampus, which have been associated with social function and emotion recognition. Brain reductions were observed in elderly group except left inferior frontal gyrus, left straight gyrus, right orbital gyrus, right inferior frontal gyrus, and right supramarginal gyrus. Path analysis was performed using the following variables: age, years of education, emotion recognition score, and the 5 regions that were not different between the groups. The analysis revealed that years of education were associated with volumes of the right orbital gyrus, right inferior frontal gyrus, and right supramarginal gyrus. Furthermore, the right supramarginal gyrus volume was associated with the emotion recognition score. These results suggest that the amount of education received contributes to maintain the right supramarginal gyrus volume, and indirectly affects emotion recognition ability.

BackgroundRespiratory syncytial virus (RSV) is a common cause of acute respiratory infection in children. One of the most important strategies for treatment of an RSV infection is to decide whether the patient needs respiratory support. This study aimed to assess the validity and clinical benefit of the Global Respiratory Severity Score (GRSS) and the Wang bronchiolitis severity score (WBSS) for clinical decision-making regarding providing respiratory support (high-flow nasal cannula, nasal continuous positive airway pressure, or ventilator) in infants with an RSV infection.Study design and methodsThis retrospective cohort study enrolled 250 infants aged under 10 months who were admitted to Atsugi City Hospital with an RSV infection between January 2012 and December 2019. The utility of these scores was evaluated for assessing the need for respiratory support through decision curve analysis by calculating the optimal GRSS and WBSS cut-offs for predicting the need for respiratory support.ResultsTwenty-six infants (10.4%) received respiratory support. The optimal cut-offs for the GRSS and the WBSS were 4.52 and 7, respectively. Decision curve analysis suggested that the GRSS was a better predictive tool than the WBSS if the probability of needing respiratory support was 10-40%.ConclusionsThe GRSS was clinically useful in determining the need for respiratory support in infants aged under 10 months with an RSV infection.

Postoperative delirium (POD) and subsyndromal delirium (SSD) among older patients is a common, serious condition associated with a high incidence of negative outcomes. However, there are few accurate methods for the early detection of POD and SSD in surgical wards. This study aimed to identify risk factors of POD and SSD in older patients who were scheduled for surgery in a surgical ward. This was a prospective observational study. Study participants were older than 65 years, underwent urology surgery, and were hospitalized in the surgical ward between April and September 2019. Delirium symptoms were assessed using the Confusion Assessment Method (CAM) on the preoperative day, the day of surgery, and postoperative days 1-3 by the surgical ward nurses. SSD was defined as the presence of one or more CAM criteria and the absence of a diagnosis of delirium based on the CAM algorithm. Personal characteristics, clinical data, cognitive function, physical functions, laboratory test results, medication use, type of surgery and anesthesia, and use of physical restraint and bed sensor were collected from medical records. Multiple logistic regression analyses were conducted to identify the risk factors for both POD and SSD. A total of 101 participants (mean age 74.9 years) were enrolled; 19 (18.8%) developed POD (n = 4) and SSD (n = 15). The use of bed sensors (odds ratio 10.2, p = .001) was identified as a risk factor for both POD and SSD. Our findings suggest that the use of bed sensors might be related to the development of both POD and SSD among older patients in surgical wards.

Background Bipolar disorder is a mental illness in which manic and depressive states are repeated, causing psychosocial dysfunction. Manic/hypomanic episodes cause problems with interpersonal, social and financial activities, but there is limited evidence regarding the predictors of manic/hypomanic episodes in real-world clinical practice. Methods The multicenter treatment survey on bipolar disorder (MUSUBI) in Japanese psychiatric clinics was administered in an observational study that was conducted to accumulate evidence regarding bipolar disorder in real-world clinical practice. Psychiatrists were asked to complete a questionnaire about patients with bipolar disorder who visited 176 member clinics of the Japanese Association of Neuro-Psychiatric Clinics by conducting a retrospective medical record survey. Our study extracted baseline patient characteristics from September to October 2016, including comorbidities, mental status, duration of treatment, Global Assessment of Functioning (GAF) score, and pharmacological treatment details. We investigated the presence or absence of manic/hypomanic episodes over the course of one year from baseline to September-October 2017. Results In total, 2231 participants were included in our study, 29.1% of whom had manic/hypomanic episodes over the course of one year from baseline. Binomial logistic regression analysis revealed that the presence of manic/hypomanic episodes was correlated with lower baseline GAF scores, rapid cycling, personality disorder, bipolar I disorder, and a mood state with manic or mixed features. Substance abuse was also a risk factor for manic episodes. There was no significant association between a baseline antidepressant prescription and manic/hypomanic episodes. Conclusions In Japan, 29.1% of outpatients with bipolar disorder had manic/hypomanic episodes over the course of one year. Our study suggested that a low GAF score, rapid cycling, personality disorder, bipolar I disorder, substance abuse, and baseline mood state could be predictors of manic/hypomanic episodes. Based on our findings, an antidepressant prescription is not a predictor of manic/hypomanic episodes.

BackgroundSince the COVID-19 pandemic began, there have been concerns related to the preparedness of healthcare workers (HCWs). This study aimed to describe the level of awareness and preparedness of hospital HCWs at the time of the first wave.MethodsThis multinational, multicenter, cross-sectional survey was conducted among hospital HCWs from February to May 2020. We used a hierarchical logistic regression multivariate analysis to adjust the influence of variables based on awareness and preparedness. We then used association rule mining to identify relationships between HCW confidence in handling suspected COVID-19 patients and prior COVID-19 case-management training.ResultsWe surveyed 24,653 HCWs from 371 hospitals across 57 countries and received 17,302 responses from 70.2% HCWs overall. The median COVID-19 preparedness score was 11.0 (interquartile range [IQR] = 6.0-14.0) and the median awareness score was 29.6 (IQR = 26.6-32.6). HCWs at COVID-19 designated facilities with previous outbreak experience, or HCWs who were trained for dealing with the SARS-CoV-2 outbreak, had significantly higher levels of preparedness and awareness (pInterpretationThere was an unsurprising high level of awareness and preparedness among HCWs who participated in COVID-19 training courses. However, disparity existed along the lines of gender and type of HCW. It is unknown whether the difference in COVID-19 preparedness that we detected early in the pandemic may have translated into disproportionate SARS-CoV-2 burden of disease by gender or HCW type.

During development of the Caenorhabditis elegans gonad, the gonadal leader cells, called distal tip cells (DTCs), migrate in a U-shaped pattern to form the U-shaped gonad arms. The ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) family metalloproteases MIG-17 and GON-1 are required for correct DTC migration. Mutations in mig-17 result in misshapen gonads due to the misdirected DTC migration, and mutations in gon-1 result in shortened and swollen gonads due to the premature termination of DTC migration. Although the phenotypes shown by mig-17 and gon-1 mutants are very different from one another, mutations that result in amino acid substitutions in the same basement membrane protein genes, emb-9/collagen IV a1, let-2/collagen IV a2 and fbl-1/fibulin-1, were identified as genetic suppressors of mig-17 and gon-1 mutants. To understand the roles shared by these two proteases, we examined the effects of the mig-17 suppressors on gon-1 and the effects of the gon-1 suppressors and enhancers on mig-17 gonadal defects. Some of the emb-9, let-2 and fbl-1 mutations suppressed both mig-17 and gon-1, whereas others acted only on mig-17 or gon-1. These results suggest that mig-17 and gon-1 have their specific functions as well as functions commonly shared between them for gonad formation. The levels of collagen IV accumulation in the DTC basement membrane were significantly higher in the gon-1 mutants as compared with wild type and were reduced to the wild-type levels when combined with suppressor mutations, but not with enhancer mutations, suggesting that the ability to reduce collagen IV levels is important for gon-1 suppression.

Higher red cell distribution width (RDW) has been reported to predict mortality among patients with various diseases, including chronic kidney disease (CKD). However, whether RDW is associated with renal outcome remains unclear. We investigated the relationship between RDW and renal outcome in patients with non-dialysis-dependent CKD (NDD-CKD). This prospective, observational study of patients with CKD was conducted at a single nephrology department. First, we performed regression analyses for the decline in estimated glomerular filtration rate (eGFR) during the first 3 months of observation to determine its short-term association with RDW. Next, we categorized baseline RDW into two groups by its median (13.5%) and performed Cox regression analyses to investigate whether higher RDW was an independent predictor of renal outcomes defined as a composite of the initiation of dialysis and doubling of the serum creatinine concentration. Furthermore, we repeated the analyses to confirm whether the transition of the RDW category during the first 3 months would also predict renal outcomes. We enrolled 703 patients. Baseline RDW showed a non-linear association with the eGFR decline during the first 3 months, with a greater negative correlation at the lower end of the RDW distribution. Over a median follow-up of 1.8 years, 178 patients (25.3%) reached the renal endpoint. Multivariable Cox regression analyses showed that patients with higher RDW had a higher risk of developing renal outcomes (adjusted hazard ratio [HR]: 1.47, 95% confidence interval [CI]: 1.05-2.07) than did those with lower RDW. Furthermore, patients with sustained, higher RDW demonstrated a significantly higher risk than did those with consistently lower RDW (adjusted HR: 1.65, 95% CI: 1.02-2.67). In conclusion, higher RDW was independently associated with worse renal outcome in patients with NDD-CKD. RDW could be an additional prognostic marker of the progression of CKD.

BACKGROUND:Anticoagulant therapy is recommended in patients with atrial fibrillation (AF) but remains underused. The proper use of anticoagulants has been encouraged in guidelines frequently published over the past two decades. MATERIALS AND METHODS:In this study, we used insurance claims data collected from 2005 to 2014 to investigate the prevalence and incidence of non-valvular AF (NVAF) patients aged 20 to 74 years standardized to the Japanese population in 2012 and subdivided by stroke prevention drug type. We estimated the frequency of coagulation monitoring in patients with incident NVAF undergoing warfarin therapy in 2011 and later. RESULTS:From 2005 to 2014, the standardized prevalence of NVAF increased from 117/100,000 to 278/100,000 and the proportion of anticoagulant users increased from 38.4% to 58.0%, while that of antiplatelet monotherapy decreased from 32.3% to 12.0%. The standardized incidence of NVAF was stable at ~40/100,000 patient-years. The proportion of those patients who started anticoagulant soon after the initial diagnosis increased from 19.9% to 49.1% from 2006 to 2013. Among patients who started warfarin, switchers to DOAC had more frequent coagulation monitoring than non-switchers. CONCLUSION:The use of anticoagulant therapy has gradually increased in patients with NVAF in Japan during the study period from 2005 to 2014.

UDP-glycosyltransferase (UGT) catalyzes the transfer of glycosyl groups (e.g., glucuronic acid) to exogenous or endogenous chemicals and plays an important role in conjugation reactions. In vertebrates, UGT genes are divided into 5 families: UGT1, UGT2, UGT3, UGT5, and UGT8. Among these UGT enzymes, UGT1 and UGT2 enzymes are known to be important xenobiotic metabolizing enzymes in mammals. However, little is known about UGT1 and UGT2 genes in avian species. In this study, we therefore aimed to classify avian UGT1 and UGT2 genes based on their evolutionary relationships. We also investigated the association between UGT molecular evolution and ecological factors, specifically feeding habits, habitat, and migration. By examining the genomes of 43 avian species with differing ecology, we showed that avian UGT1E genes are divided into 6 groups and UGT2 genes into 3 groups. Correlations between UGT gene count and ecological factors suggested that the number of UGT1E genes is decreasing in carnivorous species. Estimates of selection pressure also support the hypothesis that diet influenced avian UGT1E gene evolution, similar to mammalian UGT1A and UGT2B genes.

BACKGROUND:Chemoradiotherapy (CRT) has improved organ preservation or overall survival (OS) of locoregionally advanced head and neck squamous cell cancer (LAHNSCC), but in clinical trials of conventional CRT, increasing CRT intensity has not been shown to improve OS. In the Adjuvant ChemoTherapy with S-1 after curative treatment in patients with Head and Neck Cancer (ACTS-HNC) phase III study, OS of curative locoregional treatments improved more with adjuvant chemotherapy with S-1 (tegafur gimeracil oteracil potassium) than with tegafur/uracil (UFT). ACTS HNC study showed the significant efficacy of S-1 after curative radiotherapy in sub-analysis. We explored the efficacy of S-1 after curative CRT in a subset of patients from the ACTS-HNC study. METHODS:Patients with stage III, IVA, or IVB LAHNSCC were enrolled in this study to evaluate the efficacy of S-1 compared with UFT as adjuvant chemotherapy after curative CRT in the ACTS-HNC study. Patients received S-1 at 80-120 mg/day in two divided doses for 2 weeks, followed by a 1-week rest, or UFT 300 or 400 mg/day in two or three divided doses daily, for 1 year. The endpoints were OS, disease-free survival, locoregional relapse-free survival, distant metastasis-free survival (DMFS), and post-locoregional relapse survival. RESULTS:One hundred eighty patients (S-1, n = 87; UFT, n = 93) were included in this study. Clinical characteristics of the S-1 and UFT arms were similar. S-1 after CRT significantly improved OS (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.22-0.93) and DMFS (HR, 0.50; 95% CI, 0.26-0.97) compared with UFT. CONCLUSION:As adjuvant chemotherapy, S-1 demonstrated better efficacy for OS and DMFS than UFT in patients with LAHNSCC after curative CRT and may be considered a treatment option following curative CRT. For this study was not preplanned in the ACTS-HNC study, the results is hypothesis generating but not definitive.

Patients with a history of non-muscle-invasive bladder cancer sometimes have recurrence of tumors after transurethral resection of bladder tumor treatment. To find factors related to the recurrence of non-muscle-invasive bladder cancer, we examined tissue specimens taken at transurethral resection of bladder tumor as an initial treatment. We revealed the association between prognosis of non-muscle-invasive bladder cancer and infiltration of Foxp3+ T cells that suppress anti-tumor immunity in 115 primary non-muscle-invasive bladder cancer patients retrospectively identified and followed for at least 3 months after primary transurethral resection. In immunohistological staining, we counted the number of cells positive for CD3 and positive for CD3 and Foxp3 together and calculated the percentage of Foxp3+ T cells among the CD3+ T cells. The recurrence-free survival rate was calculated by the Kaplan-Meier method, and a Cox regression analysis of recurrence factors was performed. The median (interquartile range) percentage of Foxp3+ T cells in all cases was 17.1% (11.9, 11.4-23.3%). Compared by risk stratification, it was 11.4% (10.4, 7.8-18.2%) in the low-risk group (n = 32), 16.8% (12.6, 11.6-24.2%) in the intermediate-risk group (n = 45), and 22.0% (9.7, 16.4-26.1%) in the high-risk group (n = 38). The Kaplan-Meier survival analysis indicated that the Foxp3+ T cell high group (≥ 17.1%) had a worse RFS rate than did the low group (< 17.1%) (P = 0.006). In multivariate analysis, the percentage of Foxp3+ T cells was an independent risk factor for intravesical recurrence (hazard ratio 2.25). Thus, peritumoral Foxp3+ T cell infiltration was correlated to risk stratification and recurrence-free survival. Therefore, the percentage of Foxp3+ T cells in tumor specimens may predict a risk for intravesical recurrence.