Role of PPARα in inflammatory response of C2C12 myotubes.

Recent studies have shown a role of inflammation in muscle atrophy and sarcopenia. However, no anti-inflammatory pharmacotherapy has been established for the treatment of sarcopenia. Here, we investigate the potential role of PPARα and its ligands on inflammatory response and PGC-1α gene expression in LPS-treated C2C12 myotubes. Knockdown of PPARα, whose expression was upregulated upon differentiation, augmented IL-6 or TNFα gene expression. Conversely, PPARα overexpression or its activation by ligands suppressed 2-h LPS-induced cytokine expression, with pemafibrate attenuating NF-κB or STAT3 phosphorylation. Of note, reduction of PGC-1α gene expression by LPS treatment for 24 hours was partially reversed by fenofibrate. Our data demonstrate a critical inhibitory role of PPARα in inflammatory response of C2C12 myotubes and suggest a future possibility of PPARα ligands as a candidate for anti-inflammatory therapy against sarcopenia.

Statins inhibit protein kinase D (PKD) activation in intestinal cells and prevent PKD1-induced growth of murine enteroids.

We examined the impact of statins on protein kinase D (PKD) activation by G protein-coupled receptor (GPCR) agonists. Treatment of intestinal IEC-18 cells with cerivastatin inhibited PKD autophosphorylation at Ser916 induced by angiotensin II (ANG II) or vasopressin in a dose-dependent manner with half-maximal inhibition at 0.2 µM. Cerivastatin treatment inhibited PKD activation stimulated by these agonists for different times (5-60 min) and blunted HDAC5 phosphorylation, a substrate of PKD. Other lipophilic statins, including simvastatin, atorvastatin, and fluvastatin also prevented PKD activation in a dose-dependent manner. Using IEC-18 cell lines expressing PKD1 tagged with EGFP (enhanced green fluorescent protein), cerivastatin or simvastatin blocked GPCR-mediated PKD1-EGFP translocation to the plasma membrane and its subsequent nuclear accumulation. Similar results were obtained in IEC-18 cells expressing PKD3-EGFP. Mechanistically, statins inhibited agonist-dependent PKD activation rather than acting directly on PKD catalytic activity since exposure to cerivastatin or simvastatin did not impair PKD autophosphorylation or PKD1-EGFP membrane translocation in response to phorbol dibutyrate, which bypasses GPCRs and directly stimulates PKC and PKD. Furthermore, cerivastatin did not inhibit recombinant PKD activity determined via an in vitro kinase assay. Using enteroids generated from intestinal crypt-derived epithelial cells from PKD1 transgenic mice as a model of intestinal regeneration, we show that statins oppose PKD1-mediated increase in enteroid area, complexity (number of crypt-like buds), and DNA synthesis. Our results revealed a previously unappreciated inhibitory effect of statins on receptor-mediated PKD activation and in opposing the growth-promoting effects of PKD1 on intestinal epithelial cells.

Confocal probe based on the second harmonic generation for measurement of linear and angular displacements.

A measurement method based on a confocal probe on the second harmonic generation that can measure linear and angular displacements in the focusing point is proposed. In the proposed method, a pinhole or an optical fiber placed in front of the detector in conventional confocal probes is replaced by a nonlinear optical crystal, which is utilized as a medium generating second harmonic wave whose light intensity changes by the linear and angular displacements of a target under measurement. The feasibility of the proposed method is verified by theoretical calculations and experiments with the newly designed optical setup. Experimental results have demonstrated that the developed confocal probe has a resolution of 20 nm and 5 arc-seconds for measurement of linear and angular displacements, respectively.

Demonstration of a non-orthogonal Lloyd's mirror interferometer with a spatial light modulator for arbitrary two-dimensional pattern fabrication.

A new, to the best of our knowledge, method of generating interference patterns based on a non-orthogonal Lloyd's mirror interferometer with a spatial phase modulation is proposed. In the proposed method, a spatial light modulator (SLM) is introduced to a conventional non-orthogonal Lloyd's mirror interferometer so that arbitrary interference patterns, such as line interference patterns with varied line-spacing or two-dimensional patterns, can be generated by controlling the wavefronts of the laser beams at each position on the substrate. In this paper, as the first step of the research, the feasibility of the proposed method is theoretically confirmed by calculating interference patterns to be obtained when a spatial modulation of the phase delay is applied to the laser beams. A prototype of a non-orthogonal one-axis Lloyd's mirror interferometer with an SLM in its optical path is also designed and constructed. Some basic experiments are carried out to demonstrate the feasibility of the generation of interference patterns having varied line-spacing and two-dimensional patterns by the proposed method.

Laparoscopic observations of adhesions between peritoneal dialysis catheters and intraperitoneal organs: A retrospective, observational study.

Laparoscopy provides extensive data for the decannulation of a peritoneal dialysis catheter and is being increasingly used to diagnose encapsulating peritoneal sclerosis. However, there are few reports on the methods of decannulation of peritoneal dialysis catheters. In this study, we examined the laparoscopic findings and postoperative complications of patients undergoing peritoneal dialysis catheter removal. A total of 119 laparoscopic decannulations of peritoneal dialysis catheters were performed between 2003 and 2018 at the Juntendo University Hospital and Juntendo University Nerima Hospital. Laparoscopy was performed during peritoneal dialysis catheter removal by a gastrointestinal surgeon. Patient characteristics such as age, sex, duration of peritoneal dialysis, history of peritonitis and age at the time of peritoneal dialysis termination were assessed. Of these 119 cases, 19 (16.0%) showed adhesion between the peritoneal dialysis catheter and intraperitoneal organs. There were 13 (10.9%) cases involving a tangled omentum, 4 (3.4%) cases involving the small intestine and 2 (1.7%) cases of adhesions extending from the bowels to the abdominal wall. No postoperative complications were associated with the laparoscopic surgery. In these cases, blind decannulation of the peritoneal dialysis catheter may result in injury to the gastrointestinal tract in patients with adhesions. Therefore, we need to pay attention to adhesions between peritoneal dialysis catheters and intraperitoneal organs, and laparoscopy could be a valuable tool in detecting such adhesions and ensuring patient safety.

Impact of anemia treatment for left ventricular hypertrophy using long-acting erythropoietin-stimulating agents from the pre-dialysis to maintenance dialysis period in patients with chronic kidney disease, retrospective longitudinal cohort study.

BACKGROUND: Anemia in patients with chronic kidney disease (p-CKDs) may initiate or exacerbate left ventricular hypertrophy (LVH). This study aimed to determine whether treatment using long-acting erythropoietin-stimulating agents (L-ESAs) is independently associated with LVH during the pre-dialysis to maintenance dialysis period in p-CKDs. METHODS: Physical and laboratory examinations were performed 120 days before initiating dialysis in p-CKDs (baseline). To evaluate the left ventricular mass index (LVMI) after starting dialysis, the mean hemoglobin (Hb) was defined as the average at the start of dialysis and 6 months after starting dialysis. Changes in the LVMI were observed in three groups according to mean Hb levels (Hb < 10.1, 10.1 < Hb < 11.0, and Hb > 11.0 g/dL for Groups 1, 2, and 3, respectively). LVMI was evaluated using echocardiography at the pre-dialysis, initiation, and maintenance dialysis periods. RESULTS: A lower LVMI at dialysis initiation and an improvement in LVMI were detected in the highest tertile group of mean Hb (11.0 g/dl). Consequently, in the high Hb group (Hb level > 11.0 g/dl), LVMI remained low from dialysis initiation until after 6 months.The relationship between Hb and LVMI was not significant; however, a constant correlation with ß ≥ 0.4 in the absolute value was maintained. CONCLUSION: L-ESAs may correlate with Hb and LVMI after administration, independent of the baseline LVMI and Hb values. These findings have therapeutic implications in the treatment strategies for p-CKDs during the pre-dialysis to maintenance dialysis period.

[Analysis of Surgical Margin Recurrence Following Segmentectomy for Early-stage Non-small Cell Lung Cancer].

BACKGROUND: Surgical margin recurrence following segmentectomy is a critical issue because it may have been avoided by lobectomy. METHODS: Between January 2000 and December 2018, we retrospectively investigated 199 patients who underwent segmentectomy for c-StageⅠ non-small cell lung cancer at our hospital. RESULTS: Recurrence occurred in 20 cases, of which 3 cases had surgical margin recurrence. In our previous study, the recurrence risk factor after segmentectomy was radiologic solid tumor size( cut-off value 1.5 cm). Of the 130 patients in the low-risk group with radiologic solid tumor size of less than 1.5 cm, five had any recurrence, three of which had surgical margin recurrence. In the high-risk group with radiologic solid tumor size of 1.5 cm or more, no surgical margin recurrence was observed. Three cases of surgical margin recurrence were accompanied by lepidic components, and the tumors were difficult to identify intraoperatively and were located close to adjacent areas. CONCLUSION: Surgical margin recurrence may be avoided by carefully considering the segments to be resected and improving the method for identifying the intersegmental plane.

A mouse model of weight gain after nicotine withdrawal.

Smoking cessation increases body weight. The underlying mechanisms, however, have not been fully understood. We here report an establishment of a mouse model that exhibits an augmented body weight gain after nicotine withdrawal. High fat diet-fed mice were infused with nicotine for two weeks, and then with vehicle for another two weeks using osmotic minipumps. Body weight increased immediately after nicotine cessation and was significantly higher than that of mice continued on nicotine. Mice switched to vehicle consumed more food than nicotine-continued mice during the first week of cessation, while oxygen consumption was comparable. Elevated expression of orexigenic agouti-related peptide was observed in the hypothalamic appetite center. Pair-feeding experiment revealed that the accelerated weight gain after nicotine withdrawal is explained by enhanced energy intake. As a showcase of an efficacy of pharmacologic intervention, exendin-4 was administered and showed a potent suppression of energy intake and weight gain in mice withdrawn from nicotine. Our current model provides a unique platform for the investigation of the changes of energy regulation after smoking cessation.

Leadless pacemaker implantation sites confirmed by computed tomography and their parameters and complication rates.

BACKGROUND: Implantations of leadless pacemakers in the septum lower the risk of cardiac perforation. However, the relationship between the implantation site and the success rate, complication rate, and pacemaker parameters are not well-investigated. METHODS: Patients who underwent leadless pacemaker implantation with postprocedural computed tomography (CT) between September 2017 and November 2020 were analyzed. Septum was targeted with fluoroscopic guidance with contrast injection. We divided patients into two groups based on the implantation site confirmed by CT: septal and non-septal, which included the anterior/posterior edge of the septum and free wall. We compared the complication rates and pacemaker parameters between the two groups. RESULTS: A total of 67 patients underwent CT after the procedure; among them, 28 were included in the septal group and 39 were included in the non-septal group. The non-septal group had significantly higher R wave amplitudes (6.5 ± 3.3 vs. 9.7 ± 3.9 mV, p = .001), lower pacing threshold (1.0 ± 0.94 vs. 0.63 ± 0.45 V/0.24 ms, p = .02), and higher pacing impedance (615 ± 114.1 vs. 712.8 ± 181.3 ohms, p = .014) after the procedure compared to the septal group. Cardiac injuries were observed in four patients (one cardiac tamponade, one possible apical hematoma, two asymptomatic pericardial effusion), which were only observed in the non-septal group. CONCLUSIONS: Leadless pacemaker implantation may be technically challenging with substantial number of patients with non-septal implantation when assessed by CT. Septal implantation may have a lower risk of cardiac injury but may lead to inferior pacemaker parameters than non-septal implantation.

Different types of focus: Caregiver-child interaction and changes in preschool children's attention in two cultures.

Social contexts shape the development of attention; however, little is known about joint attention beyond infancy. This study employed behavioral and eye-tracking measurements to investigate cultural variations in how caregivers direct 3- to 4-year-old children's attention and subsequent changes in children's attention to objects and contextual backgrounds in the United States (predominantly non-Hispanic Whites) and Japan (N = 60 mother-child dyads, 29 girls, 31 boys). The findings revealed that caregivers directed children's attention to culturally sensitive information, and significant cross-cultural differences in attention emerged after caregiver-child interaction, with Japanese children shifting their attention to the backgrounds. Results provide new insights into the role of social interaction and cultural diversity in the development of attention.

Formylation Reaction of Amines Using N-Formylcarbazole.

Formamides are useful starting materials for pharmaceutical syntheses. Although various synthetic methods have been documented in this regard, the use of N-formylcarbazole as a formylation reagent for amines has not yet been reported. We report here the first examples of the use of N-formylcarbazole for the formylation of amines. The characteristic reactivity of N-formylcarbazole enables the selective formylation of sterically less hindered aliphatic primary and secondary amines. In contrast, sterically bulkier amines and weakly nucleophilic amines such as anilines are less reactive under the reaction conditions.

A New Optical Configuration for the Surface Encoder with an Expanded Z-Directional Measuring Range.

This paper proposes a new optical configuration for a two-axis surface encoder that can measure the in-plane (X-axis) and out-of-plane (Z-axis) displacements of a positioning stage. The two-axis surface encoder is composed of a scale grating and a sensor head. A transparent grating is employed in the sensor head for measurement of the Z-directional displacement of the scale grating based on the Fizeau-type measurement method; a reference beam reflected from the transparent grating and the zeroth-order diffracted beam from the scale grating are superimposed to generate an interference signal. A pair of prisms and a beam splitter are also employed in the sensor head, so that the positive and negative first-order diffracted beams can be superimposed over a long working distance to generate an interference signal for measurement of the X-directional displacement of the scale grating. Focusing on the new, extended Z-directional measurement mechanism, proof-of-principle experiments were carried out to verify the feasibility of the proposed optical configuration for the surface encoder that can measure the uni-directional displacements of a scale grating along the X- and Z-axis. Experimental results from the developed optical configuration demonstrated the achievement of a Z-directional measuring range of ±1.5 mm.

Reduction of Crosstalk Errors in a Surface Encoder Having a Long Z-Directional Measuring Range.

A modified two-axis surface encoder is proposed to separately measure both the in-plane displacement and the Z-directional out-of-plane displacement with minor crosstalk errors. The surface encoder is composed of a scale grating and a small-sized sensor head. In the modified surface encoder, the measurement laser beam from the sensor head is designed to be projected onto the scale grating at a right angle. For measurement of the X- and Y-directional in-plane scale displacement, the positive and negative first-order diffracted beams from the scale grating are superimposed on each other in the sensor head, producing interference signals. On the other hand, the Z-directional out-of-plane scale displacement is measured based on the principle of a Michelson-type interferometer. To avoid the influence of reflection from the middle area of the transparent grating, which causes periodic crosstalk errors in the previous research, a specially fabricated transparent grating with a hole in the middle is employed in the newly designed optical system. A prototype sensor head is constructed, and basic performances of the modified surface encoder are tested by experiments.

Self-Calibration of a Large-Scale Variable-Line-Spacing Grating for an Absolute Optical Encoder by Differencing Spatially Shifted Phase Maps from a Fizeau Interferometer.

A new method based on the interferometric pseudo-lateral-shearing method is proposed to evaluate the pitch variation of a large-scale planar variable-line-spacing (VLS) grating. In the method, wavefronts of the first-order diffracted beams from a planar VLS grating are measured by a commercial Fizeau form interferometer. By utilizing the differential wavefront of the first-order diffracted beam before and after the small lateral shift of the VLS grating, the pitch variation of the VLS grating can be evaluated. Meanwhile, additional positioning errors of the grating in the lateral shifting process could degrade the measurement accuracy of the pitch variation. To address the issue, the technique referred to as the reference plane technique is also introduced, where the least squares planes in the wavefronts of the first-order diffracted beams are employed to reduce the influences of the additional positioning errors of the VLS grating. The proposed method can also reduce the influence of the out-of-flatness of the reference flat in the Fizeau interferometer by taking the difference between the measured positive and negative diffracted wavefronts; namely, self-calibration can be accomplished. After the theoretical analysis and simulations, experiments are carried out with a large-scale VLS grating to verify the feasibility of the proposed methods. Furthermore, the evaluated VLS parameters are verified by comparing them with the readout signal of an absolute surface encoder employing the evaluated VLS grating as the scale for measurement.

Natriuretic peptide receptor-C releases and activates guanine nucleotide-exchange factor H1 in a ligand-dependent manner.

Although natriuretic peptide receptor-C (NPR-C) is involved in the clearance of natriuretic peptides from plasma, it also possesses other physiological functions, such as inhibition of adenylyl cyclase activity through Gαi. However, the physiological roles and intracellular signaling pathways of NPR-C have yet been not fully elucidated. In this study, we identified a RhoA-specific guanine nucleotide-exchange factor, GEF-H1, as a novel binding protein of NPR-C. We demonstrated that endogenous NPR-C interacted with GEF-H1 in HeLa cells, and that the interaction between NPR-C and GEF-H1 was dependent on a 37-amino acid cytoplasmic region of NPR-C. In contrast, another natriuretic peptide receptor, NPR-A, which includes the kinase homology and guanylyl cyclase domains in the intracellular region, did not interact with GEF-H1. We also revealed that the ligands of NPR-C (i.e., ANP, CNP, and osteocrin) caused dissociation of GEF-H1 from NPR-C. Furthermore, osteocrin treatment induced phosphorylation of GEF-H1 at Ser-886, enhanced the interaction of GEF-H1 with 14-3-3, and increased the amount of activated GEF-H1. These findings strongly supported that NPR-C may be involved in diverse physiological roles by regulating GEF-H1 signaling.

Glucagon-like peptide-1 response to whey protein is less diminished by dipeptidyl peptidase-4 in comparison with responses to dextrin, a lipid and casein in rats.

Although glucose is the best-known nutrient to stimulate glucagon-like peptide-1 (GLP-1) secretion, dietary peptides also potently stimulate GLP-1 secretion. Certain peptide fragments derived from dietary proteins possess dipeptidyl peptidase-4 (DPP-4) inhibitory activity in vitro. Hence, we hypothesised that dietary peptides protect GLP-1 from degradation through attenuating DPP-4 activity in vivo. Here, we compared GLP-1 responses with dietary proteins, a carbohydrate and a lipid (Intralipos) in rats having or not having plasma DPP-4 activity. Plasma GLP-1 concentrations clearly increased by oral administration of whey protein (2-4 g/kg), but not by that of dextrin (2-4 g/kg), in control rats (untreated Sprague-Dawley rats and F344/Jcl rats), having DPP-4 activity. In contrast, dextrin administration increased the plasma GLP-1 concentrations as the whey protein administration did, in rats having reduced or no DPP-4 activity (a DPP-4 inhibitor, sitagliptin-treated Sprague-Dawley rats or DPP-4-deficient F344/DuCrl/Crlj rats). DPP-4 inhibition by sitagliptin treatment also enhanced GLP-1 response to Intralipos, and casein, but the treatment did not further enhance GLP-1 response to whey protein. Intestinal GLP-1 content and gastric emptying rate were not associated with differences in GLP-1 responses to test nutrients. The luminal contents from rats administered whey protein decreased DPP-4 activity in vitro. These results suggest that GLP-1 released by dextrin, Intralipos and casein was immediately degraded by DPP-4, while GLP-1 released by whey protein was less degraded. Our study provides novel in vivo evidence supporting the hypothesis that dietary peptides not only stimulate GLP-1 secretion but also inhibit DPP-4 activity to potentiate GLP-1 response.

Effects of psoas major muscle volume in predicting the prognosis of patients with upper urinary tract urothelial carcinoma treated with radical nephroureterectomy.

BACKGROUND: This study evaluated the impact of sarcopenia and psoas major muscle volume on the survival of patients with upper urinary tract urothelial carcinoma who had undergone radical nephroureterectomy. METHODS: We reviewed data from 110 patients treated with radical nephroureterectomy in our department between June 2007 and February 2017. Psoas major muscle volume was quantified based on computed tomography data using Synapse Vincent software. The psoas major muscle volume index was calculated as psoas major muscle volume/height squared (cm3/m2). We analysed relapse-free survival, cancer-specific survival and overall survival after radical nephroureterectomy to identify factors that predicted patient survival. RESULTS: The median psoas major muscle volume index was 121.5 cm3/m2, and the psoas major muscle volume index was <100 cm3/m2 in 34 of 110 patients (30.9%). Multivariate analysis indicated that ≥pT3-stage cancer, lymphovascular invasion and a psoas major muscle volume index of <100 cm3/m2 were independent predictors of shorter relapse-free survival, cancer-specific survival and overall survival. Using these factors, patients were stratified into three groups: low, intermediate and high risks for relapse-free survival, cancer-specific survival and overall survival. CONCLUSIONS: Low psoas major muscle volume resulting from sarcopenia, high T stage and the presence of lymphovascular invasion was associated with poor survival in patients with urinary tract urothelial carcinoma who had undergone radical nephroureterectomy, supporting the use of psoas major muscle volume as a new objective prognostic marker.

Clinical impact of psoas muscle volume on the development of inguinal hernia after robot-assisted radical prostatectomy.

BACKGROUND: Sarcopenia, a syndrome characterized by the loss of skeletal muscle mass, has attracted attention in the field of oncology, as it reflects poor nutritional status. The present study aimed to determine the risk factors for postoperative inguinal hernia (PIH) development after robot-assisted laparoscopic radical prostatectomy (RARP) for prostate cancer, and discuss whether sarcopenia could be used as a sensitive predictor of PIH. METHODS: We reviewed the medical records of 147 patients who underwent RARP at our institution. The psoas muscle volume (PMV), as an indicator of sarcopenia, was quantified from computed tomography images using a 3-dimensional image analysis system. Multivariate cox regression analyses were performed to identify independent predictors of PIH, including pre- and peri-operative factors. RESULTS: The mean PMV was 393 cm3, and the correlation coefficient between PMV and body mass index was 0.37 (p < 0.01). The PIH-free rate at 2 years postoperatively was 78.2% among all patients. The multivariate analysis revealed that a PMV < 350 cm3 was a significant risk factor for PIH (p = 0.03; hazard ratio 2.19). Body mass index, age, prostate volume, lymph node dissection, nerve sparing, rectus muscle thickness, and console time were not related to PIH development. The PIH-free rate at 2 years postoperatively was 83.4% and 68.9% in patients with a PMV ≥ 350 cm3 and < 350 cm3, respectively (p < 0.05). CONCLUSIONS: PIH occurred significantly more frequently in patients with a PMV < 350 cm3 than in patients with a PMV ≥ 350 cm3, and a low PMV was an independent risk factor for PIH. Thus, urologists should pay attention to the cumulative incidence of IH after RARP, especially in patients with a PMV < 350 cm3.

Carcinogenesis Models Using Small Fish.

Experimental animals are indispensable in life science-related research, including cancer studies. After rats and mice, small fishes, such as zebrafish and medaka, are the second most frequently used model species. Fish models have some advantageous physical characteristics that make them suitable for research, including their small size, some transparency, genetic manipulability, ease of handling, and highly ortholog correspondence with humans. This review introduces technological advances in carcinogenesis model production using small fish. Carcinogenesis model production begins with chemical carcinogenesis, followed by mutagenesis. Gene transfer technology has made it possible to incorporate various mechanisms that act on cancer-related genes in individuals. For example, scientists may now spatiotemporally control gene expression in a single fish through methods including the localization of an expression site via a tissue-specific promoter and expression control using light, heat, or a chemical substance. In addition, genome editing technology is realizing more specific and more efficient gene disruption than conventional mutagenesis, in which the disruption of the gene of interest depends on chance. These technological advances have improved animal models and will soon create carcinogenesis models that better mimic human pathology. We conclude by discussing future expectations for cancer research using small fish.

A Self-Calibration Stitching Method for Pitch Deviation Evaluation of a Long-Range Linear Scale by Using a Fizeau Interferometer.

An interferometric self-calibration method for the evaluation of the pitch deviation of scale grating has been extended to evaluate the pitch deviation of the long-range type linear scale by utilizing the stitching interferometry technique. Following the previous work, in which the interferometric self-calibration method was proposed to assess the pitch deviation of the scale grating by combing the first-order diffracted beams from the grating, a stitching calibration method is proposed to enlarge the measurement range. Theoretical analysis is performed to realize the X-directional pitch deviation calibration of the long-range linear scale while reducing the second-order accumulation effect by canceling the influence of the reference flat error in the sub-apertures' measurements. In this paper, the stitching interferometry theory is briefly reviewed, and theoretical equations of the X-directional pitch deviation stitching are derived for evaluation of the pitch deviation of the long-range linear scale. Followed by the simulation verification, some experiments with a linear scale of 105 mm length from a commercial interferential scanning-type optical encoder are conducted to verify the feasibility of the self-calibration stitching method for the calibration of the X-directional pitch deviation of the linear scale over its whole area.