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Objectives: To investigate the association between plasma N‐terminal pro‐atrial natriuretic peptide concentration and glomerular filtration rate in dogs. Materials and Methods: Dogs were classified into four categories by bodyweight. Dogs were divided into four groups (Groups 1 to 4) based on glomerular filtration rate estimates using plasma iohexol clearance per bodyweight category. Generalised linear models were built to explore the relationship between plasma N‐terminal pro‐atrial natriuretic peptide concentration and glomerular filtration rate and the effect of confounders on plasma N‐terminal pro‐atrial natriuretic peptide concentration. Results: Fifty‐three dogs were included (Group 1, 25; Group 2, seven; Group 3, five; and Group 4, 16). The medians (interquartile range) N‐terminal pro‐atrial natriuretic peptide concentrations for Groups 1 to 4 were 7224 pg/mL (4766 to 10,254 mg/dL), 8958 pg/mL (4935 to 11,271 mg/dL), 9280 pg/mL (9195 to 10,384 mg/dL) and 12,683 pg/mL (9133 to 19,217 mg/dL), respectively. Group 4, estimated to have the highest reduction in glomerular filtration rate, had a higher plasma N‐terminal pro‐atrial natriuretic peptide concentration than Groups 1 to 3. Based on the final generalised linear model, influencing factors for plasma N‐terminal pro‐atrial natriuretic peptide concentration were plasma iohexol clearance (−0.136; 95% confidence interval, −0.227 to −0.046) and bodyweight (−0.058; 95% confidence interval, −0.098 to −0.018). Clinical Significance: N‐terminal pro‐atrial natriuretic peptide concentration is associated with the glomerular filtration rate. [ABSTRACT FROM AUTHOR]

Pimobendan is not currently approved for use in cats, although its usefulness in feline hypertrophic cardiomyopathy has been suggested. Reports indicate an increase in arrhythmic events following oral administration to healthy cats. Given the greater potency of intravenous administration compared to oral intake, it is conceivable that the incidence of arrhythmias may be increased following pimobendan injection. Therefore, this study aimed to investigate the proarrhythmic effects of pimobendan injection in cats. Five clinically healthy cats underwent physical examination, echocardiography, blood pressure measurements, and 24-hour Holter electrocardiography immediately before and after receiving pimobendan as an intravenous bolus dose of 0.15 mg/kg twice daily for 3 days. Additionally, a 24-hour Holter electrocardiography recording was conducted on the third day of pimobendan or placebo IV administration to assess heart rate, arrhythmias, and heart rate variability. Following pimobendan administration, there was a significant increase in total 24-hour heart rate. Echocardiography revealed a significant increase in mitral valve annulus systolic velocity (S') on the ventricular septal wall side, indicative of enhanced contractility. Only one cat exhibited paroxysmal ventricular tachycardia and an increase in the frequency of arrhythmic events. Conversely, in the remaining cats, a decreasing trend in the number of arrhythmias was observed. These findings indicate that intravenous administration of pimobendan may not be implicated in the onset of arrhythmias. Nevertheless, further research is warranted to explore the effects of intravenous pimobendan administration in cats with myocardial disease., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

(1) Background: HASPIN kinase is involved in regulating spindle function and chromosome segregation, as well as phosphorylating histone H3 at Thr3 in mitotic cells. Several HASPIN inhibitors suppress cancer cell proliferation. It was recently reported that coumestrol from bean sprouts inhibits HASPIN, and a cultivation method for bean sprouts containing large amounts of coumestrol has been established. Here, we showed the effects of bean sprout ingestion on intestinal polyp development, cachexia, and hypogonadism in a mouse model of familial adenomatous polyposis ( Apc Min/+ ). (2) Methods: Apc Min/+ mice were randomized into control and treatment groups. Mice in the control group were given the standard diet, while those in the treatment group were given the same standard diet with the addition of 15% bean sprouts. Treatments were commenced at 7 weeks old and analyses were performed at 12 weeks old. (3) Results: ingesting bean sprouts suppressed the development of intestinal polyps, cachexia, and hypogonadism, and also increased serum levels of testosterone in male wild-type and Apc Min/+ mice. (4) Conclusions: ingesting bean sprouts helps prevent cancer and increases serum levels of testosterone in a mouse model. These results are expected to be applicable to humans.

Background: Interval debulking surgery (IDS) following neoadjuvant chemotherapy is a treatment option for advanced ovarian cancer. Optimal surgery is required for better survival; however, while peritoneal washing cytology (PWC) has been identified as a prognostic factor, its comprehensive assessment during IDS remains unexplored. Therefore, we aimed to evaluate PWC efficacy during IDS, alongside other factors including residual disease and the modeled cancer antigen 125 (CA-125) ELIMination rate constant K (KELIM), by retrospectively reviewing the medical records of 25 patients with advanced ovarian cancer underwent neoadjuvant chemotherapy and IDS between January 2017 to June 2023., Results: Twelve (48.0%) patients were PWC-positive, and the remainder were PWC-negative. PWC was performed at laparotomy during IDS, after which five (41.7%) PWC-positive and four (30.8%) PWC-negative patients received bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, for maintenance treatment. Four (33.3%) PWC-positive and 10 (76.9%) PWC-negative patients received poly adenosine diphosphate (ADP)-ribose polymerase inhibitors. In patients who received bevacizumab and poly ADP-ribose polymerase inhibitors, overall survival and progression-free survival did not significantly differ between those who were PWC-positive and PWC-negative (p = 0.27 and 0.20, respectively). Progression-free survival significantly differed between those with favorable and unfavorable CA-125 KELIM (p = 0.02). Multivariate analysis indicated that optimal surgery and favorable CA-125 KELIM were associated with better progression-free survival (p < 0.01 and 0.02, respectively), with only optimal surgery associated with better overall survival (p = 0.04)., Conclusions: A positive PWC at IDS was not associated with survival in advanced ovarian cancer. Our findings indicate that although PWC status at IDS should be one of the factors determining survival in patients with advanced ovarian cancer, recent improvements in maintenance therapy may make the combination of CA-125 KELIM and PWC status a more useful prognostic factor in selecting treatment after IDS. Further studies are needed to validate these results, highlighting the potential importance of maintenance treatment after IDS and the need for further research to validate the clinical significance of a positive PWC., (© 2024. The Author(s).)

Testosterone production is important in males, and various physical and psychological abnormalities occur in individuals with low testosterone levels. In the present study, we aimed to examine the effects of longitudinal changes in total testosterone levels in the same cohort. We included 178 male subjects who visited our hospital multiple times between 2018 and 2023 for medical checkups for at least 3 years. The median baseline age and total testosterone level (TT) of the cohort were 61 years and 4.74 ng/mL, respectively. The patients were divided into four groups based on the difference in TT (ΔTT) between baseline and last visit (Q1, n = 45; Q2, n = 45; Q3, n = 44; Q4, n = 44). ΔTT values ranged from -3.07 to -0.78 ng/mL in Q1, from -0.75 to -0.05 ng/mL in Q2, from -0.03 to 0.73 ng/mL in Q3, and from 0.75 ng/mL to 3.4 ng/mL in Q4. The median ΔTT were -1.22 for Q1, -0.35 for Q2, +0.19 for Q3, and +1.43 for Q4. Decreased TT tended to increase body weight, body mass index, waist circumference, and visceral fat (p for trend 0.0136, 0.0272, 0.0354, and 0.0032, respectively), and decrease adiponectin level (p for trend 0.0219). Herein, we found that decreased TT increases visceral fat and decreases adiponectin levels.

Myocardial damage significantly impacts the prognosis of patients with cancer; however, the mechanisms of myocardial damage induced by cancer and its treatment remain unknown. We previously reported that medium-chain fatty acids (MCFAs) improve cancer-induced myocardial damage but did not evaluate the differences in effect according to MCFA type. Therefore, this study investigated the role of inflammatory cytokines in cancer-induced myocardial damage and the effects of three types of MCFAs (caprylic acid [C8], capric acid [C10], and lauric acid [C12]). In a mouse model, the C8 diet showed a greater effect on improving myocardial damage compared with C10 and C12 diets. Myocardial tubes differentiated from H9C2 cardiomyoblasts demonstrated increased mitochondrial oxidative stress, decreased membrane potential and mitochondrial volume, and inhibited myocardial tube differentiation following treatment with high-mobility group box-1 (HMGB1) but not interleukin-6 and tumor necrosis factor-α cytokines. However, HMGB1 treatment combined with C8 improved HMGB1-induced mitochondrial damage, enhanced autophagy, and increased mitochondrial biogenesis and maturation. However, these effects were only partial when combined with beta-hydroxybutyrate, a C8 metabolite. Thus, HMGB1 may play an important role in cancer-related myocardial damage. C8 counteracts HMGB1's effects and improves cancer-related myocardial damage. Further clinical studies are required to investigate the effects of C8.

Nutritional interventions are one focus of sarcopenia treatment. As medium-chain fatty acids (MCFAs) are oxidized in the mitochondria and produce energy through oxidative phosphorylation (OXPHOS), they are key parts of nutritional interventions. We investigated the in vitro effects of three types of MCFA, caprylic acid (C8), capric acid (C10), and lauric acid (C12), in skeletal muscle cells. Compared with C10 and C12, C8 promoted mitophagy through the phosphatase and tensin homolog (PTEN)-induced kinase 1-Parkin pathway and increased the expression of peroxisome proliferator-activated receptor gamma coactivator 1-α and dynamin-related protein 1 to reduce mitochondrial oxidative stress and promote OXPHOS. Furthermore, the expression of myogenic differentiation 1 and myosin heavy chain increased in myotubes, thus promoting muscle differentiation and maturation. These results suggest that C8 improves mitochondrial quality and promotes skeletal muscle maturation; in contrast, C10 and C12 poorly promoted mitochondrial quality control and oxidative stress and suppressed energy production. Future animal experiments are required to establish the usefulness of C8 for nutritional interventions for sarcopenia.

Skeletal muscle aging and sarcopenia result in similar changes in the levels of aging markers. However, few studies have examined cancer sarcopenia from the perspective of aging. Therefore, this study investigated aging in cancer sarcopenia and explored its causes in vitro and in vivo. In mouse aging, in vitro cachexia, and mouse cachexia models, skeletal muscles showed similar changes in aging markers including oxidative stress, fibrosis, reduced muscle differentiation potential, and telomere shortening. Furthermore, examination of mitochondrial DNA from skeletal muscle revealed a 5 kb deletion in the major arc; truncation of complexes I, IV, and V in the electron transport chain; and reduced oxidative phosphorylation (OXPHOS). The mouse cachexia model demonstrated high levels of high-mobility group box-1 (HMGB1) and tumor necrosis factor-α (TNFα) in cancer ascites. Continuous administration of neutralizing antibodies against HMGB1 and TNFα in this model reduced oxidative stress and abrogated mitochondrial DNA deletion. These results suggest that in cancer sarcopenia, mitochondrial oxidative stress caused by inflammatory cytokines leads to mitochondrial DNA damage, which in turn leads to decreased OXPHOS and the promotion of aging., Competing Interests: The authors declare no conflict of interest.

β-Casomorphin-7 (BCM), a breakdown product of milk β-casein, exhibits opioid activity. Opioids are known to affect the immune system, but the effects of BCM on ulcerative colitis (UC) are not clear. We examined the effects of BCM on mucosal immunity using a mouse dextran sulfate sodium-induced colitis model and an in vitro CD8+ T cell activation model. Human UC patients were examined to reveal the relationship between CD10 and mucosal immunity. Combined treatment of the colitis model with thiorphan (TOP) inhibited BCM degradation by suppressing CD10 in the intestinal mucosa, activating mouse mucosal CD8, and suppressing CD4 and Treg. In the CD8+ T cell in vitro activation assay using mouse splenocytes, BCM inhibited the oxidative phosphorylation (OXPHOS) of CD8+ T cells and induced the glycolytic pathway, promoting their activation. Conversely, in a culture system, BCM suppressed OXPHOS and decreased defensin α production in IEC6 mouse intestinal epithelial cells. In the mouse model, BCM reduced defensin α and butyrate levels in the colonic mucosa. During the active phase of human ulcerative colitis, the downward regulation of ileal CD10 expression by CpG methylation of the gene promoter was observed, resulting in increased CD8 activation and decreased defensin α and butyrate levels. BCM is a potential aggravating factor for UC and should be considered in the design of dietary therapy. In addition, decreased CD10 expression may serve as an indicator of UC activity and recurrence, but further clinical studies are needed.

An angiotensin receptor/neprilysin inhibitor (ARNI), a heart failure treatment, is a combination drug made up of sacubitril, a neprilysin inhibitor, and valsartan, a vascular receptor blocker. No human or veterinary studies regarding the effect of ARNI on renal haemodynamics in the absence of cardiac or renal issues exist. Therefore, we investigated the effect of ARNI on renal haemodynamics in five healthy dogs. ARNI was administered to all five dogs at an oral dose of 20 mg/kg twice daily for 4 weeks. Renal haemodynamics were assessed on the day before ARNI administration (BL), on Day 7, and on Day 28. The glomerular filtration rate (GFR) significantly increased on Day 28 compared to BL and Day 7, whereas renal plasma flow increased on Day 7 and Day 28 compared to BL. Systolic blood pressure significantly decreased between BL and Day 28. Plasma atrial natriuretic peptide (ANP) concentrations increased on Day 7 compared to BL. Additionally, ANP concentrations increased on Day 28 in three of the five dogs. Different ANP concentrations were observed in the remaining two dogs. Both urine output volume and heart rate remained relatively stable and did not exhibit significant change. In conclusion, ARNI may enhance renal haemodynamics in healthy dogs. ARNI could be a valuable drug for treating both heart and kidney disease in dogs.

Background: Pembrolizumab (PEM), an immune checkpoint inhibitor (ICI), is often used for triple-negative breast cancer, but can also be used to treat solid tumors that exhibit high microsatellite instability (MSI-High). However, patients with breast cancer rarely have MSI-High, the use of PEM in such cases in clinical practice is uncertain due to lack of sufficient supporting data. Here, we report the case of a premenopausal woman in who received PEM for MSI-High luminal-type breast cancer., Case Presentation: A 40-year-old premenopausal Asian woman was diagnosed with stage IIA (T2N0M0) breast cancer and had an Oncotype DX recurrence score of 38. After surgery, she received 4 courses of chemotherapy with docetaxel and cyclophosphamide. After 3 months of tamoxifen therapy, the patient complained of abdominal pain due to right iliac metastasis, and biopsy of the metastatic lesion showed of luminal type; she was sequentially treated with fulvestrant, a CDK4/6 inhibitor, and an anticancer drug (TS1), but over the next year, metastasis to the bone and para-aortic lymph nodes increased. Tumor was MSI-High; PEM was started, and after three courses, bone metastases were reduced, para-aortic lymph node metastases resolved, opioids were discontinued, and the patient returned to society; PEM was administered for 1 year with no worsening of bone metastases on imaging. Asymptomatic brain metastasis less than 1 cm was detected and gamma knife was performed. Six months after completion of PEM, the patient is working with no new lesions., Conclusion: We report a case of luminal-type breast cancer with bone metastases and MSI-High, which was treated with PEM and showed a rapid therapeutic response., (© 2024. The Author(s).)

Background/aim: Capecitabine plus oxaliplatin (CapeOX) therapy is used as an adjuvant chemotherapy regimen for patients with colorectal cancer (CRC). Although oxaliplatin induces thrombocytopenia, the risk factors for thrombocytopenia in oxaliplatin-treated patients with CRC are not well established. We aimed to investigate the risk factors for thrombocytopenia in CapeOX-treated patients with CRC. In addition, we evaluated platelet counts and non-invasive liver fibrosis indices, specifically the aspartate aminotransferase-to-platelet ratio index (APRI) and the fibrosis-4 index (FIB-4), during CapeOX therapy in these patients., Patients and Methods: Between July 2017 and June 2020, we enrolled CapeOX-treated patients with high-risk stage II or stage III CRC at seven hospitals collaborating with the Division of Oncology, Aichi Prefectural Society of Hospital Pharmacists (Aichi prefecture, Japan). In this retrospective study, we investigated patients' backgrounds, laboratory data, concomitant medications, number of cycles of CapeOX and oxaliplatin, cumulative dose of oxaliplatin, and administration period. The cut-off values were calculated using receiver operating characteristic analysis of platelet counts and APRI and FIB-4 scores., Results: Fifty-five patients without thrombocytopenia and 44 patients with thrombocytopenia were enrolled. During CapeOX therapy, the thrombocytopenia group showed a significant decrease in platelet count and a significant increase in APRI and FIB-4 scores compared to the non-thrombocytopenia group. Baseline albumin level ≤3.5 g/dl and platelet count ≤238×10 3 /μl were independently associated with ≥grade 2 thrombocytopenia in CapeOX-treated patients., Conclusion: Baseline albumin level and platelet count may be useful for predicting thrombocytopenia in CapeOX-treated patients with high-risk stage II or stage III CRC., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Cardiac disorders in cancer patients pose significant challenges to disease prognosis. While it has been established that these disorders are linked to cancer cells, the precise underlying mechanisms remain elusive. In this study, we investigated the impact of cancerous ascites from the rat colonic carcinoma cell line RCN9 on H9c2 cardiomyoblast cells. We found that the ascites reduced mitochondrial volume, increased oxidative stress, and decreased membrane potential in the cardiomyoblast cells, leading to apoptosis and autophagy. Although the ascites fluid contained a substantial amount of high-mobility group box-1 (HMGB1), we observed that neutralizing HMGB1 with a specific antibody mitigated the damage inflicted on myocardial cells. Our mechanistic investigations revealed that HMGB1 activated both nuclear factor κB and phosphoinositide 3-kinases-AKT signals through HMGB1 receptors, namely the receptor for advanced glycation end products and toll-like receptor-4, thereby promoting apoptosis and autophagy. In contrast, treatment with berberine (BBR) induced the expression of miR-181c-5p and miR-340-5p while suppressing HMGB1 expression in RCN9 cells. Furthermore, BBR reduced HMGB1 receptor expression in cardiomyocytes, consequently mitigating HMGB1-induced damage. We validated the myocardial protective effects of BBR in a cachectic rat model. These findings underscore the strong association between HMGB1 and cancer cachexia, highlighting BBR as a promising therapeutic agent for myocardial protection through HMGB1 suppression and modulation of the signaling system., Competing Interests: The authors have no conflicts of interest to declare.

Patients with cancer die from cardiac dysfunction second only to the disease itself. Cardiotoxicity caused by anticancer drugs has been emphasized as a possible cause; however, the details remain unclear. To investigate this mechanism, we treated rat cardiomyoblast H9c2 cells with sunitinib, lapatinib, 5-fluorouracil, and cisplatin to examine their effects. All anticancer drugs increased ROS, lipid peroxide, and iron (II) levels in the mitochondria and decreased glutathione peroxidase-4 levels and the GSH/GSSG ratio. Against this background, mitochondrial iron (II) accumulates through the unregulated expression of haem oxygenase-1 and ferrochelatase. Anticancer-drug-induced cell death was suppressed by N-acetylcysteine, deferoxamine, and ferrostatin, indicating ferroptosis. Anticancer drug treatment impairs mitochondrial DNA and inhibits oxidative phosphorylation in H9c2 cells. Similar results were observed in the hearts of cancer-free rats treated with anticancer drugs in vitro. In contrast, treatment with pterostilbene inhibited the induction of ferroptosis and rescued the energy restriction induced by anticancer drugs both in vitro and in vivo. These findings suggest that induction of ferroptosis and inhibition of oxidative phosphorylation are mechanisms by which anticancer drugs cause myocardial damage. As pterostilbene ameliorates these mechanisms, it is expected to have significant clinical applications.

PDZ domain-containing RING finger family protein 3 (PDZRN3) is expressed in various tissues, including the skeletal muscle. Although PDZRN3 plays a crucial role in the terminal differentiation of myoblasts and synaptic growth/maturation in myogenesis, the role of this molecule in postnatal muscles is completely unknown despite its lifelong expression in myofibers. In this study, we aimed to elucidate the function of PDZRN3 in mature myofibers using myofiber-specific conditional knockout mice. After tamoxifen injection, PDZRN3 deficiency was confirmed in both fast and slow myofibers of Myf6-CreER T2 ; Pdzrn3 flox/flox (Pdzrn3 mcKO ) mice. Transcriptome analysis of the skeletal muscles of Pdzrn3 mcKO mice identified differentially expressed genes, including muscle atrophy-related genes such as Smox, Amd1/2, and Mt1/2, suggesting that PDZRN3 is involved in the homeostatic maintenance of postnatal muscles. PDZRN3 deficiency caused muscle atrophy, predominantly in fast-twitch (type II) myofibers, and reduced muscle strength. While myofiber-specific PDZRN3 deficiency did not influence endplate morphology or expression of neuromuscular synaptic formation-related genes in postnatal muscles, indicating that the relationship between PDZRN3 and neuromuscular junctions might be limited during muscle development. Considering that the expression of Pdzrn3 in skeletal muscles was significantly lower in aged mice than in mature adult mice, we speculated that the PDZRN3-mediated muscle maintenance system might be associated with the pathophysiology of age-related muscle decline, such as sarcopenia., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests related to personal relationships that could have influenced the work reported in this study., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

This study examined whether two personality traits, attachment anxiety, and the Dark Triad, longitudinally promote stalking behaviors after romantic breakups through psychological maltreatment of partners during relationships and maladjusted reactions to breakups. We conducted a prospective longitudinal study across four waves of assessment for 1 year of individuals in romantic relationships in Japan. They completed measures of attachment anxiety, the Dark Triad, need for control, and psychological intimate partner violence (IPV) perpetration at Wave 1, and measures of maladjusted reactions to breakups (i.e., anger and rumination) and stalking behaviors at a wave after breakups. The final sample consisted of 356 participants who were involved in romantic relationships at Wave 1 and left by their partners during the survey period. Correlational analysis showed that the Dark Triad at Wave 1 was significantly positively associated with future stalking behaviors, but attachment anxiety was not. Structural equation modeling showed that attachment anxiety and the Dark Triad increased future stalking behaviors after breakups through psychological IPV perpetration during relationships. Additionally, attachment anxiety increased future stalking behaviors through higher levels of postbreakup anger and rumination. Conversely, we did not find any indirect effects of the Dark Triad on stalking behaviors through these reactions toward breakups. Overall, these results suggest that it is necessary to consider personality traits that could damage intimate relationships and to focus on the quality of romantic relationships to prevent stalking after romantic breakups. These results also indicate that emotion regulation may be useful in preventing stalking caused by attachment anxiety., (© 2024 Wiley Periodicals LLC.)

Introduction: Ovarian metastasis of colorectal cancer is known to have a poor prognosis. This study aimed to elucidate the characteristics of patients who underwent oophorectomy for ovarian metastasis from colorectal cancer., Methods: This retrospective study included 16 patients who underwent oophorectomy for colorectal cancer metastasis to the ovary from January 2004 to December 2017. Improvement in patient's symptoms and pre- and postoperative changes in various nutritional and inflammatory indicators were assessed. Survival analysis and identification of prognostic factors were conducted with a median follow-up of 40.7 (5-109) months., Results: Of 16 patients, 12 had (75%) synchronous and 4 (25%) had metachronous metastasis. Fourteen patients were symptomatic but symptoms resolved postoperatively. Thirteen patients (81.3%) had ascites and 5 (31.3%) had pleural effusion on preoperative computed tomography that disappeared after surgery in all cases. The median value of prognostic nutritional factor was significantly increased postoperatively (36.0 [preoperatively] vs. 47.5, p &lt; 0.0001). The median (interquartile range) values for lymphocyte-C-reactive protein ratio were 715.2 (110-2,607) preoperatively and 6,095.2 (1,612.3-14,431.8) postoperatively (p = 0.0214). The median survival of the entire cohort was 60.4 months. The 3-year survival rates for R0 + R1 and R2 cases were 83% and 24% (p = 0.018), respectively. Univariate analysis showed that R2 resection and low postoperative lymphocyte-C-reactive protein ratio were associated with poor prognosis., Conclusions: Oophorectomy for ovarian metastasis from colorectal cancers was safely performed. It improved the patients' symptoms and nutritional status and may result in improved prognosis., (© 2023 S. Karger AG, Basel.)

More specific screening systems for cervical cancer may become necessary as the human papillomavirus (HPV) vaccine becomes more widespread. Although p16/Ki-67 dual-staining cytology has several advantages, it requires advanced diagnostic skills. Here, we developed an automated on-chip immunostaining method using a microfluidic device. An electroactive microwell array (EMA) microfluidic device with patterned thin-film electrodes at the bottom of each microwell was used for single-cell capture by dielectrophoresis. Immunostaining and dual staining for p16/Ki-67 were performed on diagnosed liquid cytology samples using the EMA device. The numbers of p16/Ki-67 dual-stained cells captured by the EMA device were determined and compared among the cervical intraepithelial neoplasia (CIN) lesion samples. Seven normal, fifteen CIN grade 3, and seven CIN grade 2 samples were examined. The percentage of dual-positive cells was 18.6% in the CIN grade 2 samples and 23.6% in the CIN grade 3 samples. The percentages of dual-positive staining increased significantly as the severity of the cervical lesions increased. p16/Ki67 dual immunostaining using the EMA device is as sensitive as the conventional method of confirming the histopathological diagnosis of cervical samples. This system enables a quantified parallel analysis at the individual cell level., (© 2023. Springer Nature Limited.)

Objective: Negative events tend to reduce self-concept clarity, which could hinder self-change. Three studies (total n = 1603) including two preregistered tested whether inducing self-compassion in response to negative events promotes self-concept clarity and self-change., Methods: Participants engaged in either a self-compassionate or a control writing task regarding negative events. They responded to the scales of self-concept clarity and self-change before and after the manipulation. Self-change was assessed using two indicators: self-improvement regarding the negative aspects of the self (i.e., negativity transformation, Studies 1-3) and openness to self-change (Studies 2 and 3). In Study 3, self-esteem and affect were assessed to test alternative processes., Results: Across the studies, participants induced to be self-compassionate reported higher levels of self-concept clarity, negativity transformation (except in Study 1), and openness to self-change. Studies 2 and 3 found that self-concept clarity mediated the effect of self-compassion on openness to self-change. Study 3 indicated that this indirect effect remained significant, while the indirect effect of self-compassion on negativity transformation was nonsignificant when self-esteem and affect were considered., Conclusions: Overall, boosting self-compassion in response to negative events could help people retain self-concept clarity and, thus, be open to self-change. Self-compassion could also orient people to engage in negativity transformation., (© 2023 Wiley Periodicals LLC.)

Placenta accreta is a high-risk condition causing obstetric crisis and hemorrhage; however, its pathogenesis remains unknown. We aimed to identify the factors contributing to trophoblast invasiveness and angiogenic potential, which in turn drive the pathogenesis of placenta accreta. We focused on the transforming growth factor (TGF)-β1-Smad pathway and investigated the intrinsic relationship between the time- and dose-dependent inhibition of the ubiquitinating enzyme UCHL5 using bAP15, a deubiquitinase inhibitor, after TGF-β1 stimulation and the invasive and angiogenic potential of two cell lines, gestational choriocarcinoma cell line JEG-3 and trophoblast cell line HTR-8/SVneo. UCHL5 inhibition negatively regulated TGF-β1-induced Smad2 activation, decreasing extravillous trophoblast invasiveness. Smad1/5/9 and extracellular signal-regulated kinase (ERK) were simultaneously activated, and vascular endothelial growth factor was secreted into the trophoblast medium. However, extravillous trophoblast culture supernatant severely impaired the vasculogenic potential of human umbilical vein endothelial cells. These results suggest that the downstream ERK pathway and Smad1/5/9 potentially regulate the TGF-β1-Smad pathway in extravillous trophoblasts, whereas Smad2 contributes to their invasiveness. The abnormal invasive and angiogenic capacities of extravillous cells, likely driven by the interaction between TGF-β1-Smad and ERK pathways, underlie the pathogenesis of placenta accreta.

Primary sensory neurons regulate inflammatory processes in innervated regions through neuro-immune communication. However, how their immune-modulating functions are regulated in concert remains largely unknown. Here, we show that Neat1 long non-coding RNA (lncRNA) organizes the proinflammatory gene expressions in the dorsal root ganglion (DRG) in chronic intractable neuropathic pain in rats. Neat1 was abundantly expressed in the DRG and was upregulated after peripheral nerve injury. Neat1 overexpression in primary sensory neurons caused mechanical and thermal hypersensitivity, whereas its knockdown alleviated neuropathic pain. Bioinformatics analysis of comprehensive transcriptome changes indicated the inflammatory response was the most relevant function of genes upregulated through Neat1. Consistent with this, upregulation of proinflammatory genes in the DRG following nerve injury was suppressed by Neat1 knockdown. Expression changes of these proinflammatory genes were regulated through Neat1-mRNA interaction-dependent and -independent mechanisms. Notably, Neat1 increased proinflammatory genes by stabilizing its interacting mRNAs in neuropathic pain. Finally, Neat1 in primary sensory neurons contributed to spinal inflammatory processes that mediated peripheral neuropathic pain. These findings demonstrate that Neat1 lncRNA is a key regulator of neuro-immune communication in neuropathic pain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Maruyama, Sakai, Fukunaga, Miyagawa, Okada, Hamada and Suzuki.)

Induced pluripotent stem cell-derived mesenchymal stem cells (iMSCs) hold great promise as a cell source for transplantation into injured tissues to alleviate inflammation. However, the therapeutic efficacy of iMSC transplantation for ischemic stroke remains unknown. In this study, we evaluated the therapeutic effects of iMSC transplantation on brain injury after ischemia-reperfusion using a rat transient middle cerebral artery occlusion model and compared its therapeutic efficacy with that of bone marrow mesenchymal stem cells (BMMSCs). We showed that iMSCs and BMMSCs reduced infarct volumes after reperfusion and significantly improved motor function on days 3, 7, 14, 28, and 56 and cognitive function on days 28 and 56 after reperfusion compared with the vehicle group. Furthermore, immunological analyses revealed that transplantation of iMSCs and BMMSCs inhibited microglial activation and expression of proinflammatory cytokines and suppressed oxidative stress and neuronal cell death in the cerebral cortex at the ischemic border zone. No difference in therapeutic effect was observed between the iMSC and BMMSC groups. Taken together, our results demonstrate that iMSC therapy can be a practical alternative as a cell source for attenuation of brain injury and improvement of neurological function because of the unlimited supply of uniform therapeutic cells., Competing Interests: C.N., Y.N-K., and T.O. are co-inventors of intellectual property licensed to Kaneka Corp., (© 2023 The Authors.)

Background: Caring for patients with dementia with Lewy bodies (DLB) would be more stressful for their caregivers than those with Alzheimer's disease (AD). In this study, we compared levels of caregiver burden and the possible influential factors on the caregiver burden between DLB and AD., Methods: Ninety-three DLB patients and 500 AD patients were selected from the Kumamoto University Dementia Registry. Caregiver burden, neuropsychiatric symptoms, basic activities of daily living (BADL) and instrumental activities of daily living (IADL) were assessed by the Japanese version of the Zarit Caregiver Burden Interview (J-ZBI), the Neuropsychiatric Inventory (NPI), the Physical Self-Maintenance Scale (PSMS), and the Lawton IADL scale, respectively., Results: Despite the comparable Mini-Mental State Examination score, the J-ZBI score was significantly higher in the DLB group than the AD group (P = 0.012). A stepwise multiple regression analysis revealed that IADL score (β = -0.23, P = 0.049), PSMS score (β = -0.31, P = 0.010), disinhibition (β = 0.22, P = 0.008), and anxiety (β = 0.19, P = 0.027) were significantly associated with J-ZBI score in DLB. In AD, caregiver's relationship with patient (child) (β = 0.104, P = 0.005), caregiver's gender (female) (β = 0.106, P = 0.004), IADL score (β = -0.237, P < 0.001), irritability (β = 0.183, P < 0.001), apathy (β = 0.132, P = 0.001), agitation (β = 0.118, P = 0.007), and aberrant motor behaviour (β = 0.107, P = 0.010) were associated with caregiver burden., Conclusions: Caring for DLB patients caused a higher degree of caregiver burden than AD patients in the same level of cognitive decline. The factors responsible for the caregiver's burden were different between DLB and AD. The caregiver burden for DLB patients was associated with the disability of basic ADL, IADL impairment, anxiety and disinhibition., (© 2023 Japanese Psychogeriatric Society.)

Background: Granulosa cell tumors (GCTs) account for approximately 2% of ovarian malignancies and are considered a rare type of ovarian cancer. GCTs are characterized by irregular genital bleeding after menopause due to female hormone production as well as late recurrence around 5-10 years after initial treatment. In this study, we investigated two cases of GCTs to find a biomarker that can be used to evaluate the treatment and predict recurrence., Case Presentation: Case 1 was a 56-year-old woman who presented to our hospital with abdominal pain and distention. An abdominal tumor was found, and GCTs were diagnosed. Serum vascular endothelial growth factor (VEGF) levels decreased after surgery. Case 2 involved a 51-year-old woman with refractory GCTs. Carboplatin-paclitaxel combination therapy and bevacizumab were administered after the tumor resection. After chemotherapy, a decline in VEGF levels was observed, but serum VEGF levels increased again with disease progression., Conclusions: VEGF expression may be of clinical importance in GCTs as a clinical biomarker for disease progression, which may be used to determine the efficacy of bevacizumab against GCTs., (© 2023. The Author(s).)

Background: Plasma N-terminal pro-atrial natriuretic peptide (NT-proANP) and plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations may be affected by the hydration status., Aim: This study aimed to evaluate the effect of dehydration on plasma NT-proANP and NT-proBNP concentrations in healthy dogs., Methods: This prospective study included five clinically healthy dogs. Furosemide was administered intravenously at 2-4 mg/kg every 1-2 hours until completion of the dehydration model. The dehydration model was considered complete when weight loss was ≥5% and findings of dehydration on physical examination were observed. Plasma NT-proANP and NT-proBNP concentrations were compared at three-time points: before the dehydration model was created (point 1), at the completion of the dehydration model (point 2), and when dehydration was judged to have improved (point 3). Association between plasma NT-proANP and NT-proBNP concentrations, and each clinical variable (physical examination, blood pressure, blood chemistry, blood gases, and echocardiography) was assessed using linear regression analysis., Results: Plasma NT-proANP concentration decreased significantly from point 2 to point 1 ( p < 0.05), whereas plasma NT-proBNP concentration showed a decreasing trend but did not differ significantly between points 1 and 2. Plasma NT-proANP concentration correlated significantly with body weight ( R 2 = 0.178) and plasma NT-proBNP concentration ( R 2 = 0.284) ( p < 0.05, respectively), and plasma NT-proBNP concentration correlated significantly with electrolytes (sodium, R 2 = 0.439; potassium, R 2 = 0.444; and chloride, R 2 = 0.419), and echocardiographic parameters [diastolic left ventricular internal diameter (LVIDd) R 2 = 0.519; weight-standardized LVIDd, R 2 = 0.535] ( p < 0.01, respectively)., Conclusion: The plasma NT-proANP concentrations decreased with dehydration. However, the plasma NT-proBNP concentration did not change with mild dehydration and reflected left ventricular morphology., Competing Interests: The authors declare that there is no conflict of interest.

Ammonium (NH 4 + ) and salinity (NaCl) inhibit CH 4 production in anaerobic digestion. However, whether bioaugmentation using marine sediment-derived microbial consortia can relieve the inhibitory effects of NH 4 + and NaCl stresses on CH 4 production remains unclear. Thus, this study evaluated the effectiveness of bioaugmentation using marine sediment-derived microbial consortia in alleviating the inhibition of CH 4 production under NH 4 + or NaCl stress and elucidated the underlying mechanisms. Batch anaerobic digestion experiments under 5 gNH 4 -N/L or 30 g/L NaCl were performed with or without augmentation using two marine sediment-derived microbial consortia pre-acclimated to high NH 4 + and NaCl. Compared with non-bioaugmentation, bioaugmentation reinforced CH 4 production. Network analysis revealed the joint effects of microbial connections by Methanoculleus, which promoted the efficient consumption of propionate accumulated under NH 4 + and NaCl stresses. In conclusion, bioaugmentation with pre-acclimated marine sediment-derived microbial consortia can mitigate the inhibition under NH 4 + or NaCl stress and enhance CH 4 production in anaerobic digestion., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction and Importance: Appendiceal goblet cell adenocarcinoma is in 0.3-0.9 % of appendectomy specimens. There is still controversy regarding whether surgery with dissection or additional resection is necessary for goblet cell adenocarcinoma and whether adjuvant chemotherapy is practical. We present three cases of goblet cell adenocarcinomas., Case Presentation: Case 1: A 30-year-old woman was diagnosed with appendicitis and underwent appendicectomy. Histopathological evaluation revealed a malignant neoplasm with goblet-like cells and tumour infiltration into the subserosa. The patient underwent laparoscopic ileocecal resection, and the main lymph nodes at the root of the feeding vessels were removed. Case 2: A 50-year-old man was diagnosed with appendicitis and underwent appendicectomy. Histopathological evaluation revealed a malignant neoplasm with goblet-like cells; malignant cells were found at the surgical resection margins. The patient underwent laparoscopic ileocolic resection. Case 3: A 60-year-old man undergoing treatment for malignant melanoma. He was diagnosed with appendicitis associated with an appendiceal tumour, and emergency laparoscopic caecal resection was performed and diagnosed as goblet cell adenocarcinoma. We decided to prioritize treatment for malignant melanoma, and the patient is under follow-up for goblet cell adenocarcinoma and no metastasis was detected., Clinical Discussion: We performed additional resection in two case of goblet cell adenocarcinoma. Diagnosing appendiceal goblet cell adenocarcinoma is difficult, and the prognosis of patients with positive lymph nodes is poor. Surgical treatment should be considered for the advanced stages of this disease., Conclusion: Goblet cell adenocarcinoma, diagnosed after appendectomy, additional resection including lymph node dissection may provide a long-term prognosis., Competing Interests: Conflict of interest statement None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The isolation of the Koala retrovirus-like virus from Australian megabats and the identification of endogenous retroviruses in the bat genome have raised questions on bat susceptibility to retroviruses in general. To answer this, we studied the susceptibility of 12 cell lines from 11 bat species to four well-studied retroviruses (human and simian immunodeficiency viruses [HIV and SIV] and murine leukemia viruses [B- and N-MLV]). Systematic comparison of retroviral susceptibility among bats revealed that megabat cell lines were overall less susceptible to the four retroviruses than microbat cell lines, particularly to HIV-1 infection, whereas lineage-specific differences were observed for MLV susceptibility. Quantitative PCR of reverse transcription (RT) products, infection in heterokaryon cells, and point mutation analysis of the capsid (CA) revealed that (i) HIV-1 and MLV replication were blocked at the nuclear transport of the pre-integration complexes and before and/or during RT, respectively, and (ii) the observed lineage-specific restriction can be attributed to a dominant cellular factor constrained by specific positions in CA. Investigation of bat homologs of the three previously reported post-entry restriction factors constrained by the same residues in CA, tripartite motif-protein 5α (TRIM5α), myxovirus resistance 2/B (Mx2/MxB), and carboxy terminus-truncated cleavage and polyadenylation factor 6 (CPSF6-358), demonstrated poor anti-HIV-1 activity in megabat cells, whereas megabat TRIM5α restricted MLV infection, suggesting that the major known CA-dependent restriction factors were not dominant in the observed lineage-specific susceptibility to HIV-1 in bat cells. Therefore, HIV-1 susceptibility of megabat cells may be determined in a manner distinct from that of primate cells. IMPORTANCE Recent studies have demonstrated the circulation of gammaretroviruses among megabats in Australia and the bats' resistance to HIV-1 infection; however, the origins of these viruses in megabats and the contribution of bats to retrovirus spread to other mammalian species remains unclear. To determine the intrinsic susceptibility of bat cells to HIV-1 infection, we investigated 12 cell lines isolated from 11 bat species. We report that lineage-specific retrovirus restriction in the bat cell lines can be attributed to CA-dependent factors. However, in the megabat cell lines examined, factors known to bind capsid and block infection in primate cell culture, including homologs of TRIM5α, Mx2/MxB, and CPSF6, failed to exhibit significant anti-HIV-1 activities. These results suggested that the HIV-1 susceptibility of megabat cells occurs in a manner distinct from that of primate cells, where cellular factors, other than major known CA-dependent restriction factors, with lineage-specific functions could recognize retroviral proteins in megabats.

Background: Germline pathogenic variants in the E-cadherin gene CDH1 cause hereditary diffuse gastric cancer (HDGC), which is an autosomal dominant cancer syndrome, accounting for 1-3% of all gastric cancers. HDGC harboring a CDH 1 variant is extremely rare in Japan., Method: In this study we report the clinical courses of three cases with HDGC from a single Japanese family., Results: The proband exhibited advanced and metastatic gastric cancer, and was found to have a previously reported heterozygous frameshift variant in CDH1 (NM&#95;004360.3:c.1009&#95;1010del:p.Ser337Phefs*12). Five at-risk relatives underwent presymptomatic molecular testing after careful genetic counseling, and three were molecularly diagnosed as positive for the variant. Esophagogastroduodenoscopy was performed in these relatives revealing abnormal small pale mucosal patches, small ulcerative lesion and no abnormal findings. Moreover, random and targeted biopsies were compatible with pathological diagnosis of HDGC in the three cases, all of which underwent total prophylactic gastrectomy., Conclusion: It is critical for the assessment and management of HDGC patients to be actively offered a multidisciplinary and familial-oriented approach. Notably, genetic screening in suspected individuals and familial members is a determining piece for a higher detection rate and the identification of clinical relevant mutations in both low and high-incidence gastric cancer countries., (© 2023. The Author(s).)

Background: RAS homolog family member A (RhoA), a member of the Rho family of small GTPases, and Vav1, a guanine nucleotide exchange factor for Rho family GTPases, have been reported to activate pathways related to the actin cytoskeleton and regulation of cell shape, attachment, and motility. The interaction between these molecules in lymphoma is involved in malignant signaling, but its function in epithelial malignancy is unknown. Here, we investigated the malignant signal of mutant RhoA in gastric cancer and demonstrated the potential of RhoA G17E/Vav1 as a therapeutic target for diffuse gastric cancer., Methods: The RhoA mutants R5W, G17E, and Y42C were retrovirally transduced into the gastric cancer cell line MKN74. The stably transduced cells were used for morphology, proliferation, and migration/invasion assays in vitro. MKN74 cells stably transduced with ectopic wild-type RhoA and mutant RhoA (G17E) were used in a peritoneal xenograft assay., Results: The RhoA mutations G17E and Y42C induced morphological changes in MKN74. G17E induced Vav1 expression at the mRNA and protein levels and promoted the migration and invasion of MKN74. An RNA interference assay of Vav1 revealed that RhoA G17E enhanced cancer cell invasion via Vav1. Furthermore, immunoprecipitation revealed that Vav1 and RhoA G17E specifically bind and function together through matrix metalloproteinase -9. In a peritoneal xenograft model of nude mice, RhoA G17E promoted peritoneal dissemination, whereas Vav1 knockdown suppressed it., Conclusion: Overall, our findings indicate that RhoA G17E is associated with Vav1 and promoted cancer invasion via matrix metalloproteinase -9 in gastric cancer cells. Thus, RhoA G17E/Vav1 signaling in diffuse gastric cancer may be a useful therapeutic target.

Objectives: This study investigated whether serum fibroblast growth factor (FGF)-23 concentrations are associated with serum total calcium (tCa) and blood ionised calcium (iCa) concentrations in cats with chronic kidney disease (CKD) and upper urolithiasis., Methods: Serum samples and the medical records of cats with CKD with nephroliths, ureteroliths or both were investigated retrospectively. Cats with a serum creatinine concentration >250 μmol/l and/or a serum phosphorus concentration ⩾1.50 mmol/l were excluded. Based on cut-offs for serum tCa (2.70 mmol/l) or blood iCa (1.40 mmol/l), cats were divided into the following groups: total hypercalcaemia (H-tCa) (>2.70 mmol/l) and total normocalcaemia (N-tCa) (⩽2.70 mmol/l) groups, or ionised hypercalcaemia (H-iCa) (>1.40 mmol/l) and ionised normocalcaemia (N-iCa) (⩽1.40 mmol/l) groups, respectively. Serum FGF-23 concentrations were compared between groups and correlation analysis was performed., Results: Thirty-two cats with CKD and upper urolithiasis were included. Serum FGF-23 concentrations in the H-tCa group (median 573 pg/ml [range 125-3888]; n = 12) were significantly higher compared with the N-tCa group (median 245 pg/ml [range 94-627]; n = 20) ( P  = 0.001). Serum FGF-23 concentrations in the H-iCa group (median 1479 pg/ml [range 509-3888]; n = 6) increased significantly compared with the N-iCa group (median 245 pg/ml [range 94-637]; n = 26) ( P <0.001). Serum FGF-23 concentrations significantly correlated with serum tCa ( r  = 0.511, P  = 0.003) and blood iCa concentrations ( r  = 0.425, P  = 0.015) but not serum creatinine ( r  = 0.279, P  = 0.122) or phosphorus concentrations ( r  = 0.208, P  = 0.253). Conclusions and relevance Increased serum FGF-23 concentrations were associated with hypercalcaemia independently of creatinine and phosphate status in cats with CKD and upper urolithiasis.

Background: Laparoscopic colorectal surgery (LCRS) requires a small laparotomy at the umbilicus. The wound is small and inconspicuous, but if the patient develops an umbilical incisional hernia (UIH), the wound is visible and the patient suffers from symptoms of discomfort. However, the incidence of UIH after LCRS and its risk factors are not well understood. The purpose of this study was to investigate the risk factors for UIH after LCRS for colorectal cancer., Methods: This was a single-centre retrospective study of 135 patients with colorectal cancer, conducted at our hospital from April 2013 to March 2019. The diagnosis of UIH was based on computed tomography and physical examination findings. Preoperative patient data such as enlargement of the umbilical orifice (EUO), subcutaneous fat thickness (SFT) and intraperitoneal thickness (IPT) were collected and analysed using univariate and multivariate analyses for the presence of risk factors for UIH., Results: A total of 135 patients who underwent LCRS were analysed. The incidence of UIH was 20.7%. Univariate analysis revealed significantly high body mass index (BMI) ≥ 25 (P = 0.032), EUO (P < 0.001), SFT ≥18 mm (P = 0.011), and IPT ≥61 mm (P < 0.01) in the UIH group. Multivariate analysis revealed significant differences in EUO (P < 0.001), SFT ≥18 mm (P = 0.046) and IPT ≥61 mm (P = 0.022)., Conclusion: EUO was the most important risk factor for UIH, followed by IPT and SFT. These findings are predictive indicators of the development of UIH after LCRS and can be assessed objectively and easily with preoperative computed tomography., (© 2022 Royal Australasian College of Surgeons.)

Background: Amidst the climate crisis, a key goal of the medical sector is to reduce its large carbon footprint. Although the Coronavirus disease 2019 (COVID-19) pandemic greatly impacted the medical sector, its influence on carbon footprints remains unknown. Therefore, the aim of this study was to evaluate changes in the carbon footprint of a university hospital with a medical research centre over the past 10 years., Methods: Data on electricity, gas, and water usage, pharmaceutical and medical supply costs, and waste amounts were recorded for Nagoya University Hospital from April 2010 to March 2021. The relevant emission factors were obtained from the Japanese government and the overall monthly carbon footprint was reported according to the Greenhouse Gas Protocol. The effect of the COVID-19 pandemic on the carbon footprint was then compared for three types of emission sources. Moreover, a regression model was used to plot quadratic functions as approximate functions using monthly carbon emissions and monthly average external temperatures. Finally, the monthly carbon footprint was calculated per hospital admission., Results: The overall carbon footprint of the hospital was 73,546 tCO 2 e in 2020, revealing an increase of 26.60% over the last 10 years. Carbon emissions from electricity consumption represented 26% of total emissions. The individual carbon footprints of pharmaceuticals, medical supplies, waste, and water usage also increased from 2010 to 2020. The overall monthly carbon footprint was positively correlated with the average monthly temperature (R 2  = 0.7566, p < 0.001). Compared with 2019, the overall carbon footprint decreased by 2.19% in 2020. Moreover, the monthly carbon footprint per hospital admission increased significantly between 2018 (0.24 tCO 2 e/admission) and 2020 (0.26 tCO 2 e/admission) (p = 0.002)., Conclusion: The overall carbon footprint of the hospital generally increased over the last decade. During the COVID-19 epidemic in 2020, the carbon footprint decreased slightly, likely because of the reduced number of patients. However, the carbon footprint per admission increased, which was attributed to more complicated patient backgrounds because of the ageing population. Therefore, evaluation of carbon emissions in the medical sector is urgently required in order to act on the climate crisis as soon as possible., (© 2022. The Author(s).)

Background: Impaired cerebrospinal fluid (CSF) dynamics may contribute to the pathophysiology of neurodegenerative diseases, and play a crucial role in brain health in older people; nonetheless, such age-related changes have not been well elucidated. Disproportionately enlarged subarachnoid-space hydrocephalus (DESH) is a neuroimaging phenotype of idiopathic normal-pressure hydrocephalus, originating from impaired CSF dynamics, and closely associated with aging. This study aimed to investigate the pathophysiology of DESH and determine age-related changes in CSF dynamics., Methods: Using magnetic resonance imaging, we investigated the pathophysiology of DESH by quantitatively evaluating the volumes of DESH-related regions (ventricles [VS], Sylvian fissure [SF], and subarachnoid spaces at high convexity and midline [SHM]) and brain parenchyma in community-dwelling individuals aged  ≥ 65 years. DESH-related regions were assessed using a visual rating scale, and volumes measured using voxel-based morphometry. Brain parenchyma volumes were measured using FreeSurfer software., Results: Data from 1,356 individuals were analyzed, and 25 (1.8%) individuals had DESH. Regarding the relationships between the volume of each CSF space and age, VS and SF volumes increased with age, whereas SHM volume did not increase. VS and SF volumes increased as the whole brain volume decreased, whereas SHM volume did not increase even if the whole brain volume decreased; that is, SHM did not expand even if brain atrophy progressed. Moreover, lower Mini-Mental State Examination scores were significantly associated with lower SHM volume and higher VS volume. These associations remained significant even when individuals with DESH were excluded., Conclusions: This study showed that the volume of high-convexity and medial subarachnoid spaces did not expand and tended to decrease with age; the human brain continuously progresses toward a "DESH-like" morphology with aging in community-dwelling older persons (i.e., DESH might be an "accelerated aging stage" rather than an "age-related disorder"). Our results indicated that brain atrophy may be associated with the development of "DESH-like" morphology. In addition, this morphological change, as well as brain atrophy, is an important condition associated with cognitive decline in older adults. Our findings highlight the importance of investigating the aging process of CSF dynamics in the human brain to preserve brain health in older people., (© 2022. The Author(s).)

Neuromedin U (NMU) is a multifunctional neuropeptide implicated in regulation of smooth muscle contraction in the circulatory and digestive systems, energy homeostasis and the stress response, but especially food intake in vertebrates. Recent studies have indicated the possible involvement of NMU in the regulation of psychomotor activity in rodents. We have identified four cDNAs encoding three putative NMU variants (NMU-21, -25 and -38) from the goldfish brain and intestine. Recently, we have also purified these NMUs and the truncated C-terminal form NMU-9 from these tissues, and demonstrated their anorexigenic action in goldfish. However, there is no information on the brain localization of NMU-like immunoreactivity and the psychophysiological roles of NMU in fish. Here, we investigated the brain distribution of NMU-like immunoreactivity and found that it was localized throughout the fore- and mid-brains. We subsequently examined the effect of intracerebroventricular (ICV) administration of NMU-21, which is abundant only in the brain on psychomotor activity in goldfish. As goldfish prefer the lower to the upper area of a tank, we developed an upper/lower area preference test in a tank for evaluating the psychomotor activity of goldfish using a personal tablet device without an automatic behavior-tracking device. ICV administration of NMU-21 at 10 pmol g -1 body weight (BW) prolonged the time spent in the upper area of the tank, and this action mimicked that of ICV administration of the central-type benzodiazepine receptor (CBR) agonist tofisopam at 100 pmol g -1 BW. These results suggest that NMU-21 potently induces anxiolytic-like action in the goldfish brain., Competing Interests: Conflict of interest The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The effectiveness of laparoscopic surgery for adhesive small bowel obstruction (ASBO) remains unclear. We aimed to compare the outcomes and safety of open and laparoscopic surgeries for ASBO. Methods: In this retrospective study, we analyzed an inpatient database of 42 national university hospitals in Japan. Patients who underwent surgery for the first episode of ASBO between April 2013 and March 2018 were identified. Using the propensity score method, patients who underwent laparoscopic surgery were matched one-to-one with those who underwent open surgery. We investigated postoperative clinical outcomes, including morbidity, mortality, length of hospital stay (LOS), and recurrence. Results: Overall, 306 and 96 patients underwent open and laparoscopic surgery, respectively (96 propensity score-matched pairs). The incidence rates of postoperative morbidity, mortality, and recurrence were comparable between the two groups. Cox regression analysis revealed a hazard ratio (HR) of 1.020 ( P  = .959) for readmission due to ASBO in the laparoscopic surgery group relative to the open surgery group. Postoperative hospital stay was longer for open surgery than for laparoscopic surgery (13.0 days versus 10.0 days, P  < .001). Cox regression analysis revealed that laparoscopic surgery was associated with earlier postoperative discharge compared with open surgery (HR 1.641, P  = .002). Conclusions: The postoperative LOS was shorter with laparoscopic surgery than with open surgery for ASBO, but there were no differences between the procedures in other clinical outcomes. Laparoscopic surgery is suitable to treat patients with ASBO.

In contemporary Japanese society, it is difficult to find a marriage partner, and therefore, "Konkatsu," the search for a marriage partner, has become a socially accepted activity in Japan. In response to this social challenge, in addition to private companies, governments and non-profit organizations are supporting individuals in their search for a marriage partner. This paper reviews statistical information related to marriage hunting published in Japan. In addition, some of the authors' collaborative activities and academic publications based on these activities are reviewed. Subsequently, the paper discusses and highlights the importance of helping individuals have confidence in their physical attractiveness., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nishimura, Souma, Kito, Taniguchi, Kanemasa, Yamada and Miyagawa.)

Current antipsychotics used to treat schizophrenia have associated problems, including serious side effects and treatment resistance. We recently identified a significant association of schizophrenia with exonic copy number variations in the Rho GTPase activating protein 10 (ARHGAP10) gene using genome-wide analysis. ARHGAP10 encodes a RhoGAP superfamily member that is involved in small GTPase signaling. In mice, Arhgap10 gene variations result in RhoA/Rho-kinase pathway activation. We evaluated the pharmacokinetics of fasudil and hydroxyfasudil using liquid chromatography-tandem mass spectrometry in mice. The antipsychotic effects of fasudil on hyperlocomotion, social interaction deficits, prepulse inhibition deficits, and novel object recognition deficits were also investigated in a MK-801-treated pharmacological mouse schizophrenia model. Fasudil and its major metabolite, hydroxyfasudil, were detected in the brain at concentrations above their respective K i values for Rho-kinase after intraperitoneal injection of 10 mg kg -1 fasudil. Fasudil improved the hyperlocomotion, social interaction deficits, prepulse inhibition deficits, and novel object recognition deficits in MK-801-treated mice in a dose-dependent manner. Following oral administration of fasudil, brain hydroxyfasudil was detected at concentration above the K i value for Rho-kinase whilst fasudil was undetectable. MK-801-induced hyperlocomotion was also improved by oral fasudil administration. These results suggest that fasudil has antipsychotic-like effects on the MK-801-treated pharmacological mouse schizophrenia model. There are two isoforms in Rho-kinase, and further investigation is needed to clarify the isoforms involved in the antipsychotic-like effects of fasudil in the MK-801-treated mouse schizophrenia model., Competing Interests: Declaration of competing interest There are no conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Long non-coding RNAs (lncRNAs) play critical roles in human cancers. HOXA11 anti-sense RNA ( HOXA11-AS ) is an lncRNA belonging to the homeobox (HOX) gene cluster that promotes liver metastasis in human colon cancer. However, its role and mechanism of action in human oral squamous cell carcinoma (OSCC) are unclear. In this study, we investigated HOXA11-AS expression and function in human OSCC tissues and cell lines, as well as a mouse model of OSCC. Our analyses showed that HOXA11-AS expression in human OSCC cases correlates with lymph node metastasis, nicotinamide adenine dinucleotide (NAD)(P)H: quinone oxidoreductase 1 ( NQO1 ) upregulation, and dihydronicotinamide riboside (NRH): quinone oxidoreductase 2 ( NQO2 ) downregulation. Using the human OSCC cell lines HSC3 and HSC4, we demonstrate that HOXA11-AS promotes NQO1 expression by sponging microRNA-494. In contrast, HOXA11-AS recruits zeste homolog 2 (EZH2) to the NQO2 promoter to suppress its expression via the trimethylation of H3K27. The upregulation of NQO1 enzymatic activity by HOXA11-AS results in the consumption of flavin adenine dinucleotide (FAD), which reduces FAD-requiring glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity and suppresses glycolysis. However, our analyses show that lactic acid fermentation levels are preserved by glutaminolysis due to increased malic enzyme-1 expression, promoting enhanced proliferation, invasion, survival, and drug resistance. In contrast, suppression of NQO2 expression reduces the consumption of NRH via NQO2 enzymatic activity and increases NAD levels, which promotes enhanced stemness and metastatic potential. In mouse tumor models, knockdown of HOXA11-AS markedly suppressed tumor growth and lung metastasis. From these findings, targeting HOXA11-AS may strongly suppress high-grade OSCC by regulating both NQO1 and NQO2 .

Ammonium (NH 4 + ) and salinity are major inhibitors of CH 4 production in anaerobic digestion. This study evaluated their inhibitory effects on CH 4 production and explored the key populations for efficient CH 4 production under high NH 4 + and NaCl concentrations to understand their inhibition mechanisms. Comparative batch experiments for mesophilic anaerobic digestion were conducted using three seeding sludges under different concentrations of NH 4 + (1-5 gNH 4 -N/L) and NaCl (10-30 g/L). Although all sludges tolerated 3 gNH 4 -N/L and 10 g/L NaCl, NH 4 + or NaCl concentrations higher than these substantially reduced CH 4 production, depending on the seeding sludge, primarily by impairing the initial hydrolysis and methanogenesis steps. In addition, propionate was found to be a deterministic factor affecting CH 4 production. Based on microbial community analysis, Candidatus Brevefilum was identified as a potential syntrophic propionate-oxidizing bacterium that facilitates the mitigation of propionate accumulation, allowing the maintenance of unaffected CH 4 production under high inhibitory conditions., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Retinitis pigmentosa (RP) is a genetically heterogeneous group of inherited retinal disorders involving the progressive dysfunction of photoreceptors and the retinal pigment epithelium, for which there is currently no treatment. The rd6 mouse is a natural model of autosomal recessive retinal degeneration. Given the known contributions of oxidative stress caused by reactive oxygen species (ROS) and selective inhibition of potent ROS peroxynitrite and OH·by H 2 gas we have previously demonstrated, we hypothesized that ingestion of H 2 water may delay the progression of photoreceptor death in rd6 mice. H 2 mice showed significantly higher retinal thickness as compared to controls on optical coherence tomography. Histopathological and morphometric analyses revealed higher thickness of the outer nuclear layer for H 2 mice than controls, as well as higher counts of opsin red/green-positive cells. RNA sequencing (RNA-seq) analysis of differentially expressed genes in the H 2 group versus control group revealed 1996 genes with significantly different expressions. Gene and pathway ontology analysis showed substantial upregulation of genes responsible for phototransduction in H 2 mice. Our results show that drinking water high in H 2 (1.2-1.6 ppm) had neuroprotective effects and inhibited photoreceptor death in mice, and suggest the potential of H 2 for the treatment of RP., (© 2022. The Author(s).)

Background and Aim: Electrocardiography (ECG) is an adjunct for cardiac enlargement diagnosis. However, its efficacy in assessing left cardiac remodeling (left atrial and left ventricular enlargement) in dogs with myxomatous mitral valve disease (MMVD) remains unclear. This study aimed to evaluate the association between ECG parameters and left cardiac remodeling and to investigate whether the rate of change in ECG waveforms in the same individual reflected left cardiac remodeling in dogs with MMVD., Materials and Methods: This retrospective study included 20 healthy dogs and 140 dogs with MMVD. Data on clinical variables were obtained through physical examination, thoracic radiography, and echocardiography. The ECG parameters were the P-wave duration, PR interval, QRS complex duration, P-wave amplitude, R-wave amplitude, and mean electrical axis. Dogs with examination data that could be obtained multiple times during the study period were classified into the non-progressive and progressive groups., Results: Only the P-wave and QRS complex durations were selected as significant variables associated with imaging test parameters (p < 0.05); they had a relatively higher discriminatory ability for the left cardiac remodeling than other ECG parameters. The rates of change in the PR interval and R-wave amplitude were significantly higher in the progressive group than in the non-progressive group., Conclusion: In dogs with MMVD, the P-wave and QRS complex durations were significantly correlated with the left cardiac remodeling indicators. Furthermore, an increased rate of change in the PR interval and R-wave amplitude in the same individual may indicate left cardiac remodeling., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Ogawa, et al.)

Objectives: The aim of this study was to investigate serum fibroblast growth factor (FGF)-23 concentrations in young and mature adult cats with chronic kidney disease (CKD)., Methods: The present study retrospectively investigated the serum samples and medical records of 1-8-year-old clinically healthy cats (control group, n = 7) and cats with CKD (n = 54). Cats with CKD were divided into four stages based on serum creatinine concentrations, according to the International Renal Interest Society (IRIS) CKD guidelines. Serum FGF-23 concentrations were compared between cats in the control group, IRIS stages 1, 2 and 3-4 CKD. Continuous variables were analysed using correlations and multiple linear regression., Results: Serum FGF-23 concentrations were significantly higher in cats with IRIS stages 1, 2 and 3-4 CKD, compared with those in the control group ( P  = 0.02, P = 0.002 and P  = 0.002, respectively). Additionally, serum FGF-23 concentrations in cats with IRIS stages 3-4 CKD had higher serum FGF-23 concentrations than those with IRIS stages 1 and 2 CKD ( P  = 0.04 and P  = 0.02, respectively). In the multiple linear regression analysis, serum urea nitrogen concentration, serum phosphorus concentration and blood ionised calcium concentration were independent variables predicting serum FGF-23 concentration., Conclusions and Relevance: Serum FGF-23 concentrations in younger cats with CKD increased in early-stage CKD and were associated with mineral metabolic markers, as also occurs in geriatric cats.

High mobility group box-1 (HMGB1) is known to be a chemotactic factor for mesenchymal stem/stromal cells (MSCs), but the effect of post-translational modification on its function is not clear. In this study, we hypothesized that differences in the oxidation state of HMGB1 would lead to differences in the function of MSCs in cancer. In human colorectal cancer, MSCs infiltrating into the stroma were correlated with liver metastasis and serum HMGB1. In animal models, oxidized HMGB1 mobilized three-fold fewer MSCs to subcutaneous tumors compared with reduced HMGB1. Reduced HMGB1 inhibited the proliferation of mouse bone marrow MSCs (BM-MSCs) and induced differentiation into osteoblasts and vascular pericytes, whereas oxidized HMGB1 promoted proliferation and increased stemness, and no differentiation was observed. When BM-MSCs pretreated with oxidized HMGB1 were co-cultured with syngeneic cancer cells, cell proliferation and stemness of cancer cells were increased, and tumorigenesis and drug resistance were promoted. In contrast, co-culture with reduced HMGB1-pretreated BM-MSCs did not enhance stemness. In an animal orthotopic transplantation colorectal cancer model, oxidized HMGB1, but not reduced HMGB1, promoted liver metastasis with intratumoral MSC chemotaxis. Therefore, oxidized HMGB1 reprograms MSCs and promotes cancer malignancy. The oxidized HMGB1-MSC axis may be an important target for cancer therapy., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)