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The Hayabusa2 spacecraft returned to Earth from the asteroid 162173 Ryugu on 6 December 2020. One day after the recovery, the gas species retained in the sample container were extracted and measured on-site and stored in gas collection bottles. The container gas consists of helium and neon with an extraterrestrial 3 He/ 4 He and 20 Ne/ 22 Ne ratios, along with some contaminant terrestrial atmospheric gases. A mixture of solar and Earth's atmospheric gas is the best explanation for the container gas composition. Fragmentation of Ryugu grains within the sample container is discussed on the basis of the estimated amount of indigenous He and the size distribution of the recovered Ryugu grains. This is the first successful return of gas species from a near-Earth asteroid.

Background and Aims: Recognition of heart failure with preserved ejection fraction (HFpEF) at an early stage in mass screening is desirable, but difficult to achieve. We examined whether the fibrosis (Fib)-4 index, a simple index of liver stiffness/fibrosis, could be used as a screening tool to select candidates requiring expert diagnostics., Methods: Individuals who participated in annual health checks between 2006 and 2007 in Arita-cho, Saga, Japan, with no history of cardiovascular disease and EF ≥ 50% were enrolled (total 710; 258 men; median age, 59 years)., Results: Participants were divided into 5 groups according to HFpEF risk: 215 (30%), 100 (14%), 171 (24%), 163 (23%), and 61 (9%) with Heart Failure Association (HFA)-PEFF scores of 0, 1, 2, 3, and 4-6 points, respectively. The highest HFpEF risk group (HFA-PEFF score, 4-6 points) showed poor prognosis for the clinical events of all-cause mortality and hospitalization for HF (log-rank test, P  = .002). The Fib-4 index was correlated with HFpEF risk stratification (r s  = 0.526), and increment in the Fib-4 index was independently linked to high HFpEF risk by multiple logistic regression analysis (adjusted odds ratio, 1.311; 95% confidence interval, 1.078-1.595; P  = .007). The Fib-4 index stratified clinical prognosis (log-rank test, P < .001) was an independent predictor of all-cause mortality and hospitalization for HF (hazard ratio, 1.305; 95% confidence interval, 1.139-1.495; P < .001)., Conclusion: The Fib-4 index can be used to select appropriate candidates for a detailed examination of HFpEF in a subclinical population., (© 2023 The Authors.)

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that shows progressive muscle weakness. A few treatments exist including symptomatic therapies, which can prolong survival or reduce a symptom; however, no fundamental therapies have been found. As a therapeutic strategy, enhancing muscle force is important for patients' quality of life. In this study, we focused on skeletal muscle-specific myosin regulatory light chain kinase (skMLCK), which potentially enhances muscle contraction, as overexpression of skMLCK was thought to improve muscle function. The adeno-associated virus serotype 6 encoding skMLCK (AAV6/skMLCK) and eGFP (control) was produced and injected intramuscularly into the lower limbs of SOD1 G37R mice, which are a familial ALS model. AAV6/skMLCK showed the successful expression of skMLCK in the muscle tissues. Although the control did not affect the muscle force in both of the WT and SOD1 G37R mice, AAV6/skMLCK enhanced the twitch force of SOD1 G37R mice and the tetanic force of WT and SOD1 G37R mice. These results indicate that overexpression of skMLCK can enhance the tetanic force of healthy muscle as well as rescue weakened muscle function. In conclusion, the gene transfer of skMLCK has the potential to be a new therapy for ALS as well as for other neuromuscular diseases.

Aims: Natriuretic peptides have reportedly been associated with cardiac hypertrophy and insulin resistance; however, it has not been established if B-type natriuretic peptide (BNP) is associated with either insulin resistance or cardiac remodelling in a population with normal plasma BNP levels. We investigated the relationship among plasma BNP levels, insulin resistance, and left ventricular (LV) remodelling in a population with normal physiological plasma BNP levels., Methods and Results: Among 1632 individuals who participated in annual health checks between 2005 and 2008 in Arita-cho, Saga, Japan, 675 individuals [median (interquartile range) for age 62 (51-69) years; 227 men (34%)] with LV ejection fraction 50% and BNP level <35 pg/mL were enrolled in this study. Insulin resistance was assessed using homeostatic model assessment of insulin resistance (HOMA-IR). LV geometry, including LV concentric remodelling, was classified based on relative wall thickness (RWT) and LV mass index values derived from echocardiographic findings. Factors associated with insulin resistance and LV geometry were investigated using multiple logistic regression analysis. Tertiles of BNP were inversely associated with HOMA-IR [1st tertile, 1.33 (0.76-1.74); 2nd tertile, 1.05 (0.72-1.59); 3rd tertile, 0.95 (0.66-1.58), P = 0.005]. Lower BNP was associated with the prevalence of insulin resistance, defined as HOMA-IR ≥1.37, even after full multivariate adjustment [1 SD increment in BNP = adjusted odds ratio (aOR) 0.740; 95% confidence interval (CI) 0.601-0.912; P = 0.005]. LV concentric remodelling (RWT >0.42; LV mass index ≤115 g/m 2 in men and ≤95 g/m 2 in women) was observed in 107 (16%) participants, while normal LV geometry (RWT ≤0.42; LV mass index ≤115 g/m 2 in men and ≤95 g/m 2 in women) was seen in 423 (63%), and LV hypertrophy (LV mass index >115 g/m 2 in men and >95 g/m 2 in women) in 145 (21%). Both low BNP level and higher insulin resistance were independently linked to LV concentric remodelling after multivariate adjustment (1 SD increment in BNP = aOR 0.714, 95% CI 0.544-0.938, P = 0.015; HOMA-IR ≥ 1.37 vs. <1.37: aOR 1.694, 95% CI 1.004-2.857, P = 0.048, respectively)., Conclusions: Lower BNP levels are linked to either insulin resistance or LV concentric remodelling in a population with normal plasma BNP levels, suggesting that participants with lower natriuretic peptide level might be vulnerable to the development of metabolic disorders and LV morphological abnormalities., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Dynamin (DNM) is a family of large GTPases possessing a unique mechanical ability to "pinch" off vesicles entering cells. DNM2 is the most ubiquitously expressed member of the DNM family. We developed a novel tool based on elastin-like polypeptide (ELP) technology to quickly, precisely, and reversibly modulate the structure of DNM2. ELPs are temperature-sensitive biopolymers that self-assemble into microdomains above sharp transition temperatures. When linked together, DNM2 and a temperature-sensitive ELP fusion organize into a range of distinct temperature-dependent structures above a sharp transition temperature, which were not observed with wild-type DNM2 or a temperature-insensitive ELP fusion control. The structures comprised three different morphologies, which were prevalent at different temperature ranges. The size of these structures was influenced by an inhibitor of the DNM2 GTPase activity, dynasore; furthermore, they appear to entrap co-expressed cytosolic ELPs. Having demonstrated an unexpected diversity of morphologically distinct structures, DNM2-ELP fusions may have applications in the exploration of dynamin-dependent biology.

The Z-scanner is the major component limiting the speed performance of all current high-speed atomic force microscopy systems. Here, we present an ultrafast piezoelectric Z-scanner with a resonance frequency above 1.1 MHz, achieving a record response time of ∼0.14 µs, approximately twice as fast as conventional piezoelectric-based Z-scanners. In the mechanical design, a small piezo-stack is supported at its bottom four vertices on a cone-like hollow, allowing the resonance frequency of the Z-scanner to remain as high as that of the piezo in free vibration. Its maximum displacement, ∼190 nm at 50 V, is large enough for imaging bio-molecules. For imaging bio-molecules in a buffer solution, the upper half of the Z-scanner is wrapped in a thin film resistant to water and chemicals, providing an excellent waterproof and mechanical durability without lowering the resonance frequency. We demonstrate that this Z-scanner can observe actin filaments, fragile biological polymers, for more than five times longer than the conventional Z-scanner at a tip velocity of 800 µm/s.

Presented here are the observations and interpretations from a comprehensive analysis of 16 representative particles returned from the C-type asteroid Ryugu by the Hayabusa2 mission. On average Ryugu particles consist of 50% phyllosilicate matrix, 41% porosity and 9% minor phases, including organic matter. The abundances of 70 elements from the particles are in close agreement with those of CI chondrites. Bulk Ryugu particles show higher δ 18 O, Δ 17 O, and ε 54 Cr values than CI chondrites. As such, Ryugu sampled the most primitive and least-thermally processed protosolar nebula reservoirs. Such a finding is consistent with multi-scale H-C-N isotopic compositions that are compatible with an origin for Ryugu organic matter within both the protosolar nebula and the interstellar medium. The analytical data obtained here, suggests that complex soluble organic matter formed during aqueous alteration on the Ryugu progenitor planetesimal (several 10's of km), <2.6 Myr after CAI formation. Subsequently, the Ryugu progenitor planetesimal was fragmented and evolved into the current asteroid Ryugu through sublimation.

Purpose: Evaluate the patients in two neonatal intensive care units in Paraná/Brazil and identify the risk factors for the development of retinopathy of prematurity., Methods: We performed a prospective cohort study on premature infants with gestational age ≤32 wk and/or with birth weight ≤1500 g who were admitted to the neonatal intensive care unit of Hospital do Trabalhador and Hospital Infantil Waldemar Monastier. These hospitals admit patients referred from other maternity hospitals in the state of Paraná. The study duration was 12 mon., Results: The incidence of retinopathy of prematurity was higher in the Hospital Infantil Waldemar Monastier than in the Hospital do Trabalhador for premature infants who needed to be transported from their birthplace to the intensive care unit (52.2% vs. 29.6%). The following risk factors were associated with the development of the disease: longer hospitalization, low gestational age at birth, longer oxygen use, vasoactive drugs use, no antenatal corticosteroids use, intracranial hemorrhage, and any glycemic disorder. Low birth weight was an independent risk factor for the development of retinopathy of prematurity., Conclusion: Early neonatal care and transportation of premature infants may influence the occurrence and prognosis of retinopathy of prematurity.

Aims/introduction: This cohort study assessed the risk for bodyweight gain and development of glucose intolerance based on the frequency of consumption of balanced meals including grain, fish or meat and vegetables., Materials and Methods: The participants (8,573 men, 3,327 women) were employees of a company in Japan. A self-administered questionnaire was used to evaluate the frequency of balanced meal consumption. Bodyweight changes and the incidence of glucose intolerance (glycated hemoglobin >6.0%) during the 3-year follow-up period were determined through annual health examinations., Results: The mean bodyweight change over a period of 3 years was 0.78 kg for men and 0.84 kg for women. A lower frequency of balanced meals was associated with a higher bodyweight gain for men (P for trend = 0.004), but not for women. During the study, 464 men and 115 women developed glucose intolerance. Overall, the frequency of balanced meals was not associated with the risk of glucose intolerance in either sex. However, the interaction between the frequency of balanced meals and degree of obesity had a significant effect on the incidence of glucose intolerance in men (P = 0.005), with less frequent consumption of balanced meals being associated with a higher risk for glucose intolerance among men with a BMI ≥25.0 kg/m 2 (P for trend = 0.007)., Conclusions: A higher frequency of balanced meals, including grain, fish or meat and vegetable dishes - important components of healthy Japanese food - was associated with a lower risk of glucose intolerance in obese men, but not in non-obese men and women., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Introduction: Oncology nurses are key in caring for older adults with cancer, but few have received specialized training in gerontology. To address this, a geriatric oncology curriculum was developed for oncology nurses., Materials & Methods: The Geriatric Oncology Workshop (GrOW) was developed and delivered to oncology nurses (n = 387) from 2016 to 2019. Workshops were evaluated using: 1) Assessment of preparedness, comfort, and skills; 2) Knowledge gained; 3) Participant evaluations of workshop (4-point Likert-type scale); 4) Faculty evaluations (10-point Likert-type scale); and 5) Follow-up assessment of goals. Descriptive statistics (frequencies, proportions, medians, means) were used to describe participants and results. Paired t-test was used to evaluate participants' knowledge gain, and linear mixed modeling was used to evaluate longitudinal changes in preparedness, comfort, and skill levels., Results: Overall, 387 oncology nurses participated in GrOW. Participant-rated workshop evaluation means were 3.7 to 3.9. Overall, nurses had statistically significant increases in pre- to post- questionnaire scores of 18.8% (p < 0.001) in workshop 1, 26.8% (p < 0.001) in workshop 2, 24.9% (p < 0.001) in workshop 3, and 18.6% (p < 0.001) in workshop 4, with an overall mean of 22.4% (p < 0.001) knowledge gained for all four workshops. Nurses reported an increase in skill, comfort, and preparedness at 18 months for workshop 1, 2, and 3 and in skill and comfort at 12 months for workshop 4 (p < 0.01). Faculty evaluation scores ranged from 9.3 to 10.0., Discussion: A geriatric oncology curriculum designed for oncology nurses can improve levels of evidence-based knowledge and provide more skill, comfort, and preparedness in caring for this population., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Enhancers regulate gene expressions in a tissue- and pathology-specific manner by altering its activities. Plasma levels of atrial and brain natriuretic peptides, encoded by the Nppa and Nppb, respectively, and synthesized predominantly in cardiomyocytes, vary depending on the severity of heart failure. We previously identified the noncoding conserved region 9 (CR9) element as a putative Nppb enhancer at 22-kb upstream from the Nppb gene. However, its regulatory mechanism remains unknown. Here, we therefore investigated the mechanism of CR9 activation in cardiomyocytes using different kinds of drugs that induce either cardiac hypertrophy or cardiac failure accompanied by natriuretic peptides upregulation. Chronic treatment of mice with either catecholamines or doxorubicin increased CR9 activity during the progression of cardiac hypertrophy to failure, which is accompanied by proportional increases in Nppb expression. Conversely, for cultured cardiomyocytes, doxorubicin decreased CR9 activity and Nppb expression, while catecholamines increased both. However, exposing cultured cardiomyocytes to mechanical loads, such as mechanical stretch or hydrostatic pressure, upregulate CR9 activity and Nppb expression even in the presence of doxorubicin. Furthermore, the enhancement of CR9 activity and Nppa and Nppb expressions by either catecholamines or mechanical loads can be blunted by suppressing mechanosensing and mechanotransduction pathways, such as muscle LIM protein (MLP) or myosin tension. Finally, the CR9 element showed a more robust and cell-specific response to mechanical loads than the -520-bp BNP promoter. We concluded that the CR9 element is a novel enhancer that responds to mechanical loads by upregulating natriuretic peptides expression in cardiomyocytes., (© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Heme has been receiving considerable interest as a prosthetic group of ribozymes and deoxyribozymes, because heme-bound nucleic acids exhibit peroxidase-like catalytic activities (Travascio, P., Li, Y., and Sen, D. (1998) Chem. Biol, 5, 505-517). The interaction of heme with dimeric G-quadruplexes formed from d(TAGGGTTAGGGT) and d(TAGGGTTAGGGA) has been characterized to gain a deeper understanding of the molecular recognition of G-quadruplex DNAs by heme. We found that heme binds selectively to the 3'-terminal G-quartet of a dimeric parallel G-quadruplex of d(TAGGGTTAGGGT), whereas binding of heme to a dimeric antiparallel G-quadruplex of d(TAGGGTTAGGGA) does not occur, suggesting that an orderly arrangement of the constituent guanine deoxyribose rings, with respect to the G-quartet plane, is crucial for the binding of heme to the DNA. The preferential binding of heme to the 3'-terminal G-quartet of parallel G-quadruplex DNAs allowed a systematic modification of the heme environment in the complex through the DNA sequence. The activity of the complexes was found to increase with increasing number of adenine bases adjacent to the heme in the complexes, possibly due to improvement of the accessibility of aromatic substrate, i.e., 10-acetyl-3,7-dihydroxyphenoxazine, to the heme, and an increase in the frequency of appearance of a specific orientation of the adenine bases, with respect to the heme, optimized for its activity as an acid-base catalyst to enhance the peroxidase activity of the complex., (Copyright © 2020. Published by Elsevier Inc.)

Objective: Atrial functional mitral regurgitation (A-FMR) has been suggested as a new aetiology of functional MR (MR); however, its prognosis and prognostic predictors are not fully elucidated. Aim of this study was to investigate the prognosis and prognostic predictors of A-FMR in comparison with ventricular functional MR (V-FMR)., Methods: Three hundred and seventy-eight consecutive patients with moderate-to-severe or severe functional MR were studied. Functional MR was classified into V-FMR (N=288) and A-FMR (N=90) depending on the alterations of left ventricle (LV) or left atrium (LA) along with clinical context and diagnosis of ischaemic heart disease or cardiomyopathy., Results: During a median follow-up of 4.1 (2.0-6.7) years, all-cause mortality, cardiovascular mortality and heart failure (HF) hospitalisation occurred in 98 (26%), 81 (21%) and 177 (47%) patients, respectively, and rates of these events and the composite end point of all-cause mortality and HF hospitalisation were consistently higher in V-FMR than A-FMR (unadjusted HR 1.762 (95% CI 1.250 to 2.438), p<0.001; adjusted HR 1.654 (95% CI 1.027 to 2.664), p=0.038, for the composite end point). Further analysis showed different prognostic predictors between V-FMR and A-FMR; while age and LA volume index were independent prognostic predictors of both V-FMR and A-FMR, systolic blood pressure and B-type natriuretic peptide were also those of V-FMR, and estimated glomerular filtration rate, LV end-systolic dimension and tricuspid regurgitation were also those of A-FMR., Conclusions: The prognosis of V-FMR was significantly worse than that of A-FMR, and prognostic predictors were different between V-FMR and A-FMR. Our study suggests the importance of discriminating A-FMR and V-FMR, and that different treatment strategies may be considered for each aetiology., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Interaction between an Ga(III) phthalocyanine (Pc) derivative bearing eight N-methylpyridinium groups at peripheral β-positions (2,3,6,7,10,11,14,15-octakis-[N-methyl-(4-methylpyridinium-3-yloxy)phthalocyaninato] chloro gallium(III) iodide (GaPc)) and an all parallel-stranded tetrameric G-quadruplex formed from a heptanucleotide d(TTAGGGT) ([d(TTAGGGT)] 4 ) has been investigated to elucidate the molecular recognition of G-quadruplex DNA by the Pc derivative, which provides a useful insight as to the design of G-quadruplex ligands suitable for various in vitro and in vivo applications. We found that GaPc binds to the A3G4 and G6T7 steps of [d(TTAGGGT)] 4 , with binding constants of (21 ± 2) × 10 6 and (0.09 ± 0.06) × 10 6  M -1 , respectively, to form a 2:1 complex. Obviously, upon the binding of GaPc to each of the sites, the π-π stacking and electrostatic interactions of the Pc moiety and positively-charged side chains of GaPc with a G-quartet and the negatively-charged phosphate groups in nearby phosphodiester bonds of the DNA, respectively, are major driving forces for the complexation. Considering the similarity in the local structural environment between the A3G4 and G6T7 steps of [d(TTAGGGT)] 4 , the remarkably large difference in the GaPc-binding affinity between them is most likely accounted for by the effect of the polarity of the GaPc-binding site on the intermolecular electrostatic interaction. This finding provides valuable insights as to the design of Pc derivatives as G-quadruplex ligands., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Touch is fundamental to the doctor-patient relationship. Touch can produce neuromodulatory effects that mitigate pain and put patients at ease. Touch begins with a confident handshake and continues throughout the physical examination. Touching patients where they hurt is a clear indication that a provider understands their complaint. Touch often continues as a function of treatment. This article updates evidence surrounding human touch and addresses mechanisms of action for manual therapy, the impact of manual therapy on pain management, health care conditions for which manual therapy may be beneficial, treatment plans with dose-response evidence, and the impact of manual therapy on the health care system., Competing Interests: Disclosure N. Hinkeldey: (1) VA Central Iowa Health Care System. The views expressed in the following are the views of the authors only and do not represent the views of the Veteran Health Care Administration or the local affiliate. (2) Palmer College of Chiropractic Board of Trustees. The views expressed in the following do not represent the views of the Palmer College of Chiropractic Board of Trustees or Palmer College of Chiropractic. C. Okamoto, J. Khan: no disclosures., (Published by Elsevier Inc.)

Background: The incidence of Alzheimer's disease (AD) along with depression is high in the elderly. In the present study, a program that allows the elderly individuals to voluntarily manage and develop lifestyles that may reduce the risk factors for cognitive decline was applied to the participants to evaluate its effect on the mental health of these individuals., Methods: The participants were randomly assigned to an intervention group and a control group. The program was conducted during 7 months in the intervention group, and it had seven times of group activities, performed once a month for about 1 h, and individual activities to reduce the risk factors for cognitive decline, performed every day. To evaluate the effects of the program on the mental health of the participants, the Geriatric Depression Scale (GDS) and Philadelphia Geriatric Center Morale Scale (PGC) were used. These two scales were applied twice to the intervention and control groups., Results: The GDS score revealed no change in the score in the intervention group before and after the 7-month program implementation; however, in the control group, the score was significantly higher after program implementation than that before. The PGC score revealed no change in the intervention group before and after 7-month program implementation; however, in the control group, the score was significantly lower after program implementation than that before. Additionally, it revealed no change in the GDS score in the depression-prone control group before and after 7-month program implementation; however, in the depression-prone intervention group, the GDS score was significantly lower after program implementation than that before., Conclusions: The intervention program that allows the elderly individuals to voluntarily manage and develop lifestyles that may reduce the risk factors for cognitive decline is expected to maintain mental health in elderly individuals., (© 2020 Japanese Psychogeriatric Society.)

Hyperspectral imaging (HSI) provides more detailed information than red-green-blue (RGB) imaging, and therefore has potential applications in computer-aided pathological diagnosis. This study aimed to develop a pattern recognition method based on HSI, called hyperspectral analysis of pathological slides based on stain spectrum (HAPSS), to detect cancers in hematoxylin and eosin-stained pathological slides of pancreatic tumors. The samples, comprising hyperspectral cubes of 420-750 nm, were harvested for HSI and tissue microarray (TMA) analysis. As a result of conducting HAPSS experiments with a support vector machine (SVM) classifier, we obtained maximal accuracy of 94%, a 14% improvement over the widely used RGB images. Thus, HAPSS is a suitable method to automatically detect tumors in pathological slides of the pancreas., Competing Interests: The authors declare that there are no conflicts of interest related to HSI article., (© 2019 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

Tissue amino acid profiles depend on the cell types and extracellular components that constitute the tissue, and their functions and activities. We aimed to characterize the tissue amino acid profiles in several types of pancreatic tumors and lesions. We examined tissue amino acid profiles in 311 patients with pancreatic tumors or lesions. We used newly developed LC-MS/MS methods to obtain the profiles, which were compared with clinicopathological data. Each tumor or lesion presented a characteristic tissue amino acid profile. Certain amino acids were markedly altered during the multistep pancreatic carcinogenesis and pancreatic ductal adenocarcinoma (PDAC) progression. A tissue amino acid index (TAAI) was developed based on the amino acids that were notably changed during both carcinogenesis and cancer progression. Univariate and multivariate survival analyses revealed that PDAC patients with a high TAAI exhibited a significantly shorter survival rate, and these findings were validated using a second cohort. We suggest that tissue amino acid profiles are characteristic for normal tissue type, tumor histological type, and pathological lesion, and are representative of the cancer grade or progression stage in multistep carcinogenesis and of malignant characteristics. The TAAI could serve as an independent prognosticator for patients with PDAC.

To assess the use of plasma free amino acids (PFAAs) as biomarkers for metabolic disorders, it is essential to identify genetic factors that influence PFAA concentrations. PFAA concentrations were absolutely quantified by liquid chromatography-mass spectrometry using plasma samples from 1338 Japanese individuals, and genome-wide quantitative trait locus (QTL) analysis was performed for the concentrations of 21 PFAAs. We next conducted a conditional QTL analysis using the concentration of each PFAA adjusted by the other 20 PFAAs as covariates to elucidate genetic determinants that influence PFAA concentrations. We identified eight genes that showed a significant association with PFAA concentrations, of which two, SLC7A2 and PKD1L2, were identified. SLC7A2 was associated with the plasma levels of arginine and ornithine, and PKD1L2 with the level of glycine. The significant associations of these two genes were revealed in the conditional QTL analysis, but a significant association between serine and the CPS1 gene disappeared when glycine was used as a covariate. We demonstrated that conditional QTL analysis is useful for determining the metabolic pathways predominantly used for PFAA metabolism. Our findings will help elucidate the physiological roles of genetic components that control the metabolism of amino acids.

Background: Oral mucositis and body weight loss are the most critical conditions known to lead to the discontinuation of chemoradiotherapy for head and neck cancer. We investigated the effect of a nutritional supplement with a high blend ratio of w-3 fatty acids(Prosure®)on body weight loss, oral mucositis, and the completion rate of chemoradiotherapy in patients with oropharyngeal and hypopharyngeal cancer., Patients and Methods: The study group comprised patients with oropharyngeal and hypopharyngeal cancer who were treated with concomitant cisplatin and 70 Gy of radiotherapy. These patients received 2 packs of Prosure®per day during chemoradiotherapy., Results: A total of 17 patients were included in this study. The reduction in body weight was significantly improved compared with that in the historical control group that did not receive Prosure®(7.3% vs 10.3%, p<0.01), and the rate of Grade 3-4 oral mucositis was significantly reduced for the patient groups that received Prosure®(CTCAE v3.0 GradeB3; 24% vs 58%, p<0.05). The completion rate of chemoradiotherapy was not significantly different between both groups(77% vs 60%, NS)., Conclusions: A nutritional supplement with a high blend ratio of w-3 fatty acids(Prosure®)had effects on oral mucositis and body weight loss in head and neck cancer patients treated with chemoradiotherapy.

Objective: Appropriate timing of mitral valve surgery in asymptomatic mitral regurgitation (MR) remains controversial. Peak mitral inflow velocity (peak E wave velocity) has been reported as a simple and easy predictor of quantitative MR severity; however, its prognostic significance in asymptomatic MR remains unclear. Therefore, we sought to investigate the prognostic impact of peak E wave velocity in asymptomatic MR., Methods: Among 529 consecutive patients with degenerative MR of grade 3+ (moderate to severe) or 4+ (severe), 188 asymptomatic patients in sinus rhythm without left ventricular (LV) dysfunction (end-systolic dimension ≥40 mm or ejection fraction <60%) or pulmonary hypertension were studied. Cardiovascular events were defined as a composite endpoint of cardiovascular death or events that indicated mitral surgery including congestive heart failure, atrial fibrillation, LV dysfunction or pulmonary hypertension., Results: Average peak E wave velocity was 1.05±0.26 m/s, and was significantly higher in grade 4+ than grade 3+ (1.20±0.28 vs 0.98±0.21 m/s, p<0.001). Peak E wave velocity was associated with quantitative MR severity, as well as clinical characteristics of advanced MR (higher brain natriuretic peptide, larger LV and left atrium, higher tricuspid regurgitation pressure gradient and dilated inferior vena cava). During a median follow-up of 4.3 years, 66 (35%) patients developed cardiovascular events. Multivariate Cox proportional hazards analysis showed that peak E wave velocity was an independent predictor of cardiovascular events (adjusted HR 1.245 (95% CI 1.126 to 1.378) per 0.1 m/s, p<0.001)., Conclusions: Peak E wave velocity was an independent predictor of cardiovascular events in asymptomatic degenerative MR with preserved LV function., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

We examined whether the stimulation of the angiotensin II AT1 receptor increases the expression of the cardiac (pro)renin receptor ((P)RR) and its downstream signals and whether the blockade of the angiotensin II AT1 receptor by azilsartan decreases the expression of the cardiac (P)RR and its signaling in spontaneously hypertensive rats (SHRs) with a high-salt intake. Rats received normal-salt (0.9%) chow, high-salt (8.9%) chow, normal-salt chow with 1 mg/day of azilsartan, and high-salt chow with 1 mg/day of azilsartan from 6 to 12 weeks of age. Rats with normal-salt chow were administered 100 ng/kg/min of angiotensin II by osmotic minipump from 6 to 12 weeks of age. A high-salt diet and angiotensin II significantly increased the systolic blood pressure; overexpressed cardiac (P)RR, phosphorylated (p)-ERK1/2, p-p38MAPK, p-HSP27, and TGF-ß1; enhanced cardiac interstitial and perivascular fibrosis, cardiomyocyte size, interventricular septum (IVS) thickness, and left ventricular (LV) end-diastolic dimension; and decreased LV fractional shortening. Azilsartan decreased systolic blood pressure, cardiac expressions of (P)RR, p-ERK1/2, p-p38MAPK, p-HSP27, and TGF-ß1, cardiac interstitial and perivascular fibrosis, cardiomyocyte size, and LV diastolic dimension, and improved LV fractional shortening. In conclusion, azilsartan attenuates cardiac damage caused by high salt intake through the downregulation of the cardiac (pro)renin receptor and its downstream signals in SHRs.

We acquired a direct-type flat panel detector (FPD) developed for mammography systems and investigated its physical image properties, as its characteristics may affect future mammography in the clinic. The pixel size of the detector is 50 µm, the smallest size used in clinical mammography. Amorphous selenium (a-Se) film is used in direct-type FPDs. Due to its inferior temperature properties, the temperature of the imaging room should be set to approximately 25 °C. A novel a-Se film with superior heat resistance has been developed by the HAMAMATSU photonics KK Electron Tube Division that is suitable for high electric field driving. However, the associated trade-offs in image properties are unknown. The purposes of the current study were to investigate whether the detector maintains a high image quality in the presence of a high electric field, and to evaluate the image properties. The signal readout mechanism incorporates a complementary metal-oxide-semiconductor with superior noise properties. We measured the input-output characteristics, resolution, noise properties, and detection quantum efficiency, and investigated the effects of the exposure of the a-Se film to different applied voltages under standard mammography conditions prescribed by the International Electrotechnical Commission. The resolution and noise properties associated with the direct-type FPD were not affected by differences in applied voltage. The CMOS imager had a higher resolution than conventional systems with an equivalent pixel size. It also had a high detective quantum efficiency value. Thus, this detector may be useful in mammography.

Objective: A high salt intake causes hypertension and leads to cardiovascular disease. Therefore, a low salt diet is now recommended to prevent hypertension and cardiovascular disease. However, it is still unknown whether an excessively low salt diet is beneficial or harmful for the heart., Methods: Wistar Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) received normal salt chow (0.9% salt diet) and excessively low salt chow (0.01% salt diet referred to as saltless diet) for 8 weeks from 8 to 16 weeks of age. The effects of the excessively low salt diet on the cardiac (pro) renin receptor, renin-angiotensin-aldosterone, and sympatho-adrenal systems were investigated., Results: The excessively low salt diet did not affect the systolic blood pressure but significantly increased the heart rate both in WKYs and SHRs. The excessively low salt diet significantly elevated plasma renin activity, plasma angiotensin I, II and aldosterone concentrations, and plasma noradrenaline and adrenaline concentrations both in WKYs and SHRs. Cardiac expressions of renin, prorenin, (P)RR, angiotensinogen, and angiotensin II AT1 receptor and phosphorylated (p)-ERK1/2, p-HSP27, p-38MAPK, and TGF-ß1 were significantly enhanced by the excessively low salt diet in both WKYs and SHRs. The excessively low salt diet accelerated cardiac interstitial and perivascular fibrosis and increased the cardiomyocyte size and interventricular septum thickness in WKYs and SHRs but the extent was greater in SHRs., Conclusion: An excessively low salt diet damages the heart through activation of plasma renin-angiotensin-aldosterone and sympatho-adrenal systems and activation of cardiac (P)RR and angiotensin II AT1 receptor and their downstream signals both in WKYs and SHRs.

The rhythmic locomotor behavior of flies and mice provides a phenotype for the identification of clock genes, and the underlying molecular mechanism is well studied. However, interestingly, when examining locomotor rhythm in the wild, several key laboratory-based assumptions on circadian behavior are not supported in natural conditions. The rooster crowing 'cock-a-doodle-doo' is a symbol of the break of dawn in many countries. Previously, we used domestic inbred roosters and showed that the timing of roosters' crowing is regulated by the circadian clock under laboratory conditions. However, it is still unknown whether the regulation of crowing by circadian clock is observed under natural conditions. Therefore, here we used red jungle fowls and first confirmed that similar crowing rhythms with domesticated chickens are observed in red jungle fowls under the laboratory conditions. Red jungle fowls show predawn crowing before light onset under 12:12 light : dim light conditions and the free-running rhythm of crowing under total dim light conditions. We next examined the crowing rhythms under semi-wild conditions. Although the crowing of red jungle fowls changed seasonally under semi-wild conditions, predawn crowing was observed before sunrise in all seasons. This evidence suggests that seasonally changed crowing of red jungle fowls is under the control of a circadian clock., (© 2016 Japanese Society of Animal Science.)

We investigated the seroprevalence of antibodies against Erysipelothrix in wild animals in Japan. Serum samples were collected from 48 wild boar, 26 Yezo deer and 26 Japanese deer in Japan. Growth agglutination (GA) test was performed to estimate antibody titers. As a result, positive results were obtained from 32 (66.7%), 1 (3.6%) and 6 (23.1%) samples from wild boar, Yezo deer and Japanese deer, respectively. Our findings suggest that wild animals may be an important reservoir of Erysipelothrix.

Objective: It has not yet been fully elucidated whether cardiac tissue levels of prorenin, renin and (P)RR are activated in hypertension with a high salt intake. We hypothesized that a high salt intake activates the cardiac tissue renin angiotensin system and prorenin-(pro)renin receptor system, and damages the heart at an early stage of hypertension., Methods: Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) received regular (normal-salt diet, 0.9%) and high-salt (8.9%) chow for 6 weeks from 6 to 12 weeks of age. The systolic blood pressure, plasma renin activity (PRA) and plasma angiotensin II concentration were measured, and the protein expressions of prorenin, (pro)renin receptor, angiotensinogen, angiotensin II AT1 receptor, ERK1/2, TGF-β, p38MAPK and HSP27 in the myocardium were investigated. The cardiac function was assessed by echocardiography, and histological analysis of the myocardium was performed., Results: The high-salt diet significantly increased the systolic blood pressure, and significantly reduced the PRA and plasma angiotensin II concentration both in the WKYs and SHRs. Cardiac expressions of prorenin, renin, (P)RR, angiotensinogen, angiotensin II AT1 receptor, phosphorylated (p)-ERK1/2, p-p38MAPK, TGF-β and p-HSP27 were significantly increased by the high salt diet both in the WKYs and SHRs. The high-salt diet significantly increased the interventricular septum thickness and cardiomyocyte size, and accelerated cardiac interstitial and perivascular fibrosis both in the WKYs and SHRs. On the other hand, dilatation of left ventricular end-diastolic dimension and impairment of left ventricular fractional shortening was shown only in salt loaded SHRs., Conclusion: The high-salt diet markedly accelerated cardiac damage through the stimulation of cardiac (P)RR and angiotensin II AT1 receptor by increasing tissue prorenin, renin and angiotensinogen and the activation of ERK1/2, TGF-β, p38MAPK and HSP27 under higher blood pressure.

Despite observations that the lacrimal gland has been identified as the principal source of dimeric immunoglobulin A (dIgA) in tears, the mechanism used by lacrimal gland acinar cells (LGACs) to transcytose dIgA produced by interstitial plasma cells is not well-characterized. This study identifies a transcytotic pathway in LGACs regulated by Rab11a for polymeric immunoglobulin receptor (pIgR) and dIgA. EGFP-tagged Rab11a expressed in primary LGACs labeled a unique membrane compartment of comparable localization to endogenous Rab11a beneath the apical plasma membrane. This compartment was enriched in pIgR and clearly distinct from the regulated secretory pathway. Comparison of dIgA uptake in LGACs expressing wild type and dominant negative EGFP-Rab11a showed that the rapid exocytosis of dIgA was inhibited in acini expressing the dominant-negative protein, which additionally redistributed subapical pIgR. The trafficking of EGFP-Rab11a-enriched vesicles was regulated by microtubule-based and myosin Vb motors at distinct steps. Our data suggest that Rab11a is a crucial regulator of dIgA trafficking in primary acinar secretory epithelial cells and further support a role for microtubules, cytoplasmic dynein, actin filaments and myosin Vb in the maintenance of the Rab11a compartment in this primary secretory epithelial cell.

Malignant-phase hypertension is characterized clinically by severe accelerating hypertension with neuroretinopathy or papilledema and by evidence of renal damage. A Japanese male in his early thirties presented with hemoptysis and general fatigue. He had a 5-year history of hypertension, but had not received any treatment. His blood pressure was 290/150 mmHg and his serum creatinine level was 8.24 mg/dL. Chest X-rays and computed tomography scans of the chest revealed a pulmonary alveolar hemorrhage. He was suspected of having vasculitis syndrome or Goodpasture's syndrome, but his renal biopsy specimen showed malignant nephrosclerosis. Myeloperoxidase antineutrophil cytoplasmic antibody (ANCA), proteinase-3 ANCA and antiglomerular basement membrane antibody were negative. He was treated with a calcium antagonist and a β-blocker, followed by an angiotensin-converting enzyme inhibitor. After the administration of the β-blocker, his blood pressure decreased and his renal function gradually improved. This is a rare case of malignant-phase hypertension with pulmonary alveolar hemorrhage; this condition should be considered in the differential diagnosis in order to avoid unnecessary treatment such as immunosuppressive therapy.

Purpose: To quantitatively evaluate the effect of overnight orthokeratology lenses intentionally left decentered after 3 months of wear and assess the influence on clinical outcomes such as ocular higher-order wavefront aberrations and contrast sensitivity function., Setting: Department of Ophthalmology, Tsukuba University Hospital, Ibaraki, Japan., Methods: This prospective study assessed refraction, visual acuity, corneal topography, wavefront aberration, and contrast sensitivity function before and 3 months after overnight orthokeratology treatment. Decentration of the treatment zone from the center of the entrance pupil was determined using computerized videokeratography (TMS-4) and data-analysis software (MatLab). The relationship between decentration and the clinical parameters was analyzed., Results: The mean age of the 23 patients (46 eyes) was 24.2 years+/-3.3 (SD) and the mean spherical equivalent refraction before treatment, -2.38+/-0.98 diopters. The mean magnitude of decentration (0.85+/-0.51 mm) was statistically significantly correlated with the amount of myopic correction (P<.05), increases in coma-like aberration (P<.01), increases in spherical-like aberration (P<.01), and reductions in contrast sensitivity function (P<.0001). Changes in contrast sensitivity function were also statistically significantly correlated with the amount of myopic correction (P<.05), changes in coma-like aberration (P<.01), and changes in spherical-like aberration (P<.01). Stepwise multiple regression analysis showed that the magnitude of decentration was the only explanatory variable related to contrast sensitivity function (P<.0001)., Conclusion: Decentered treatment of orthokeratology resulted in decreased contrast sensitivity after treatment, showing that centration of the procedure is crucial to good outcomes.

Microscopic polyangiitis is a vasculitis which primarily affects capillaries, venules or arterioles. Involvement of small and medium-sized arteries may also occur. A 70-year-old Japanese female with a fever and cough was diagnosed with pneumonia and antibiotics were administered. Her symptoms initially improved, but her fever recurred and she experienced malaise and loss of appetite. Her renal function gradually worsened and she was positive for myeloperoxidase antineutrophil cytoplasmic antibodies (MPO-ANCA). She was referred to our hospital on the suspicion of ANCA-associated glomerulonephritis. However, her depressive mental symptoms did not allow her to undergo a renal biopsy. She was clinically diagnosed with ANCA-associated glomerulonephritis, and oral corticosteroids and intravenous methylprednisolone were administered. Her symptoms and renal function were improved, but she died suddenly 15 days after admission. An autopsy disclosed approximately 700 mL bloody ascites. Coagulation adhered to the lesser curvature of the stomach, but the source of hemorrhage could not be detected macroscopically because the gastric mucosa did not show abnormal findings. The histological findings revealed that the left gastric artery showed necrotizing angiitis and rupture. In the kidneys, cellular crescents were found in approximately 10%, fibrous crescents were found in approximately 10%, sclerosis and collapse were found approximately 30% of the glomeruli, and necrotizing angiitis was observed in interlobular arteries and arterioles. From these findings, she was finally diagnosed with microscopic polyangiitis. Microscopic polyangiitis is an extremely rare cause of spontaneous intraperitoneal bleeding, but it must be carefully considered in the differential diagnosis for the appropriate management of such patients.

Purpose: To investigate relationship between mesopic contrast sensitivity (CS) function and ocular higher-order aberrations in eyes implanted with conventional spherical intraocular lenses (IOL)., Design: Prospective, nonrandomized case series., Methods: Sixty-eight eyes of 48 patients who attained best spectacle-corrected visual acuity (BSCVA) of 20/20 or better after phacoemulsification and spherical IOL implantation were included in the study. At 2 months postoperatively, mesopic CS was measured with the Mesotest II (Oculus; Wetsler, Germany), and ocular higher-order aberrations for a 4-mm pupil were measured with the Hartmann-Shack aberrometer. CS and letter CS under photopic conditions were recorded with the CSV-1000 charts (Vector Vision Co, Greenville, Ohio, USA)., Results: There was significant correlation between mesopic CS and ocular fourth-order root mean square (RMS) of wavefront aberration (Spearman r(s) = -0.293; P = .017), but no correlation was found between mesopic CS and ocular third-order RMS (r(s) = 0.196; P = .189). Ocular third- and fourth-order RMS did not correlate with other parameters, including BSCVA, and CS and letter CS under photopic conditions., Conclusions: Mesopic CS is significantly associated with ocular fourth-order RMS of wavefront aberrations in eyes implanted with conventional spherical IOLs.

Ehime University Hospital has been conducting a four-week practical hospital training course, consisting of 18 programs, for undergraduate students. The course includes experience-oriented programs, such as drug counseling training using case-based learning procedures (CBL practice), evidence based medicine (EBM practice) based on the provision of drug information, and training to avoid adverse drug reactions (pre-avoid practice). A previous study based on a questionnaire survey showed that experience-oriented programs enhanced students' understanding of the hospital practical training, while also increasing their satisfaction. In this trial, written examinations were given to 24 students to evaluate their clinical knowledge and problem-solving abilities at the start and the end of the practical hospital training course to evaluate the educational effects of this curriculum objectively. The problem-solving abilities were examined using a test of a case analysis, which required the students to answer multiple clinical problems or proposals. The examination scores on the clinical knowledge at the end of the practical hospital training course had significantly increased by 9.5% (p<0.01) in comparison to that at the start. In addition, the accuracy rate regarding their problem-solving abilities markedly increased by 28.8% (p<0.001). Moreover, the number of answers also significantly increased by about 1.5-fold (p<0.001). These results suggested that the experience-oriented programs for hospital practical training increased the clinical knowledge and the problem-solving abilities of these students.

Purpose: To investigate prospectively the time course of changes in ocular higher-order aberration and contrast sensitivity after overnight orthokeratology., Methods: Data from 34 eyes of 17 patients who completed 1-year follow-up examinations were analyzed. The manifest refraction was -2.17 +/- 0.86 D at baseline. Ocular higher-order aberrations for a 4-mm pupil were measured, and the root-mean-square (RMS) of the third-, fourth-, and total higher-order aberrations were determined. Contrast sensitivity was assessed at four spatial frequencies, and the area under the log contrast sensitivity function (AULCSF) was calculated. These examinations were performed before and 1, 2, 3, 6, and 12 months after commencement of the procedure., Results: The treatment significantly increased third-, fourth-, and total higher-order RMS (all P < 0.0001, paired t-test). Log contrast sensitivity significantly decreased at all four spatial frequencies, and AULCSF was also significantly reduced after the treatment (P < 0.0001). To assess the time course of changes in these parameters, posttreatment data were analyzed by using repeated-measures analysis of variance. There were no significant fluctuations in manifest refraction; uncorrected visual acuity; third-, fourth-, and total higher-order RMS; and AULCSF (all P > 0.05). In addition, there was no significant variance in log contrast sensitivity at each spatial frequency during the 1-year follow-up period (all P > 0.05)., Conclusions: The initial reduction in optical quality of the eye and quality of vision after the procedure is stable during the treatment period of at least 1 year, and the reduction does not worsen further after 1 month. Orthokeratology candidates should be fully informed of these changes.

Plasmin is an essential enzyme located in the pericellular microenvironment of liver cells during liver regeneration. Previously, we reported that liver regeneration ability was significantly increased in alpha2-antiplasmin gene knockout mice as compared to wild-type mice, but it was significantly decreased in plasminogen knockout mice, or Plg/alpha2-antiplasmin gene knockout mice. The present study aimed to demonstrate direct interaction between plasminogen and mouse hepatocytes in the process of liver regeneration. Using the isolated hepatocytes from mice we analyzed following subjects: binding capacity of plasminogen to hepatocytes, plasminogen activation in the presence of hepatocytes, and proliferation ability of hepatocytes cocultured with liver nonparenchymal cells. The isolated hepatocytes from plasminogen wild-type mice bound to immobilized plasminogen. The mouse hepatocytes enhanced plasminogen activation, and impaired the inhibitory effect of alpha2-antiplasmin. The proliferation ability of hepatocytes after liver injury was studied. In plasminogen wild-type and plasminogen knockout mice, the hepatocytes cocultured with nonparenchymal cells, which were obtained from mice without CCl4 injection, showed similar proliferation abilities. On the contrary, the proliferation ability of hepatocytes cocultured with nonparenchymal cells, which were obtained from CCl4-treated plasminogen knockout mice, was significantly impaired as compared to wild-type mice. These results indicate that the plasminogen-plasmin system on the surface of mouse hepatocytes plays an important role in liver regeneration.

Objective: Alpha2-antiplasmin (alpha2-AP) is the major circulating inhibitor of plasmin, which plays a determining role in the regulation of intravascular fibrinolysis. We investigated the role of alpha(2)-AP on vascular remodeling in response to angiotensin II (Ang II)., Methods and Results: alpha2-AP-deficient mice were performed. Ang II and N(omega)-nitro- L-arginine methyl ester (L-NAME)-induced perivascular fibrosis was significantly decreased in alpha2-AP-/- mice compared with wild-type mice. In situ gelatinolytic activity analysis shows that perivascular gelatinolytic activity was increased in alpha2-AP-/- mice, which was responsible for decreased perivascular fibrosis in response to Ang II and L-NAME. Ang II-induced arterial wall thickening, vascular cell proliferation, apoptosis, c-Myc, and collagen I expression were significantly decreased in alpha2-AP-/- mice compared with wild-type mice. Further analysis shows that increased p53 and p21 expression were responsible for inhibition of Ang II-induced vascular remodeling in alpha2-AP-/- mice., Conclusions: The results show that alpha2-AP is a critical regulator for vascular remodeling by inhibiting p53/p21 pathway, suggesting that alpha2-AP is proposed to be a potential therapeutic target for vascular remodeling.

Purpose: To investigate mesopic contrast sensitivity and night driving ability in eyes undergoing overnight orthokeratology, and to analyze the relationship among mesopic contrast sensitivity, ocular higher-order aberrations, and myopic correction., Design: Prospective, noncomparative, consecutive case series., Methods: In 44 eyes of 22 subjects (mean age +/- standard deviation [SD], 24.0 +/- 3.2 years) with orthokeratology, ocular aberrations and mesopic contrast sensitivity were determined before and three months after commencement of the procedure. Mean spherical equivalent refraction +/- SD was -2.34 +/- 0.99 diopters at baseline. Mesopic contrast sensitivity with and without glare was assessed using the Mesotest II (Oculus, Wetzlar, Germany)., Results: Orthokeratology significantly reduced the log mesopic contrast sensitivity from 0.25 +/- 0.08 to 0.08 +/- 0.10 without glare (P < .0001, Wilcoxon) and from 0.21 +/- 0.11 to 0.07 +/- 0.10 with glare (P < .0001). The proportion of eyes that fulfilled the German standard recommendation level for night driving was 36%. The induced changes in log mesopic contrast sensitivity showed significant negative correlation with the changes in third-order (r = -0.490, P = .0013 without glare; r = -0.362, P = .0177 with glare; Spearman rank correlation coefficient) and fourth-order root mean square (r = -0.586, P = .0001 and r = -0.306, P = .0450, respectively). Furthermore, significant correlation was found between the amount of myopic correction and the induced changes in log mesopic contrast sensitivity (r = -0.442, P = .0038 without glare; r = -0.464, P = .0024 with glare). The induced changes in higher-order aberrations significantly correlated with the amount of myopic correction (P < .0001, Pearson correlation coefficient)., Conclusions: Mesopic contrast sensitivity after overnight orthokeratology is deteriorated significantly as ocular higher-order aberrations increase, and these changes depend on the amount of myopic correction.

Three lipopeptides, ciliatamides A-C ( 1- 3), were isolated from the deep-sea sponge Aaptos ciliata, and their structures were elucidated on the basis of spectroscopic and chemical methods. Ciliatamides A ( 1) and B ( 2) were found to be antileishmanial, while 2 also exhibited marginal cytotoxicity to HeLa cells.

A female in her late 60s with chronic kidney disease was admitted to the emergency department with complaints of dizziness four days prior to hospitalization. Cibenzoline (300 mg/day) was administered for atrial fibrillation, which was detected in an electrocardiogram. After three days, she experienced blepharoptosis and was admitted for suspected myasthenia gravis. However, the anti-acetylcholine receptor antibody and edrophonium tests were negative. On day four after hospitalization, she suffered from pneumonia with pleural effusion and she was put on a respirator for four days. From day 16 after hospitalization, she had diarrhea and her renal function worsened. At the same time, a gradual aggravation of right blepharoptosis, dull headache, weakness and difficulty in chewing were noted. She experienced dyspnea on day 31 after hospitalization. Chest X-ray film did not show a pneumonia shadow or pleural effusion, and arterial blood gases revealed hypercapnia; she was diagnosed as having CO2 narcosis due to respiratory muscle fatigue and was put on a respirator again. Myasthenia-like syndrome was suspected because of a probable overdose of cibenzoline and administration of cibenzoline was withdrawn. Her condition improved and she was taken off the respirator on day 35 after hospitalization. Repetitive stimulation of 5 Hz was applied to her right facial nerve along with evoked electromyogram(EMG) on days 2 and 11 after discontinuing cibenzoline. On day 2, the EMG showed a waning phenomenon, whereas no such phenomenon was seen on day 11. The blood concentration of cibenzoline immediately after withdrawal was extremely high (2448 ng/mL). When this drug is administered to a patient with chronic kidney disease, attention must be paid to the indication, dose, and manifestation of the possible side effects.

Two new polyacetylene carboxylic acids, petroformynic acids B (3) and C (4), were isolated from a marine sponge Pertrosia sp. as cytotoxic constituents. Their structures were determined by interpretation of 2D NMR data and tandem FABMS data. Absolute stereochemistry of 3 was assigned by application of the modified Mosher analysis. Petroformynic acids exhibit moderate cytotoxic activity against P388 cells.

Since the signal transduction mechanisms responsible for liver regeneration mediated by the plasminogen/plasmin system remain largely undetermined, we have investigated whether plasmin regulates the pro-apoptotic protein Bim(EL) in primary hepatocytes. Plasmin bound to hepatocytes in part via its lysine binding sites (LBS). Plasmin also triggered phosphorylation of ERK1/2 without cell detachment. The plasmin-induced phosphorylation of ERK1/2 was inhibited by the LBS inhibitor epsilon-aminocaproic acid (EACA), the serine protease inhibitor aprotinin, and the MEK inhibitor PD98059. DFP-inactivated plasmin failed to phosphorylate ERK1/2. Plasmin temporally decreased the starvation-induced expression of Bim(EL) and activation of caspase-3 via the ERK1/2 signaling pathway, resulting in an enhancement of cell survival. The amount of mRNA for Bim increased 1 day after the injection of CCl(4) in livers of plasminogen knockout (Plg-KO) and the wild-type (WT) mice. The increase in Bim(EL) protein persisted for at least 7 days post-injection in livers of Plg-KO mice, whereas WT mice showed an increase in Bim(EL) protein 1 day after the injection. Plg-KO and WT mice showed notable phosphorylation of ERK1/2 7 and 3 days after the injection of CCl(4), respectively. Our data suggest that the plasminogen/plasmin system could decrease Bim(EL) expression via the ERK1/2 signaling pathway during liver regeneration.

Staphylokinase (SAK) expresses plasminogen activator (PA) activity by forming a complex with plasmin. The interaction between the plasmin-SAK complex and plasminogen was investigated using synthesized peptides, which were constructed according to the amino acid sequence of the SAK molecule. A synthetic nonadecapeptide (SAK22-40) corresponding to Glu22-Leu40 by the SAK molecule enhanced the activation of Glu-plasminogen by the plasmin-SAK complex. Analysis of IAsys resonant mirror biosensor showed that SAK22-40 bound to Glu-plasminogen. This binding was completely inhibited by IgG against the B-chain in the plasminogen molecule. But, this binding was not inhibited by IgG against lysine-binding sites (LBS) of the A-chain in the plasminogen molecule. The substitution of Lys35 with Ala in SAK22-40 did not enhance the activation of Glu-plasminogen by the plasmin-SAK complex. When SAK22-40 was administrated in a mouse thrombosis model, earlier recanalization was observed than in mice with vehicle administration. Thus, a newly synthesized peptide, SAK22-40 enhanced Glu-plasminogen activation and induced effective thrombolysis.

Aim: To investigate the influence of tilt and decentration of scleral-sutured intraocular lenses (IOLs) on ocular higher-order wavefront aberrations., Methods: In 45 eyes of 36 patients who had undergone scleral suture fixation of posterior chamber IOL, tilt and decentration of IOLs were determined by Scheimpflug videophotography, and higher-order aberration for a 4-mm pupil was measured using the Hartmann-Shack aberrometer. In another 100 eyes of 100 patients after standard cataract surgery with posterior chamber IOL implantation, ocular higher-order aberration was measured., Results: In eyes with scleral-sutured IOL, the mean (SD) tilt angle and decentration were 4.43 degrees (3.02 degrees ) and 0.279 (0.162) mm, respectively. Ocular coma-like aberration in the sutured IOL group was 0.324 (0.170) microm, which was significantly greater than that of the standard cataract surgery group (0.169 (0.061) microm, p<0.001, Student's t test). No significant difference was found in ocular spherical-like aberration between the sutured IOL group (0.142 (0.065) microm) and standard surgery group (0.126 (0.033) microm; p = 0.254). In the sutured IOL group, IOL tilt significantly correlated with ocular coma-like aberration (Pearson's correlation coefficient r = 0.628, p<0.001), but no significant correlation was found between IOL tilt and ocular spherical-like aberration (r = 0.222, p = 0.175). The IOL tilt did not correlate with corneal coma-like (r = 0.289, p = 0.171) and spherical-like (r = 0.150, p = 0.356) aberrations. The IOL decentration did not correlate with any higher-order aberrations., Conclusion: In eyes with scleral-sutured posterior chamber IOL, tilting of the lens induces considerable amount of ocular coma-like aberrations.

Purpose: To evaluate relationships among contrast sensitivity function, ocular higher-order aberration, and myopic correction in eyes undergoing overnight orthokeratology for myopia., Methods: A prospective study was conducted in 46 eyes of 23 patients undergoing orthokeratology. Inclusion criteria were spherical equivalent refraction between -1.00 and -4.00 diopters (D), refractive astigmatism up to 1.00 D, and best-corrected visual acuity of 20/20 or better. Ocular higher-order aberrations and contrast sensitivity function were determined before and 3 months after initiation of the procedure. We measured three indices of contrast sensitivity function: contrast sensitivity, low-contrast visual acuity, and letter contrast sensitivity with the CSV-1000 charts (Vector Vision Co., Greenville, OH). Area under the log contrast sensitivity function (AULCSF) was calculated from the contrast sensitivity data., Results: Orthokeratology significantly improved logMAR uncorrected visual acuity (P < 0.0001; paired t-test) but significantly increased ocular higher-order aberrations (P < 0.0001) and decreased contrast sensitivity function, including AULCSF (P < 0.0001), low-contrast visual acuity (P = 0.0025), and letter contrast sensitivity (P < 0.0001; Wilcoxon signed-rank test). The induced changes in AULCSF, low-contrast visual acuity, and letter contrast sensitivity by orthokeratology showed significant correlation with changes in third-order (Pearson r = -0.430, P = 0.0026; r = 0.423, P = 0.0031; and Spearman r(s) = -0.351, P = 0.0186, respectively), fourth-order (r = -0.418, P = 0.0035; r = 0.425, P = 0.0029; and r(s) = -0.566, P = 0.0001, respectively), and total higher-order (r = -0.460, P = 0.0011; r = 0.471, P = 0.0008; and r(s) = -0.434, P = 0.0036, respectively) aberrations. The induced changes in contrast sensitivity function and higher-order aberrations significantly correlated with the amount of myopic correction (P < 0.01)., Conclusions: Orthokeratology significantly increases ocular higher-order aberrations and compromises contrast sensitivity function, depending on the amount of myopic correction.

Proteins of the developing enamel matrix include amelogenin, ameloblastin and enamelin. Of these three proteins amelogenin predominates. Protein-protein interactions are likely to occur at the ameloblast Tomes' processes between membrane-bound proteins and secreted enamel matrix proteins. Such protein-protein interactions could be associated with cell signaling or endocytosis. CD63 and Lamp1 are ubiquitously expressed, are lysosomal integral membrane proteins, and localize to the plasma membrane. CD63 and Lamp1 interact with amelogenin in vitro. In this study our objective was to study the molecular events of intercellular trafficking of an exogenous source of amelogenin, and related this movement to the spatiotemporal expression of CD63 and Lamp1 using various cell lineages. Exogenously added amelogenin moves rapidly into the cell into established Lamp1-positive vesicles that subsequently localize to the perinuclear region. These data indicate a possible mechanism by which amelogenin, or degraded amelogenin peptides, are removed from the extracellular matrix during enamel formation and maturation.

Purpose: To investigate the relation between contrast sensitivity function and ocular higher-order wavefront aberrations in normal human eyes., Study Design: Prospective observational case series., Participants: Three hundred seven eyes of 161 normal subjects, ranging in age from 15 to 60 years (30.9+/-8.0 [mean +/- standard deviation])., Methods: Ocular higher-order aberrations were measured for a 4-mm pupil using the Hartmann-Shack wavefront analyzer. The root-mean-square of the third- and fourth-order Zernike coefficients was used to represent comalike and spherical-like aberrations, respectively. We measured contrast sensitivity, low-contrast visual acuity (VA), and letter contrast sensitivity. From the contrast sensitivity data, the area under the log contrast sensitivity function (AULCSF) was calculated. Pupil diameter in a photopic condition was recorded using a digital camera., Results: Multiple linear regression analysis revealed that comalike aberration (P = 0.002) was significantly associated with AULCSF, but spherical-like aberration (P = 0.200), age (P = 0.185), and photopic pupil diameter (P=0.252) were not. Comalike aberration showed a significant correlation with low-contrast VA (P<0.001), but spherical-like aberration (P = 0.293), age (P = 0.266), and pupil diameter (P = 0.756) did not. Comalike aberration was found to be significantly associated with letter contrast sensitivity (P<0.001), but spherical-like aberration (P=0.082), age (P = 0.370), and pupil diameter (P = 0.160) were not., Conclusions: In normal human eyes, comalike aberration of the eye significantly influences contrast sensitivity function.

Two experiments were conducted to compare the effect of estrus induction by controlled internal drug release (CIDR) and intravaginal cream containing 500 mg progesterone (P cream) in ewes during the non-breeding season. In the first experiment, twenty-four ewes were randomly grouped for two treatments with the different intravaginal devices for 12 days: Group A was the CIDR group and Group B was the P cream group. Blood was collected from all treated ewes, and progesterone (P(4)), estradiol 17-beta (E(2)) and luteinizing hormone (LH) concentrations were measured by enzyme immunoassay. In the second experiment, the conception rates from natural mating, estrus-detected AI (inseminated 12 h after estrus detection), or fixed-time AI (inseminated 42 h after removal of an intravaginal device) in 127 ewes treated with CIDR or P cream were compared. In Experiment 1, the rate of estrus induction and the time of estrus onset after device removal were 91.7% and 36.3 +/- 15.7 h in Group A, and 100% and 35.0 +/- 12.6 h in Group B, respectively. There were no significant differences between the devices. The mean plasma P(4) concentration in Group B was significantly (P < 0.01) lower than Group A between day -9 and day -1 (Day 0: the day of device removal). However, no significant differences were found in the mean E(2) concentrations of the two groups after treatment. The mean time of estrus onset in ewes with an observed LH surge and the time of LH surge after treatment were 23.3 +/- 8.7 h and 30.3 +/- 5.0 h for Group A and 27.6 +/- 6.5 and 26.3 +/- 8.0 h for Group B, respectively, and there were no significant differences. However, a significant difference (P < 0.05) was found in the mean time from the time of estrus onset to LH surge between Group A (6.4 +/- 6.7 h) and Group B (-1.3 +/- 4.1 h). In Experiment 2, the conception rates for natural mating, estrus-detected AI, and fixed-time AI were 55.0, 29.4, and 25.0% for Group A and 40.7, 25.0, and 42.1% for Group B, respectively, and there were no significant differences. These results suggest that the effect of induction of estrus and ovulation and the rate of conception after treatment were comparable to CIDR even though the plasma P(4) concentration of the P cream method tended to be low during the insertion period.