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Aims: We aimed to investigate whether Saccharomyces boulardii strain might exert renoprotective effects by modulating renal renin angiotensin system, oxidative stress and intestinal microbiota in streptozotocin-diabetic mice., Main Methods: Thirty-six C57BL/6 male mice were divided into four groups: control (C), control + probiotic (CP), diabetes (D), diabetes + probiotic (DP). Diabetes was induced by one intraperitoneal injection of streptozotocin and Saccharomyces boulardii was administered by oral gavage for 8 weeks. Blood glucose, albuminuria and urinary volume were measured. Renal levels of angiotensin peptides (angiotensin I, II and 1-7) and the activities of angiotensin-converting enzyme (ACE) and ACE2 were determined, besides that, renal morphology, serotonin and dopamine levels and also microbiota composition were analyzed., Key Findings: Probiotics significantly increased C-peptide secretion and reduced blood glucose of diabetic animals. Saccharomyces boulardii also improved renal antioxidant defense, restored serotonin and dopamine concentration, and activated the renin-angiotensin system (RAS) vasodilator and antifibrotic axis. The modulation of these markers was associated with a beneficial impact on glomerular structure and renal function of diabetic treated animals. The phenotypic changes induced by Saccharomyces boulardii were also related to modulation of intestinal microbiota, evidenced by the decreased abundance of Proteus and Escherichia-Shigella, considered diabetic nephropathy biomarkers., Significance: Therefore, probiotic administration to streptozotocin-induced diabetic mice improves kidney structure and function in a murine model and might represent a reasonable strategy to counteract nephropathy-associated maladaptive responses in diabetes., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Japan has the highest number of cases of infertility treatment in the world. Studies have indicated that women undergoing infertility treatment feel stigmatized and suffer from psychological symptoms such as anxiety and depression. However, in Japan, few studies have quantitatively examined the association between the stigma of infertility and psychological symptoms, and, to our knowledge, no study has examined its association using a scale with tested reliability and validity. This study aims to quantitatively examine the relationship between infertility stigma and anxiety, depression, and psychological distress among women undergoing infertility treatment, using a scale that has been validated for reliability and validity. The cross-sectional study was conducted in December 2021 through a web-based survey of 254 participants undergoing infertility treatment. A multiple regression analysis was performed to examine the relationship between stigma and anxiety, depression, and psychological distress. Stigma was a statistically significant predictor of anxiety, depression, and psychological distress (standardized β = 0.58, p < 0.001; β = 0.50, p < 0.001; β = 0.62, p < 0.001, respectively) after controlling for sociodemographic and infertility characteristics. Future studies should examine the causal relationship between stigma and anxiety, depression, and psychological distress and how to intervene to reduce stigma among women undergoing infertility treatment.

The stigma of infertility negatively affects health, resulting in mental distress and poor quality of life. An appropriate scale is essential to examine the stigma experienced by infertile women and provide adequate interventions. Therefore, we developed a Japanese version of the Infertility Stigma Scale (ISS). After examining the content validity of this scale, we conducted an online survey of women undergoing fertility treatment to test the scale’s structural validity, internal consistency, intra-rater reliability, known-groups validity, convergent validity, and discriminant validity. A total of 254 participants were included in the analysis. The results of confirmatory factor analysis of four factors based on the original scale revealed the optimal fit. Cronbach’s alpha was 0.95 for the total score. Concerning test−retest analysis, the total score of the ISS and subscale had a high Spearman correlation coefficient (ρ = 0.61−0.88, p < 0.001). For convergent validity, the association between the ISS and social support, self-esteem, and family functioning was significantly negatively correlated. The results of the multitrait scaling analysis scale showed that correlations of all items exceeded 0.40, and scaling errors (7/81, 8.6%) were few. The Japanese version of the ISS was confirmed to have acceptable reliability and validity.

Objectives: Cardiovascular manifestations occur in over 80% of Williams syndrome (WS) patients and are the leading cause of morbidity and mortality. One-third of patients require cardiovascular surgery. Renal artery stenosis (RAS) is common in WS. No studies have assessed postoperative cardiac surgery-related acute kidney injury (CS-AKI) in WS. Our objectives were to assess if WS patients have higher risk of CS-AKI postoperatively than matched controls and if RAS could contribute to CS-AKI., Design: This was a retrospective study of all patients with WS who underwent cardiac surgery at our center from 2010 to 2020. The WS study cohort was compared with a group of controls matched for age, sex, weight, and surgical procedure., Setting: Patients underwent cardiac surgery and postoperative care at Lucile Packard Children's Hospital Stanford., Patients: There were 27 WS patients and 43 controls (31% vs 42% female; p = 0.36). Median age was 1.8 years (interquartile range [IQR], 0.7-3.8 yr) for WS and 1.7 years (IQR, 0.8-3.1 yr) for controls., Interventions: None., Measurements and Main Results: Postoperative hemodynamics, vasopressor, total volume input, diuretic administration, and urine output were collected in the first 72 hours. Laboratory studies were collected at 8-hour intervals. Multivariable analysis identified predictors of CS-AKI.Controlled for renal perfusion pressure (RPP) and vasoactive inotrope score (VIS), compared with controls, the odds ratio (OR) of CS-AKI in WS was 4.2 (95% CI, 1.1-16; p = 0.034). Higher RPP at postoperative hours 9-16 was associated with decreased OR of CS-AKI (0.88 [0.8-0.96]; p = 0.004). Increased VIS at hour 6 was associated with an increased OR of CS-AKI (1.47 [1.14-1.9]; p = 0.003). Younger age was associated with an increased OR of CS-AKI (1.9 [1.13-3.17]; p = 0.015)., Conclusions: The OR of CS-AKI is increased in pediatric patients with WS compared with controls. CS-AKI was associated with VIS at the sixth postoperative hour. Increases in RPP and mean arterial pressure were associated with decreased odds of CS-AKI., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Large-scale distributed training of deep neural networks results in models with worse generalization performance as a result of the increase in the effective mini-batch size. Previous approaches attempt to address this problem by varying the learning rate and batch size over epochs and layers, or ad hoc modifications of batch normalization. We propose scalable and practical natural gradient descent (SP-NGD), a principled approach for training models that allows them to attain similar generalization performance to models trained with first-order optimization methods, but with accelerated convergence. Furthermore, SP-NGD scales to large mini-batch sizes with a negligible computational overhead as compared to first-order methods. We evaluated SP-NGD on a benchmark task where highly optimized first-order methods are available as references: training a ResNet-50 model for image classification on ImageNet. We demonstrate convergence to a top-1 validation accuracy of 75.4 percent in 5.5 minutes using a mini-batch size of 32,768 with 1,024 GPUs, as well as an accuracy of 74.9 percent with an extremely large mini-batch size of 131,072 in 873 steps of SP-NGD.

Aim: The aim of this retrospective study was to investigate the incidence of cardiovascular thrombotic complications after laparoscopic resection in colorectal cancer., Methods: This study involved 2017 patients with stages 0-III colorectal cancer who underwent laparoscopic surgery at 17 Japanese hospitals between January 2010 and December 2013. We assessed the incidence of postoperative cardiovascular thrombotic and haemorrhagic complications., Results: Laparoscopic surgeries were performed in 1152 men and 865 women with 1405 colon and 612 rectal cancers, respectively. Overall, 3%, 38%, 17%, 8%, and 9% of patients had comorbidities of heart failure, high blood pressure, diabetes, history of stroke, and vascular disease, respectively. Antithrombotic agents were being consumed by 17% of patients. The types (and perioperative rest periods) of the antithrombotic agents were aspirin in 58% (18.6 days), clopidogrel in 19% (21.1 days), cilostazol in 13% (13.3 days), and warfarin potassium in 21% (14.6 days) of cases with antithrombotic agents. Surgical time and blood loss in the total cohort were 234 minutes and 56 mL. Four cases (0.2%) had cardiovascular thrombotic complications, including one severe cardiac infarction and one stroke with major sequelae (CHADS2 scores were 2 points in both cases). Hemorrhagic complications occurred in 19 cases (0.9%). In particular, the incidence of the major gastroduodenal haemorrhagic ulcer was higher in cases with antithrombotic agents than without them (0.05% vs 0%, P  = .02)., Conclusion: The incidence of cardiovascular thrombotic complications was rare, although severe cardiac infarction and stroke could occur even after minimally invasive surgery in colorectal cancer., (© 2021 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterology.)

Objectives: Public health institutions have alerted consumers about advertising for dietary supplements with false claims of preventing or treating COVID-19. We quantitatively and qualitatively examined newspaper advertisements for dietary supplements before and after the COVID-19 spread., Design: Content analysis., Participants: We analysed advertisements for dietary supplements in two major Japanese newspapers in February-July 2019 and February-July 2020. Our analysis covered 2167 advertisements., Results: The number of advertisements for dietary supplements that claimed to be effective in infection prevention (p=0.009) and improving joint (p=0.002) and digestive functions (p=0.002) significantly increased after the spread of COVID-19 compared with before. Dietary supplements that claimed to be effective in preventing infection were advertised in combination with recommendations for gargling and handwashing. Such terms as 'defence' and 'prevent' were used to promote the preventive effect., Conclusions: False and misleading claims in advertising for dietary supplements may result in consumer harm, such as overdosing and failure to take preventive behaviour. While the pandemic continues, there will be an increasing need for disseminating accessible information about the appropriate use of dietary supplements, consumer education and warnings to manufacturers., 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.)

Background: The changing pattern of anxiety and stress experienced by pregnant women during the COVID-19 pandemic is unknown., Objective: We aimed to examine the sources of anxiety and stress in pregnant women in Japan during the COVID-19 pandemic., Methods: We performed content analysis of 1000 questions posted on the largest social website in Japan (Yahoo! Chiebukuro) from January 1 to May 25, 2020 (end date of the national state of emergency). The Gwet AC1 coefficient was used to verify interrater reliability., Results: A total 12 categories were identified. Throughout the study period, anxiety related to going outdoors appeared most frequent, followed by anxiety regarding employment and infection among family and friends. Following the declaration of the state of national emergency at the peak of the infection, infection-related anxiety decreased, whereas anxiety about social support and mood disorders increased. Stress regarding relationships appeared frequent throughout the pandemic., Conclusions: The sources of anxiety and stress in pregnant women in Japan changed during the pandemic. Our results suggest the need for rapid communications in the early phase of a pandemic as well as long-term psychosocial support to provide optimal support to pregnant women in Japan. Health care professionals should understand the changing pattern of requirements among pregnant women., (©Ritsuko Shirabe, Tsuyoshi Okuhara, Rie Yokota, Hiroko Okada, Eiko Goto, Takahiro Kiuchi. Originally published in JMIR Pediatrics and Parenting (https://pediatrics.jmir.org), 15.07.2021.)

Dietary supplements are widely advertised and the market is expanding worldwide. Research suggests that dietary supplement advertising may lead consumers to make inappropriate health-related decisions, to express behaviors such as overdosing, and to neglect healthy lifestyle behaviors. We conducted a content analysis of video advertisements for dietary supplements and described the content of advertisements with high numbers and frequent views. We analyzed 82 video advertisements on YouTube that promoted fat-reduction effects. We extracted 22 themes and classified them into 10 categories. The categories with the highest numbers of advertisements were "Exemption" (i.e., consuming the product frees the audience from refraining from binge eating) (20 ads, 24.4%) and "Health Concerns" (i.e., the product intake solves the health concerns of the audience) (19 ads, 23.2%). These advertisements may stimulate negative audience attitudes toward appropriate health behaviors. The category with the most frequent views was "Lifestyle" (i.e., adding product intake to a healthy lifestyle) (3,035,298 views). "Lifestyle" advertisements portray physical activity in a positive light and may promote appropriate health behaviors in the audience. We discuss the possible effects of the advertisements on audiences and consider issues for future research and practice.

BACKGROUND Superior mesenteric vein thrombosis (SMVT) is a relatively rare form of acute abdominal disease; less than 0.1% of laparotomy surgeries are performed for SMVT. In the presence of severe intestinal ischemia or necrosis caused by SMVT, immediate surgical intervention is required. Macroscopic diagnosis of intestinal viability is sometimes difficult; its over-resection may carry the risk of short bowel syndrome. A near-infrared fluorescence imaging system with indocyanine green (ICG) has recently been developed for intraoperative, real-time evaluation of intestinal perfusion. This is the first report on the use of ICG fluorescence imaging during surgery for intestinal ischemia caused by venous thrombosis. CASE REPORT A 70-year-old man presented with a general feeling of weariness. On examination, he was diagnosed with intravascular large B cell lymphoma. R-CHOP therapy was initiated. On day 3 of initial R-CHOP therapy, the patient experienced sudden severe abdominal pain while in the hospital. Contrast-enhanced computed tomography revealed SMVT and loss of contrast effect in the small intestine. We diagnosed small bowel necrosis caused by SMVT, and exploratory laparotomy was performed, which revealed a continuous ischemia of 150 cm. Intraoperative ICG fluorescence imaging was utilized, and the color boundary was consistent with the ischemic area detected by visualization. The necrotic small intestine was excised and anastomosed. The patient was transferred to the hematology department on postoperative day 10 with no severe complications such as anastomotic leakage or re-thrombosis, and re-embolization was not observed 6 months later. CONCLUSIONS Venous thrombosis should be listed as a differential diagnosis when acute abdominal disease presents during chemotherapy for malignant lymphoma. ICG fluorescence imaging may be useful in the evaluation of intestinal blood flow for venous thrombosis.

Type 1 diabetes (T1DM) is a chronic disease characterized by hyperglycemia due to a deficiency in endogenous insulin production, resulting from pancreatic beta cell death. Persistent hyperglycemia leads to enhanced oxidative stress and liver injury. Several studies have evaluated the anti-diabetic and protective effects of probiotic strains in animal models. In the present study, we investigated, through histopathological and biochemical analyses, the effects of eight weeks of administration of Saccharomyces boulardii (S. boulardii) yeast on the liver of streptozotocin (STZ) induced diabetic C57BL/6 mice. Our results demonstrated that S. boulardii attenuates hepatocytes hydropic degeneration and hepatic vessels congestion in STZ-induced diabetic mice. The treatment attenuated the oxidative stress in diabetic mice leading to a reduction of carbonylated protein concentration and increased activity of antioxidant enzymes superoxide dismutase and glutathione peroxidase, compared to untreated diabetic animals. The results also show the beneficial influence of S. boulardii in regulating the hepatic concentration of renin angiotensin system (RAS) peptides. Therefore, our results demonstrated that S. boulardii administration to STZ-induced diabetic mice reduces oxidative stress and normalizes the concentration of RAS peptides, supporting the hypothesis that this yeast may have a role as a potential adjunctive therapy to attenuate diabetes-induced liver injury.

The highly personalized human skin microbiome may serve as a viable marker in personal identification. Amplicon sequencing resolution using 16S rRNA cannot identify bacterial communities sufficiently to discriminate between individuals. Thus, novel higher-resolution genetic markers are required for forensic purposes. The clustered regularly interspaced short palindromic repeats (CRISPRs) are prokaryotic genetic elements that can provide a history of infections encountered by the bacteria. The sequencing of CRISPR spacers may provide phylogenetic information with higher resolution than other markers. However, using spacer sequencing for discrimination of personal skin microbiome is difficult due to limited information on CRISPRs in human skin microbiomes. It remains unclear whether personal microbiome discrimination can be achieved using spacer diversity or which CRISPRs will be forensically relevant. We identified common CRISPRs in the human skin microbiome via metagenomic reconstruction and used amplicon sequencing for deep sequencing of spacers. We successfully reconstructed 24 putative CRISPR arrays using metagenomic data sets. A total of 1,223,462 reads from three CRISPR arrays revealed that spacers in the skin microbiome were highly personalized, and conserved repeats were commonly shared between individuals. These individual specificities observed using CRISPR typing were confirmed by comparing the CRISPR diversity to microbiome diversity assessed using 16S rRNA amplicon sequencing. CRISPR typing achieved 95.2% accuracy in personal classification, whereas 16S rRNA sequencing only achieved 52.6%. These results suggest that sequencing CRISPRs in the skin microbiome may be a more powerful approach for personal identification and ecological studies compared to conventional 16S rRNA sequencing. IMPORTANCE Microbial community diversity analysis can be utilized to characterize the personal microbiome that varies between individuals. CRISPR sequences, which reflect virome structure, in the human skin environment may be highly personalized similar to the structures of individual viromes. In this study, we identified 24 putative CRISPR arrays using a shotgun metagenome data set of the human skin microbiome. The findings of this study expand our understanding of the nature of CRISPRs by identifying novel CRISPR candidates. We developed a method to efficiently determine the diversity of three CRISPR arrays. Our analysis revealed that the CRISPR spacer diversity in the human skin microbiome is highly personalized compared with the microbiome diversity assessed by 16S rRNA sequencing, providing a new perspective on the study of the skin microbiome., (Copyright © 2021 Toyomane et al.)

Sphingolipids are now considered not only as constitutional components of the cellular membrane but also as essential bioactive factors regulating development and physiologic functions. Ceramide is a vital intermediate of sphingolipid metabolism, synthesized by de novo and salvage pathways, producing multiple types of sphingolipids and their metabolites. Although mutations in gene-encoding enzymes regulating sphingolipid synthesis and metabolism cause distinct diseases, an abnormal sphingolipid metabolism contributes to various pathologic conditions, including kidney diseases. Excessive accumulation of glycosphingolipids and promotion of the ceramide salvage and sphingosine-1-phosphate (S1P) pathways are found in the damaged kidney. Acceleration of the sphingosine kinase/S1P/S1P receptor (SphK/S1P/S1PR) axis plays a central role in deteriorating kidney functions. The SphK/S1P/S1PR signaling impairment is also found during pregnancy complications, such as preeclampsia and intrauterine growth restriction (IUGR). This mini-review discusses the current state of knowledge regarding the role of sphingolipid metabolism on kidney diseases, and the possible involvement of preeclampsia and IUGR conditions., Competing Interests: All authors have nothing to disclose., (Copyright © 2021 by the American Society of Nephrology.)

BACKGROUND Treatment methods for appendiceal-colonic fistulas differ greatly depending on whether lesions are benign or malignant. If the tumor is malignant, appendectomy with lymph node resection (ileocecal resection or right hemicolectomy) should be performed. There is no consensus on the method of surgery for organs infiltrated by appendiceal cancer. Furthermore, there are no reported laparoscopic cases that could be prevented from over-surgery by laparoscopy examination or rapid intraoperative pathological examination. CASE REPORT A 76-year-old man presented with positive fecal occult blood. Lower endoscopy revealed a 10-mm tumor in the rectosigmoid colon accompanied by white moss. A biopsy showed inflammatory granulation and no malignancy. Fluorodeoxyglucose-positron emission tomography showed highly increased accumulation at the tip of the appendix, and the standardized uptake value max was 7.3. We suspected a benign lesion rather than appendiceal cancer with infiltration into the rectosigmoid colon; therefore, we performed laparoscopic appendectomy and wedge-shaped resection of the rectum of the sigmoid colon. An intraoperative rapid pathological examination showed no appearance of malignancy; therefore, additional resection was omitted, and an ileostomy was created in the right lower quadrant. A permanent pathological examination showed complicated appendicitis, with no appearance of malignancy. The ileostomy was closed on postoperative day 25, and the patient was discharged on postoperative day 32. CONCLUSIONS In cases where there is difficulty in identifying whether the appendiceal-colonic fistula lesion is benign or malignant, laparoscopy and intraoperative rapid pathological examination may be useful in avoiding excessive treatment.

BACKGROUND The upper stomach can be involved in 1 type of esophageal hiatal hernia in which the degree of stomach insertion is considerable and accompanied by a twist in the shaft of the stomach. The diagnostic accuracy of upper endoscopy or barium meal examination decreases in patients with upside-down stomach, thus making diagnosis of stomach lesions very difficult. No previous reports have described scirrhous gastric cancer in a patient with upside-down stomach. CASE REPORT An 85-year-old woman presented with loss of appetite and vomiting after eating oxalic acid-containing food 2 months previously. Computed tomography revealed an upside-down stomach, and upper endoscopy revealed loss of distensibility and superficial gastritis of the entire stomach. Upside-down stomach was diagnosed; accordingly, laparoscopic hernia repair was planned. Laparoscopic exploration revealed retention of serous fluid (i.e., ascites) containing gastric carcinoma cells (pathologically identified intraoperatively) and induration of the entire stomach. After converting to laparotomy, induration of the stomach was confirmed, continuing to the adjacent 4 cm of the distal esophagus. The patient was diagnosed with scirrhous gastric cancer. Esophageal hiatus hernia repair was performed due to the patient's age and the risks associated with esophagojejunostomy. Preoperative complaints of symptoms disappeared. The patient was transferred to the medical hospital on postoperative day 52 with no complications. CONCLUSIONS Specific symptoms of gastric cancer can mimic those of esophageal hiatal hernia in patients with hernia. In cases of upside-down stomach with loss of distensibility and increased wall thickness, physicians should be aware of the possibility of scirrhous gastric cancer.

Background: Approximately one-third of Japanese couples currently worry or previously worried about infertility. To develop strategies for the primary prevention of infertility as a population approach, it is important for the general population to be knowledgeable about fertility and infertility. The internet may contribute to the dissemination of information regarding infertility and fertility. However, few studies have examined online information about fertility., Objective: This study aimed to quantitatively examine online Japanese-language information about lifestyle factors associated with reduced fertility., Methods: We conducted online searches, using the 10 search terms with the highest numbers of searches that people hoping to conceive are likely to input in two major search engines in Japan (Google Japan and Yahoo! Japan). From the 2200 retrieved websites, 1181 duplicates and 500 websites unrelated to our objective were excluded, resulting in a final dataset of 519 websites. Coding guidelines were developed for the following lifestyle factors associated with reduced fertility: sexually transmitted diseases, psychological stress, cigarette smoking, alcohol use, nutrition and diet, physical activity and exercise, underweight, overweight and obesity, and environmental pollutants., Results: In terms of the website author's professional expertise, 69.6 % of the coding instances for the selected lifestyle factors were mentioned by hospitals, clinics, or the media, whereas only 1.7% were mentioned by laypersons. Psychological stress (20.1%) and sexually transmitted diseases (18.8%) were the most frequently mentioned lifestyle factors associated with reduced fertility. In contrast, cigarette smoking, alcohol use, nutrition and diet, physical activity and exercise, underweight, overweight and obesity, and environmental pollutants were mentioned relatively infrequently. The association between reduced fertility and sexually transmitted diseases was mentioned significantly more frequently by hospitals and clinics than by the media (P<.001). The association between reduced fertility and nutrition and diet was mentioned significantly more frequently by the media than by hospitals and clinics (P=.008). With regard to the sex of the target audience for the information, female-specific references to psychological stress, sexually transmitted diseases, nutrition and diet, underweight, physical activity and exercise, and overweight and obesity were significantly more frequent than were male-specific references to these lifestyle factors (psychological stress: P=.002, sexually transmitted diseases: P<.001, nutrition and diet: P<.001, underweight: P<.001, physical activity and exercise: P<.001, overweight and obesity: P<.001)., Conclusions: Of the lifestyle factors known to be related to reduced fertility, cigarette smoking, alcohol use, and male-specific lifestyle factors are mentioned relatively infrequently in online information sources in Japan, and these factors should be discussed more in information published on websites., (©Rie Yokota, Tsuyoshi Okuhara, Haruka Ueno, Hiroko Okada, Emi Furukawa, Takahiro Kiuchi. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 25.08.2020.)

Background/aim: Adult T-cell leukemia (ATL) is a hematological malignancy caused by infection with human T-cell leukemia virus type 1 (HTLV-1). Chemotherapy, antibody therapy, and bone marrow transplantation are used to treat this disease, however, median survival time has not been significantly improved. Our aim was to develop and evaluate a novel antibody-drug conjugate (ADC) with regards to cell cytotoxicity and target specificity., Materials and Methods: In this study, we have constructed a novel ADC, which is composed of an anti-CD70 single chain Fv-Fc antibody conjugated with the anticancer agent emtansine using a novel antibody modification method. Cell cytotoxicity and target specificity were assessed using a cell proliferation assay., Results: The anti-CD70 ADC selectively killed HTLV-1-infected cells and ATL cells without affecting other cells., Conclusion: The anti-CD70 ADC offers some chemotherapeutic potential for the treatment of ATL., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The prognosis for renal function in anti-GBM glomerulonephritis (anti-GBM GN) is extremely poor, and when renal impairment progresses severely, it is difficult to expect improvement. In addition, it is also known that once the disease activity can be controlled by aggressive treatment, its recurrence is rare. We experienced an anti-GBM GN that improved from severe renal dysfunction and relapsed. A possible cause was the superimpose of nephrotic syndrome due to minimal change disease (MCD)., Case Presentation: A 30-year-old man was admitted to our hospital because of general malaise, fever, oliguria and renal dysfunction. The patient's laboratory data showed serum creatinine as high as 6.6 mg/dl, and severe inflammation (C-reactive protein 20.6 mg/dl). Anti-glomerular basement membrane antibody (anti-GBM Ab) was detected in his serum, which led to the diagnosis of anti-GBM GN. Treatment was initiated with high-dose glucocorticoid (GC) and plasma exchange therapy (PE), and the patient's renal function and oliguria improved rapidly and he was discharged 40 days after admission. Renal biopsy findings showed cellular crescents associated with linear IgG depositions along the glomerular tufts compatible with anti-GBM GN, but only about one-third of the glomeruli was involved, suggesting that it still remains an early stage of the disease. However, 2 months after discharge, he had a relapse and was readmitted due to severe proteinuria with positive anti-GBM Ab. On the second admission, after high-dose GC and PE combined with intravenous cyclophosphamide, and remission was achieved. Despite the relatively minor renal biopsy findings, the patient showed rapid renal dysfunction and relatively rapid improvement with our treatment. Electron microscopy of the renal biopsy tissue showed significant foot process effacement on podocytes in the apparently normal glomeruli, without electron dense deposits., Conclusion: On the basis of clinical course and renal pathology, it is suggested that the present case was a rare complication of an early stage of anti-GBM GN and minimal change nephrotic syndrome. Although the simultaneous development of anti-GBM GN and MCD with anti-GBM antibody is unclear, it might have been precipitated by influenza infection or some unknown factor.

Thymic crosstalk, a set of reciprocal regulations between thymocytes and the thymic environment, is relevant for orchestrating appropriate thymocyte development as well as thymic recovery from various exogenous insults. In this work, interactions shaping thymic crosstalk and the resultant dynamics of thymocytes and thymic epithelial cells are inferred based on quantitative analysis and modeling of the recovery dynamics induced by irradiation. The analysis identifies regulatory interactions consistent with known molecular evidence and reveals their dynamic roles in the recovery process. Moreover, the analysis also predicts, and a subsequent experiment verifies, a previously unrecognized regulation of CD4+CD8+ double positive thymocytes which temporarily increases their proliferation rate upon the decrease in their population size. Our model establishes a pivotal step towards the dynamic understanding of thymic crosstalk as a regulatory network system., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2019.)

Purpose: The aim of this study was to assess the safety of rectal surgery after 5-fluorouracil-leucovorin-oxaliplatin chemotherapy (FOLFOX6)., Methods: This was a prospective, multicenter study in 11 Japanese hospitals. We included patients with rectal cancer who received 4 courses of modified FOLFOX6 (mFOLFOX6) before rectal surgery and examined the postoperative complication rate, the clinicopathological response, and the rate of chemotherapy-related adverse events (UMIN 000012559)., Results: The study population included 36 men and 5 women. The average age of the patients was 60.8 years and the average body mass index was 23.1 kg/m 2 . After 4 courses of chemotherapy, grade 2 peripheral nerve disorder and other grade 3 adverse events were seen in 3 patients each (7.3%). Twenty-eight (73.7%) and 8 (21.1%) patients underwent low anterior resection and abdominoperineal resection, respectively. The pelvic nerves were preserved in 35 patients. Surgical morbidity (grade ≥ 3) occurred in 4 patients (10.5%). Anastomotic leakage occurred after surgery in 2 patients (7.1%). No patients achieved pathologically complete remission. However, downstaging of the clinical stage and N stage was seen in 17 (41.5%) and 22 (53.7%) patients, respectively., Conclusions: Surgery after four courses of mFOLFOX6 chemotherapy can be a safe and promising strategy for patients with locally advanced rectal cancer.

Background: Urinary tract infection (UTI) is one of the most common diseases in children, and urinary angiotensinogen (U-AGT) is a new biomarker gathering attention in many renal diseases. U-AGT reflects intrarenal renin-angiotensin system (RAS) activity. We conducted a study to measure U-AGT in children <4 months old with UTI., Methods: All children <4 months old who came to Toshima Hospital with fever between January 2015 and December 2015 were included. Patients were divided into a UTI group and a non-UTI group, and U-AGT was measured., Results: Median U-AGT was higher in patients with UTI compared with patients without UTI: (0.56 ng/dL, range, 0.025-2.753 ng/dL vs 0.13 ng/dL, range, 0.008-1.697 ng/dL, respectively; P < 0.05)., Conclusions: U-AGT is elevated in UTI patients, and RAS activation may contribute to renal injury caused by UTI., (© 2019 Japan Pediatric Society.)

The kidney is an important target of the renin-ANG-aldosterone system (RAAS). To date, several studies have demonstrated the existence of a local RAAS in various tissues, including the renal tissue. The mineralocorticoid aldosterone is known to play a critical role in the classical RAAS; however, its effect on mesangial cells (MCs) remains to be elucidated. Based on this, our aim was to investigate whether aldosterone stimulation can modulate the intracellular RAAS of immortalized human MCs by evaluating ANG-converting enzyme (ACE)/ANG II/ANG II receptor type 1 (AT1) and ANG-converting enzyme 2 (ACE2)/ANG (1-7)/MAS receptor axes. To realise this, protein expression, enzyme activity, and immunofluorescence were performed under aldosterone stimulation and in the presence of the mineralocorticoid receptor (MR) antagonist spironolactone (SPI). We observed that high doses of aldosterone increase ACE activity. The effect of aldosterone on the catalytic activity of ACE was completely abolished with the pretreatment of SPI suggesting that the aldosterone-induced cell injuries through ANG II release were attenuated. Aldosterone treatment also decreased the expression of MAS receptor, but did not alter the expression or the catalytic activity of ACE 2 and ANG (1-7) levels. Spironolactone modulated the localization of ANG II and AT1 receptor and decreased ANG (1-7) and MAS receptor levels. Our data suggest that both aldosterone and the MR receptor antagonist can modulate both of these axes and that spironolactone can protect MCs from the damage induced by aldosterone., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Aim: We investigated the kidney morphofunctional consequences of high-fat diet intake since post-weaning in adult rats. Main Methods: Male Wistar rats were divided into two groups: ND (normal diet; n = 10) and HD (high-fat diet; n = 10). The high-fat diet was introduced post-weaned and animals were followed for 8 weeks. Key Findings: HD group did not change body weight gain even though food consumption has decreased with no changes in caloric consumption. The HD group showed glucose intolerance and insulin resistance. The glomerular filtration rate (GFR) was decreased in vivo (ND: 2.8 ± 1.01; HD: 1.1 ± 0.14 ml/min) and in the isolated perfusion method (34% of decrease). Renal histological analysis showed a retraction in glomeruli and an increase in kidney lipid deposition (ND: 1.5 ± 0.17 HD: 5.9 ± 0.06%). Furthermore, the high-fat diet consumption increased the pro-inflammatory cytokines IL-6 (ND: 1,276 ± 203; HD: 1,982 ± 47 pg/mL/mg) and IL-1b (ND: 97 ± 12 HD: 133 ± 5 pg/mL/mg) without changing anti-inflammatory cytokine IL-10. Significance: Our study provides evidence that high-fat diet consumption leads to renal lipid accumulation, increases inflammatory cytokines, induces glomeruli retraction, and renal dysfunction. These damages observed in the kidney could be associated with an increased risk to advanced CKD in adulthood suggesting that reduction of high-fat ingestion during an early period of life can prevent metabolic disturbances and renal lipotoxicity.

Artificially modified IgG molecules are increasingly utilized in industrial and clinical applications. In the present study, the method of chemical conjugation by affinity peptide (CCAP) for site-specific chemical modification has been developed by using a peptide that bound with high affinity to human IgG-Fc. This method enabled a rapid modification of a specific residue (Lys248 on Fc) in a one-step reaction under mild condition to form a stable amide bond between the peptide and Fc. The monovalent peptide-IgG conjugate not only maintained complete antigen binding but also bound to Fc receptors (FcRn, FcγRI, and FcγRIIIa), indicating that it is a suitable conjugate form that can be further developed into highly functional antibody therapeutics. CCAP was applied for the preparation of an antibody-drug conjugate and a bispecific antibody to demonstrate the usefulness of this method.

Background: Tonin, a serine-protease that forms Angiotensin II (AngII) from angiotensinogen, is increased in failing human heart samples. Increased blood pressure (BP) and decreased heart rate (HR) variabilities are associated with higher risk of cardiovascular morbidity. Losartan has been used to reduce hypertension and, therefore, lowers the risk of fatal and non-fatal cardiovascular events. Determination of tonin's impact on BP and HR variabilities as well as the impact of losartan remain questions to be elucidated. Aim: Evaluation of cardiovascular autonomic profile in transgenic mice overexpressing the rat tonin enzyme TGM'(rton) and the impact of AT1 receptor blocker, losartan. Methods: Male C57BL/6 (WT) and TGM'(rTon) mice were cannulated for recording BP (Windaq, 4 MHz) for 30 min at baseline and 30 min after losartan injection (20 mg/kg). BP and HR variabilities were analyzed in time and frequency domain method. Low-frequency (LF) and high-frequency (HF) components were identified for sympathetic and parasympathetic modulations analysis. Ang I, AngII, and Ang1-7 were quantified by high performance liquid chromatography method. The total enzymatic activity for AngI, AngII, and Ang1-7 formation was evaluated in the heart and plasma by Liquid chromatography mass spectrometry (LC-MS/MS). Results: At the baseline TGM'(rTon) exhibited higher BP, lower cardiac LF, higher cardiac HF, lower LF/HF, and lower alpha index than wild type (WT). After losartan injection, TGM'(rTon) mice presented an additional decrease in cardiac LF and increase in HF in relation to baseline and WT. In the vasculature, losartan caused decreased in BP and LF of systolic BP in WT mice in relation to its baseline. A similar effect was observed in the BP of TGM'(rTon) mice; however, LF of systolic BP increased compared to baseline. Our data also indicates that AT1R receptor signaling has been altered in TGM'(rTon)mice. Interestingly, the dynamics of the renin-angiotensin system kinetics change, favoring production of Ang1-7. Conclusion: Autonomic evaluation of TGM'(rTon) mice indicates an unclear prognosis for diseases that affect the heart. HR variability in TGM'(rTon) mice indicates high risk of morbidity, and sympathetic and parasympathetic modulation indicate low risk of morbidity. The low risk of morbidity could be the biased production of Ang1-7 in the heart and circulation; however, the altered response of AT1R in the TGM'(rTon) remains to be elucidated, as well aswhether that signaling is pro-protection or pro-pathology.

Maintenance of normal blood pressure under conditions of drug treatment is a measure of system-wide neuro-hormonal controls and electrolyte/fluid volume homeostasis in the body. With increased interest in designing and evaluating novel drugs that may functionally select or allosterically modulate specific GPCR signaling pathways, techniques that allow us to measure acute and long-term effects on blood pressure are very important. Therefore, this chapter describes techniques to measure acute and long-term impact of novel GPCR ligands on blood pressure regulation. We will use the angiotensin type 1 receptor, a powerful blood pressure regulating GPCR, in detailing the methodology. Normal blood pressure maintenance depends upon dynamic modulation of angiotensin type 1 receptor activity by the hormone peptide angiotensin II. Chronic activation of angiotensin type 1 receptor creates hypertension and related cardiovascular disease states which are treated with angiotensin type 1 receptor blockers (ARBs). Thus, a prototype for evaluation of blood pressure control under experimental evaluation of novel drugs., (© 2019 Elsevier Inc. All rights reserved.)

Overconsumption of fructose leads to metabolic syndrome as a result of hypertension, insulin resistance, and hyperlipidemia. In this study, the renal function of animals submitted to high fructose intake was analyzed from weaning to adulthood using in vivo and ex vivo methods, being compared with a normal control group. We investigated in ex vivo model of the role of the renin Angiotensin system (RAS) in the kidney. The use of perfused kidney from animals submitted to 8-week fructose treatment showed that high fructose intake caused metabolic and cardiovascular alterations that were consistent with other studies. Moreover, the isolated perfused kidneys obtained from rats under high fructose diet showed a 33% increase in renal perfusion pressure throughout the experimental period due to increased renal vascular resistance and a progressive fall in the glomerular filtration rate, which reached a maximum of 64% decrease. Analysis of RAS peptides in the high fructose group showed a threefold increase in the renal concentrations of angiotensin I (Ang I) and a twofold increase in angiotensin II (Ang II) levels, whereas no change in angiotensin 1-7 (Ang 1-7) was observed when compared with the control animals. We did not detect changes in angiotensin converting enzyme (ACE) activity in renal tissues, but there is a tendency to decrease. These observations suggest that there are alternative ways of producing Ang II in this model. Chymase the enzyme responsible for Ang II formation direct from Ang I was increased in renal tissues in the fructose group, confirming the alternative pathway for the formation of this peptide. Neprilysin (NEP) the Ang 1-7 forming showed a significant decrease in activity in the fructose vs. control group, and a tendency of reduction in ACE2 activity. Thus, these results suggest that the Ang 1-7 vasodilator peptide formation is impaired in this model contributing with the increase of blood pressure. In summary, rats fed high fructose affect renal RAS, which may contribute to several deleterious effects of fructose on the kidneys and consequently an increase in blood pressure.

Background and Aims: Chronic ethanol consumption is associated with hypertension and atherosclerosis. Vascular oxidative stress is described as an important mechanism whereby ethanol predisposes to atherosclerosis. We hypothesized that nebivolol would prevent ethanol-induced hypertension and vascular oxidative stress., Methods: Male Wistar rats were treated with ethanol 20% (vol./vol.) or nebivolol (10 mg/kg/day, p. o., gavage), a selective β 1 -adrenergic receptor antagonist., Results: Ethanol-induced increase in blood pressure and in the circulating levels of adrenaline and noradrenaline was prevented by nebivolol. Similarly, nebivolol prevented ethanol-induced increase in plasma levels of renin, angiotensin I and II. Chronic ethanol consumption increased the aortic levels of superoxide anion (O 2 - ), thiobarbituric acid reactive species (TBARS) as well as the expression of Nox1 and nitrotyrosine immunostaining in the rat aorta. Treatment with nebivolol prevented these responses. The decrease in aortic levels of nitrate/nitrite (NOx) induced by ethanol was prevented by the treatment with nebivolol. Finally, nebivolol attenuated ethanol-induced increase in phenylephrine- and noradrenaline-induced contraction of endothelium-intact and endothelium-denuded aortic rings., Conclusions: The novelty of our study is that nebivolol prevented ethanol-induced hypertension and vascular oxidative stress. Additionally, we showed that the sympathetic nervous system (SNS) and the renin-angiotensin system (RAS) are important endogenous mediators of the cardiovascular effects of ethanol., (Copyright © 2018 Elsevier B.V. All rights reserved.)

We evaluated the possible mechanisms underlying the oxidative stress induced by ethanol withdrawal. With this purpose, we verified the role of AT 1 receptors in such response. Male Wistar rats were treated with ethanol 3%-9% (vol./vol.) for 21 days. Ethanol withdrawal was induced by abrupt discontinuation of the treatment. Experiments were performed 48 hours after ethanol discontinuation. Increased plasma levels of angiotensin II were detected after ethanol withdrawal. Losartan (10 mg/kg; p.o. gavage), a selective AT 1 receptor antagonist, impeded the increase in blood pressure induced by ethanol withdrawal. Increased lipoperoxidation and superoxide anion (O 2 - ) levels were detected in aortas after ethanol withdrawal, and losartan prevented these responses. Decreased hydrogen peroxide and nitrate/nitrite concentration were detected in aortas after ethanol withdrawal, and losartan prevented these effects. Nitrotyrosine immunostaining in the rat aorta was increased after ethanol withdrawal, and AT 1 blockade impeded this response. Increased expression of PKCδ and p47 phox was detected after ethanol withdrawal, and treatment with losartan prevented these responses. Our study provides novel evidence that ethanol withdrawal increases vascular oxidative stress and blood pressure through AT 1 -dependent mechanisms. These findings highlight the importance of angiotensin II in ethanol withdrawal-induced increase in blood pressure and vascular oxidative damage., (Copyright © 2018 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the ultrastructure of the internal limiting membranes (ILMs) excised during vitrectomy from highly myopic eyes with myopic traction maculopathy (MTM). The clinical findings before and after the vitrectomy were compared., Methods: Seven eyes of 7 patients with macular retinoschisis were studied. Four of these eyes also had a foveal detachment but without a retinal break. All the eyes underwent vitrectomy with the creation of a posterior vitreous detachment and ILM peeling. The excised ILMs were examined by transmission electron microscopy (TEM)., Results: The retinas were reattached in all eyes after the vitrectomy. No retinal breaks including macular holes were identified intraoperatively. Transmission electron microscopy showed glial cells in 4 eyes, retinal pigment epithelium-like cells in 4 eyes, and myofibroblast-like cells in 4 eyes on the excised ILMs. A newly produced basement membrane appeared to merge with the ILM in 5 eyes. Thick collagen was seen in 2 eyes, and fibrous long-spacing collagen in the newly synthesized collagen fibers was seen in 3 eyes. The cellular components of the glial cells appeared to have migrated through the thinner parts of the retina or through a defect of the ILM in 2 eyes., Conclusions: Cells that migrate onto the surface of the ILM synthesize new collagen, which can create tangential traction. This may explain the success of vitrectomy with ILM peeling in treating MTM in highly myopic eyes.

Inter-sample comparisons of T-cell receptor (TCR) repertoires are crucial for gaining a better understanding of the immunological states determined by different collections of T cells from different donor sites, cell types, and genetic and pathological backgrounds. For quantitative comparison, most previous studies utilized conventional methods in ecology, which focus on TCR sequences that overlap between pairwise samples. Some recent studies attempted another approach that is categorized into Poisson abundance models using the abundance distribution of observed TCR sequences. However, these methods ignore the details of the measured sequences and are consequently unable to identify sub-repertoires that might have important contributions to the observed inter-sample differences. Moreover, the sparsity of sequence data due to the huge diversity of repertoires hampers the performance of these methods, especially when few overlapping sequences exist. In this paper, we propose a new approach for REpertoire COmparison in Low Dimensions (RECOLD) based on TCR sequence information, which can estimate the low-dimensional structure by embedding the pairwise sequence dissimilarities in high-dimensional sequence space. The inter-sample differences between repertoires are then quantified by information-theoretic measures among the distributions of data estimated in the embedded space. Using datasets of mouse and human TCR repertoires, we demonstrate that RECOLD can accurately identify the inter-sample hierarchical structures, which have a good correspondence with our intuitive understanding about sample conditions. Moreover, for the dataset of transgenic mice that have strong restrictions on the diversity of their repertoires, our estimated inter-sample structure was consistent with the structure estimated by previous methods based on abundance or overlapping sequence information. For the dataset of human healthy donors and Sézary syndrome patients, our method also showed robust estimation performance even under the condition of high sparsity in TCR sequences, while previous studies failed to estimate the structure. In addition, we identified the sequences that contribute to the pairwise-sample differences between the repertoires with the different genetic backgrounds of mice. Such identification of the sequences contributing to variation in immune cell repertoires may provide substantial insight for the development of new immunotherapies and vaccines.

Purpose: To determine the outcomes of vitrectomy with scleral imbrication in highly myopic eyes with either myopic traction maculopathy (MTM) or macular hole retinal detachment (MHRD)., Methods: The medical records of 17 patients who had undergone vitrectomy with internal limiting membrane (ILM) peeling and scleral imbrication for MTM or MHRD were reviewed. The best-corrected visual acuities (BCVAs), the axial length, the macular hole (MH) closure rate, and the shape of the posterior segment determined by optical coherence tomography were evaluated. Three-dimensional magnetic resonance imaging (3D-MRI) was also performed on five eyes., Results: The postoperative BCVA improved significantly from 0.76 ± 0.39 logarithm of the minimum angle of resolution (logMAR) units to 0.53 ± 0.35 logMAR units (P = 0.0004). The axial length decreased from 29.42 ± 1.81 mm to 27.97 ± 1.71 mm at 1 month. The MTM was resolved or decreased in all eyes. The MH was closed in 44 % of the MHRD eyes, and the retina was reattached in all of the MHRD eyes. The horizontal distance between the optic disc and the bottom of the posterior staphyloma was significantly decreased at 1 month (P = 0.012) but not at later times. The 3D-MRI images showed a reduction in the distance between the bottom of the posterior staphyloma and the center of the eye (P = 0.029) and a flattening of the posterior staphyloma (P = 0.010)., Conclusions: Vitrectomy with ILM peeling and scleral imbrication may be helpful in treating MTM and MHRD by reducing the degree of curvature of the posterior staphyloma.

In water, diketopiperazines cyclo(L-Pro-L-Xxx) and cyclo(L-Pro-D-Xxx) (Xxx=Phe, Tyr) formed an intramolecular hydrophobic interaction between the main skeleton part and their benzene ring, and both cyclo(L-Pro-L-Xxx) and cyclo(L-Pro-D-Xxx) took a folded conformation. The conformational changes from folded to extended conformation by addition of several deuterated organic solvents (acetone-d 6 , metanol-d 4 , dimethyl sulfoxide-d 6 (DMSO-d 6 )) and the temperature rise were investigated using 1 H-NMR spectra. The results suggested that the intrarmolecular hydrophobic interaction of cyclo(L-Pro-D-Xxx) formed more strongtly than that of cyclo(L-Pro-L-Xxx). Under a basic condition of 1.0×10 -1  mol/L potassium deuteroxide, enolization of O 1 -C 1 -C 9 -H 9 moiety of cyclo(L-Pro-L-Xxx) occurred, while that of the O 4 -C 4 -C 3 -H 3 moiety did not. Cyclo(L-Pro-L-Xxx) epimerized to cyclo(D-Pro-L-Xxx), while cyclo(L-Pro-D-Xxx) did not change.

Sepsis is an uncontrolled systemic inflammatory response against an infection and a major public health issue worldwide. This condition affects several organs, and, when caused by Gram-negative bacteria, kidneys are particularly damaged. Due to the importance of renin-angiotensin system (RAS) in regulating renal function, in the present study, we aimed to investigate the effects of endotoxemia over the renal RAS. Wistar rats were injected with Escherichia coli lipopolysaccharide (LPS) (4 mg/kg), mimicking the endotoxemia induced by Gram-negative bacteria. Three days after treatment, body mass, blood pressure, and plasma nitric oxide (NO) were reduced, indicating that endotoxemia triggered cardiovascular and metabolic consequences and that hypotension was maintained by NO-independent mechanisms. Regarding the effects in renal tissue, inducible NO synthase (iNOS) was diminished, but no changes in the renal level of NO were detected. RAS was also highly affected by endotoxemia, since renin, angiotensin-converting enzyme (ACE), and ACE2 activities were altered in renal tissue. Although these enzymes were modulated, only angiotensin (ANG) II was augmented in kidneys; ANG I and ANG 1-7 levels were not influenced by LPS. Cathepsin G and chymase activities were increased in the endotoxemia group, suggesting alternative pathways for ANG II formation. Taken together, our data suggest the activation of noncanonical pathways for ANG II production and the presence of renal vasoconstriction and tissue damage in our animal model. In summary, the systemic administration of LPS affects renal RAS, what may contribute for several deleterious effects of endotoxemia over kidneys., (Copyright © 2016 the American Physiological Society.)

Identifying causal relations from time series is the first step to understanding the behavior of complex systems. Although many methods have been proposed, few papers have applied multiple methods together to detect causal relations based on time series generated from coupled nonlinear systems with some unobserved parts. Here we propose the combined use of three methods and a majority vote to infer causality under such circumstances. Two of these methods are proposed here for the first time, and all of the three methods can be applied even if the underlying dynamics is nonlinear and there are hidden common causes. We test our methods with coupled logistic maps, coupled Rössler models, and coupled Lorenz models. In addition, we show from ice core data how the causal relations among the temperature, the CH4 level, and the CO2 level in the atmosphere changed in the last 800,000 years, a conclusion also supported by irregularly sampled data analysis. Moreover, these methods show how three regions of the brain interact with each other during the visually cued, two-choice arm reaching task. Especially, we demonstrate that this is due to bottom up influences at the beginning of the task, while there exist mutual influences between the posterior medial prefrontal cortex and the presupplementary motor area. Based on our results, we conclude that identifying causality with an appropriate ensemble of multiple methods ensures the validity of the obtained results more firmly.

Purpose: To evaluate clinical characteristics of rhegmatogenous retinal detachment in high myopic and phakic eyes., Subjects and Method: The subjects were 1174 eyes of phakic rhegmatogenous retinal detachment detected in 1199 eyes that underwent initial vitreoretinal surgery between April 2006 and March 2011. Eyes with macular hole retinal detachment or secondary retinal detachment were excluded. The 486 eyes with high myopia (spherical equivalent ≤ -6.0 D or axial length ≥ 26.5 mm) and the 688 eyes with non-high myopia were compared., Results: The mean age was significantly younger in the high myopia group (42.7 ± 14.2 years old, p < 0.001) with a single peak of higher incidence in 40 years old. The retinal detachment caused by retinal hole was significantly frequent in the high myopia group (p < 0.001) and that caused by retinal tear was less frequent (p = 0.021). The initial retinal attachment rate and the final attachment rate were not significant. In the fellow eye of the high myopia group, the incidence of retinal detachment and lattice degeneration were more frequent (16.7%, 20.4%, respectively)., Conclusions: The incidences of the retinal detachment in younger age and those caused by retinal holes were higher in the high myopia group. Higher incidence of retinal detachment and lattice degeneration in the fellow eyes of the high myopia group indicated that careful observation also in the fellow eyes was recommended.

Purpose: Metabolic syndrome (MS) increases the risk of type 2 diabetes and cardiovascular disease. High consumption of fructose is a proposed cause of increased MS, manifested through hypertension, obesity, insulin resistance, and dyslipidemia. High NaCl also increases the risk of CD. The purpose of this study is to evaluate the influence of fructose and sodium on autonomic dysfunction and its relation with CD in MS. Fructose overload was started at weaning and continued through adulthood., Methods: Male Wistar rats (21 days) were divided into four groups: Control (C), fructose consumption (10%, F), NaCl consumption (salt 1% for the 10 last days, S), and fructose and NaCl (FS), and monitored for 8 weeks. Metabolic evaluations consisted of Lee index, glycemia, insulin and glucose tolerance tests, triglycerides, and total cholesterol measurements. Cardiovascular parameters measured were arterial pressure (AP) and cardiac function performed by echocardiography. They also measured the influence of renin angiotensin (RAS) and autonomic nervous systems by drug blockage with losartan, atropine, and atenolol., Results: Energy analysis showed no change between groups. Fructose overload induced a MS state, confirmed by insulin resistance, glucose intolerance, and dyslipidemia. Fasting glucose was increased in F and FS rat groups compared with C and S groups. AP was higher in F, S, and FS groups in comparison with the C group. The hypotensive response after sympathetic blockade was increased in F, S, and FS versus C. The cardiac vagal tonus was reduced in F and FS animal groups. The intrinsic heart rate was decreased in the FS group (372 ± 9 bpm) compared with the C group (410 ± 13 bpm). The morphometric measurements evaluated through left ventricular diameter during diastole and the left ventricular diameter during systole decreased in the FS group (16 and 26%, respectively). Diastolic function was reduced in F and FS. The depressor response induced by losartan was increased in the F group in comparison with other groups. However, there was a uniform increase in plasma ACE activity in all treated groups compared with the C group., Conclusions: Data suggest that early exposure to high fructose intake produced marked alterations in metabolic and cardiovascular function. When stimulated by NaCl, the fructose-fed subjects showed further impairment in cardiac function.

Immature T cell neoplasms in three young Holstein cattle with neoplastic involvement of the thymus are described. Case 1, with a precursor T lymphoblastic leukemia (calf form of leukosis), was an 86-day-old female calf. The leukemia was characterized by replacement of the bone marrow and spleen by leukemia cells, but preservation of epithelial frameworks throughout the thymus. The other two neoplasms were thymic γδ T cell lymphomas, which were observed in a 246-day-old steer (case 2) and a 16-month-old heifer (case 3). Histological examination revealed obliteration of the normal thymic architecture and stromal fibrosis, with the spleen and liver far less severely affected than in case 1. There were cytological differences bewteen the tumors in case 1 and cases 2 and 3. Additionally, WC1 and CD8 were expressed only in the latter. Thus, the leukemia and these lymphomas should be regarded as independent disease entities on the basis of histological and immunohistochemical characteristics.

Purpose: To compare the outcomes of 23-gauge (G) and 25G vitrectomy to 20G vitrectomy on eyes with severe proliferative diabetic retinopathy (PDR)., Methods: The medical records of 424 eyes of 347 patients with severe PDR were reviewed. There were 80 eyes that had 23G, 174 eyes that had 25G, and 170 eyes that had 20G vitrectomy. The incidences of postoperative vitreous hemorrhage, intraoperative retinal breaks, retinal detachment, and neovascular glaucoma were compared., Results: The incidence of intraoperative retinal breaks was significantly lower in the 23G group (21 %) than in the 20G group (35 %, P = 0.03) but not in the 25G group (26 %, P = 0.057). The incidence of postoperative retinal detachment was not significantly different among the three groups (P = 0.73). The incidence of postoperative vitreous hemorrhage that developed ≥1 month after vitrectomy was not different whether the eyes had panretinal photocoagulation or not (P = 0.15). The incidence of postoperative neovascular glaucoma was significantly lower in the 25G group (3 %) than in the 20G group (11 %, P = 0.01) but not significant compared with that in the 23G group (8 %, P = 0.72)., Conclusion: The lower incidence of intraoperative retinal breaks and postoperative neovascular glaucoma after microincision vitrectomy indicates that microincision vitrectomy should be considered for eyes with severe PDR.

Purpose: Retinal detachment associated with atopic dermatitis has been reported to have several similarities to retinal detachment with blunt trauma both in location and types of retinal breaks. To clarify the difference between these two types of retinal detachment, the clinical features of retinal detachment associated with atopic dermatitis to those with blunt trauma were compared., Method: Among phakic eyes of rhegmatogenous retinal detachment which underwent surgery in our clinic between 2006 and 2011, 51 eyes of 41 cases of retinal detachment associated with atopic dermatitis (Atopy group) and 53 eyes of 51 cases of retinal detachment with blunt trauma (Trauma group) were compared., Results: In the Atopy group, the patients were younger, and the incidence of cataracts and bilateral detachment were more frequent. In the Trauma group, the occurence was more frequent in men and associated vitreous hemorrhage and iritis were more frequent. Shallow retinal detachments and ciliary breaks located at the superotemporal quadrant were more frequent in the Atopy group and bullous detachments and retinal breaks located at the superonasal quadrant were more frequent in the trauma group. Oral dialysis and ciliary breaks were frequent in both groups. The initial retinal reattachment rates were similar between both groups but the final reattachment rate was worse in the trauma group., Conclusions: Retinal detachment associated with atopic dermatitis had many similarities to the detachment with blunt trauma in types of retinal breaks. However, it was distinct in featuring higher incidence of bilateral retinal detachment, cataracts, and ciliary breaks at the superotemporal quadrant.

Temporal coherence among neural populations may contribute importantly to signal encoding, specifically by providing an optimal tradeoff between encoding reliability and efficiency. Here, we considered the possibility that learning modulates the temporal coherence among neural populations in association with well-characterized map plasticity. We previously demonstrated that, in appetitive operant conditioning tasks, the tone-responsive area globally expanded during the early stage of learning, but shrank during the late stage. The present study further showed that phase locking of the first spike to band-specific oscillations of local field potentials (LFPs) significantly increased during the early stage of learning but decreased during the late stage, suggesting that neurons in A1 were more synchronously activated during early learning, whereas they were more asynchronously activated once learning was completed. Furthermore, LFP amplitudes increased during early learning but decreased during later learning. These results suggest that, compared to naïve encoding, early-stage encoding is more reliable but energy-consumptive, whereas late-stage encoding is more energetically efficient. Such a learning-stage-dependent encoding strategy may underlie learning-induced, non-monotonic map plasticity. Accumulating evidence indicates that the cholinergic system is likely to be a shared neural substrate of the processes for perceptual learning and attention, both of which modulate neural encoding in an adaptive manner. Thus, a better understanding of the links between map plasticity and modulation of temporal coherence will likely lead to a more integrated view of learning and attention.

Interaction only within specific molecules is a requisite for accurate operations of a biochemical reaction in a cell where bulk of background molecules exist. While structural specificity is a well-established mechanism for specific interaction, biophysical and biochemical experiments indicate that the mechanism is not sufficient for accounting for the antigen discrimination by T cells. In addition, the antigen discrimination by T cells also accompanies three intriguing properties other than the specificity: sensitivity, speed, and concentration compensation. In this work, we review experimental and theoretical works on the antigen discrimination by focusing on these four properties and show future directions towards understanding of the fundamental principle for molecular discrimination.

The coexistence of electrical conductivity and ferromagnetism has been achieved in a reduced graphene oxide/manganese oxide hybrid (rGO-Mn) synthesized by chemical reduction of a graphene oxide and Mn(2+) (as its GO-Mn(2+) complex) using hydrazine. The rGO-Mn and GO-Mn(2+) complexes were characterized by Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS) and transmission electron microscopy (TEM). In rGO-Mn the Mn was present as manganese oxide nanoparticles located on the rGO nanosheets. This rGO-Mn exhibits both electrical conductivity and ferromagnetism. The synthesis of hybrids incorporating rGO and metal oxides is proposed as a useful strategy for generation of new multifunctional nano-composite materials.

The hydroxyl radical-mediated oxidation of peptides and proteins constitutes a large group of post-translational modifications that can result in structural and functional changes. These oxidations can lead to hydroxylation, sulfoxidation, or carbonylation of certain amino acid residues and cleavage of peptide bonds. In addition, hydroxyl radicals can convert the N-terminus of peptides to an α-ketoamide via abstraction of the N-terminal α-hydrogen and hydrolysis of the ketimine intermediate. In the present study, we identified N-terminal cyclization as a novel modification mediated by a hydroxyl radical. The reaction of angiotensin (Ang) II (DRVYIHPF) and the hydroxyl radical generated by the Cu(II)/ascorbic acid (AA) system or UV/hydrogen peroxide system produced N-terminal cyclized-Ang II (Ang C) and pyruvamide-Ang II (Ang P, CH3COCONH-RVYIHPF). The structure of Ang C was confirmed by mass spectrometry and comparison to an authentic standard. The subsequent incubation of isolated Ang P in the presence of Cu(II)/AA revealed that Ang P was the direct precursor of Ang C. The proposed mechanism involves the formation of a nitrogen-centered (aminyl) radical, which cyclizes to form a five-membered ring containing the alkoxy radical. The subsequent β-scission reaction of the alkoxyl radical results in the cleavage of the terminal CH3CO group. The initial aminyl radical can be stabilized by chelation to the Cu(II) ions. The affinity of Ang C toward the Ang II type 1 receptor was significantly lower than that of Ang II or Ang P. Ang C was not further metabolized by aminopeptidase A, which converts Ang II to Ang III. Hydroxyl radical-mediated N-terminal cyclization was also observed in other Ang peptides containing N-terminal alanine, arginine, valine, and amyloid β 1-11 (DAEFRHDSGYE).

Population studies have shown an association between diabetic nephropathy (DN) and insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene (ACE in humans, Ace in mice). The aim was to evaluate the modulation of Ace copies number and diabetes mellitus (DM) on renal RAS and correlate it with indicators of kidney function. Increased number of copies of the Ace gene, associated with DM, induces renal dysfunction. The susceptibility to the development of DN in 3 copies of animals is associated with an imbalance in activity of RAS enzymes leading to increased synthesis of Ang II and Ang-(1-7). Increased concentration of renal Ang-(1-7) appears to potentiate the deleterious effects triggered by Ang II on kidney structure and function. Results also show increased bradykinin concentration in 3 copies diabetic group. Taken together, results indicate that the deleterious effects described in 3 copies diabetic group are, at least in part, due to a combination of factors not usually described in the literature. Thus, the data presented here show up innovative and contribute to understanding the complex mechanisms involved in the development of DN, in order to optimize the treatment of patients with this complication.

Unlabelled: We evaluated the ultra-wide-field retinal images for a 53-year-old man who developed peripheral retinal tears in an eye implanted with a Kamra corneal inlay after laser in situ keratomileusis. The peripheral fundus was photographed using the ultra-wide-field Optos imaging system. The images had a dark ring in the center of the retinal images that moved with eye movement. Photographs of the peripheral retinal tears were taken by directing the eye laterally to move the dark ring away from the retinal tears. The retinal tears were photocoagulated while viewing the retina through a wide-angle contact lens and with the eye directed laterally. We recommend using a wide-angle viewing lens to examine and treat an eye implanted with a corneal inlay., Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned., (Copyright © 2015 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.)