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Abstract Thallium bromide (TlBr) semiconductor detectors are being developed as promising candidates for high-detection-efficiency, high-energy-resolution, and room-temperature gamma-ray spectrometers. This study presents methods for evaluating TlBr crystal quality and carrier transport characteristics using neutron Bragg-dip imaging and the time-of-flight method for pulsed-laser-induced carriers, respectively. Neutron Bragg-dip imaging effectively determines the crystal orientation distribution, revealing crystal imperfections and grain boundaries. Time-of-flight measurements provide a spatial distribution of carrier mobility. In this study, two samples obtained from both the upstream and downstream region in the crystal ingot were evaluated. Although both samples show similar crystal quality, the upstream sample showed high carrier mobility across all areas, whereas the downstream sample exhibits low mobility in some areas. These findings suggest that, at least within the range of carrier mobility currently obtained, the effect of crystal integrity on carrier mobility is less significant than that of impurities. In conclusion, combining neutron Bragg-dip imaging with carrier mobility measurements offers a comprehensive approach to evaluating and improving TlBr detectors.

Abstract Palbociclib combined with endocrine therapy is approved for treating patients with hormone-receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced breast cancer; however, data on palbociclib combined with tamoxifen are limited. We investigated the efficacy and safety of palbociclib–tamoxifen in patients with HR+/HER2− advanced breast cancer. This double-blind phase 3 study included 184 women who were randomly assigned 1:1 to receive palbociclib–tamoxifen or placebo–tamoxifen. Pre/perimenopausal women also received goserelin. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Median PFS was 24.4 months (95% confidence interval [CI], 13.1–32.4) with palbociclib–tamoxifen and 11.1 months (95% CI, 7.4–14.6) with placebo–tamoxifen (hazard ratio [HR], 0.60; 95% CI, 0.43–0.85; P = 0.002). Palbociclib–tamoxifen improved PFS in patients who were treated with first-line or second-line endocrine therapy and pre-, peri-, and postmenopausal patients. Though OS data are still immature (median not reached in both groups), an overall risk reduction of 27% (HR, 0.73; 95% CI, 0.44–1.21) with palbociclib–tamoxifen was observed at the time of PFS analysis. The most common grade 3/4 adverse event with palbociclib–tamoxifen was neutropenia (89.0% [none were febrile] versus 1.1% with placebo–tamoxifen). There were no deaths owing to adverse events in either group. Among patients with HR+/HER2− advanced breast cancer, palbociclib–tamoxifen resulted in significantly longer PFS than tamoxifen alone. Early OS data showed a trend favoring palbociclib–tamoxifen. Trial registration: ClinicalTrials.gov number, NCT03423199. Study registration date: February 06, 2018.

Introduction: Segmental spinal deformity results from vertebral compression fracture (VCF) and progressive collapse of the fractured vertebral body (VB). The VB stenting (VBS) systemⓇ comprises a balloon-assisted, expandable, intrasomatic, metal stent that helps maintain the restored VB during balloon removal and cement injection, which minimizes cement leakage. We performed a prospective, multicenter, clinical trial of the VBS system in Japanese patients with acute VCF owing to primary osteoporosis. Methods: Herein, 88 patients, 25 men and 63 women aged 77.4±8.3 years, with low back pain, numerical rating scale (NRS) score of 4, and mean VB compression percentage (VBCP) of

Metabolic compromise is crucial in aggravating age-associated chronic inflammation, oxidative stress, mitochondrial damage, increased LDL and triglycerides, and elevated blood pressure. Excessive adiposity, hyperglycemia, and insulin resistance due to aging are associated with elevated levels of damaging free radicals, inducing a proinflammatory state and hampering immune cell activity, leading to a malfunctioning cardiometabolic condition. The age-associated oxidative load and redox imbalance are contributing factors for cardiometabolic morbidities via vascular remodelling and endothelial damage. Recent evidence has claimed the importance of gut microbiota in maintaining regular metabolic activity, which declines with chronological aging and cardiometabolic comorbidities. Genetic mutations, polymorphic changes, and environmental factors strongly correlate with increased vulnerability to aberrant cardiometabolic changes by affecting key physiological pathways. Numerous studies have reported a robust link between biological aging and cardiometabolic dysfunction. This review outlines the scientific evidence exploring potential mechanisms behind the onset and development of cardiovascular and metabolic issues, particularly exacerbated with aging.

Gadolinium pyrosilicate (GPS, Gd2Si2O7) single crystals with different doping concentrations of Tb (0.1–2.0 mol%) are successfully fabricated using the floating-zone technique. In this work, the dependence of Tb-doping concentration on the photoluminescence (PL) and scintillation properties of Tb-doped GPS (Tb:GPS) has been investigated. The PL emission contour graph shows multiple emissions, with the strongest emissions at 378 nm for 0.1% and 0.5% Tb-doping and 544 nm for 1.0% and 2.0% Tb-doping, corresponding to Tb3+ 4f-4f transitions. The PL lifetimes of the specimens range from 4.89 to 5.22 ms. The scintillation spectra exhibit comparable wavelength and intensity trends to the PL emission. The scintillation lifetimes of the specimens range from 2.41 to 3.88 ms. The Tb:GPS specimens demonstrate a relatively excessive afterglow level, with Af20 values ranging from 1640 to 7250 ppm and Af40 values ranging from 136 to 362 ppm. Using recently developed pulse height measurement for millisecond decay scintillators, under excitation at 662 keV γ-rays, the 1.0% Tb:GPS specimen exhibits the highest scintillation light yield among all other specimens at 95,600 ph/MeV, making Tb:GPS one of the highest light yield oxide scintillators.

Tonsillectomy with steroid pulse therapy (SPT) has been established as an effective treatment for immunoglobulin A nephropathy (IgAN) in Japan. However, the underlying mechanisms supporting tonsillectomy remain unclear. This study assessed palatine tonsils from 77 patients with IgAN, including 14 and 63 who received SPT before and after tonsillectomy, respectively. Tonsils from 21 patients with chronic tonsillitis were analyzed as controls. Specific tonsillar lesions were confirmed in patients with IgAN, correlating with active or chronic renal glomerular lesions and SPT. T-nodule and involution of lymphoepithelial symbiosis scores in tonsils correlated with the incidence of active crescents and segmental sclerosis in the glomeruli, respectively. The study revealed an essential role of the tonsil–glomerular axis in early active and late chronic phases. Moreover, the SPT-preceding group demonstrated no changes in the T-nodule score, which correlated with active crescent formation, but exhibited a considerable shrinkage of lymphatic follicles that produced aberrant IgA1. The study underscores the involvement of innate and cellular immunity in IgAN and advocates for tonsillectomy as a necessary treatment alongside SPT for IgAN, based on a stepwise process.

Abstract We aimed to clarify the relationship between apolipoprotein C3 (apo-C3) and the vascular composition of lesion plaque in stable coronary disease (SCD) before percutaneous coronary intervention (PCI), and to investigate major adverse cardiovascular events (MACEs) within 4 years. Data of 98 consecutive patients with SCD who underwent PCI between November 1, 2012, and March 10, 2015, were analyzed. Laboratory and virtual histology-intravascular ultrasound (VH-IVUS) examinations of culprit lesions were conducted before PCI. Patients were divided according to median apo-C3 into low apo-C3 (≤ 8.5 mg/dL) and high apo-C3 (> 8.5 mg/dL) groups. VH-IVUS data indicated that the percentage of necrotic core volume (%NC) was significantly higher in the high apo-C3 group than in the low apo-C3 group. Moreover, the %NC significantly correlated with the apo-C3 level (R = 0.2109, P = 0.037). Kaplan–Meier curve analysis revealed that freedom from MACEs exhibited a greater decrease in the high apo-C3 group than in the low apo-C3 group, and in the high %NC group than in the low %NC group. Multivariate Cox hazards analysis showed that the %NC and high apo-C3 were independent predictors of 4 year MACEs. Apo-C3 may be a useful marker of future MACEs in patients with SCD after PCI and contribute to %NC growth.

Distal transradial approach (dTRA) for neuroendovascular procedures has received much attention in recent years as a newer and less invasive alternative to the conventional transfemoral or transradial approaches. We present the case of an 89-year-old woman with a basilar artery aneurysm requiring simultaneous catheterization of the bilateral vertebral arteries who was successfully embolized using bilateral dTRA. The aneurysm was accessed from the right vertebral artery using the right dTRA. Control angiograms during the procedure were performed from the left vertebral artery via the left dTRA. The operator's posture was ergonomically comfortable, and the catheters were easy to handle during the procedure. To the best of our knowledge, this is the first case of a bilateral dTRA used for neuroendovascular procedures. Bilateral dTRA is a safe and minimally invasive method for patients and ergonomically comfortable for operators.

The Nagoya University Accelerator-driven Neutron Source (NUANS) is an accelerator-based neutron source by 7Li(p,n)7Be reaction with a 2.8 MeV proton beam up to 15 mA. The fast neutrons are moderated and shaped to beam with a Beam Shaping Assembly (BSA). NUANS is aiming at the basic study of the Boron Neutron Capture Therapy (BNCT) such as an in vitro cell-based irradiation experiment using a water phantom. Moreover, the BSA is developed as a prototype of one for human treatment. We have evaluated the radiation field of NUANS by a Monte Carlo code PHITS. It is confirmed that the radiation characteristics at the BNCT outlet meet the requirement of IAEA TECDOC-1223. Additionally, the radiation field in the water phantom located just in front of the BSA outlet is calculated. In the in vitro irradiation experiment, the boron dose of 30 Gy-eq, which is the dose to kill tumor cells, is expected for 20 min of irradiation at the beam current of 15 mA.

Introduction The antibody-drug conjugate trastuzumab deruxtecan (T-DXd) has led to a change in the clinical management of breast cancer. Nausea and vomiting are the most common adverse events of T-DXd, which cannot be completely alleviated by standard prophylactic regimens. Olanzapine is particularly effective in preventing delayed nausea caused by chemotherapy. In this study, we will evaluate the efficacy of olanzapine in managing persistent nausea and vomiting during T-DXd treatment.Methods and analysis The ERICA study is a multicentre, placebo-controlled, double-blind, randomised phase II study with the aim to evaluate the antiemetic effects of the prophylactic olanzapine (5 mg orally, on days 1–6) or placebo combined with a 1,5-hydroxytryptamine-3 (5-HT3)–receptor antagonist and dexamethasone in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer undergoing T-DXd treatment. For a period of 22 days from the day of T-DXd treatment, patients will document their experience in an electronic symptom diary daily during observational periods. The primary endpoint is the complete response rate, defined as no vomiting and no rescue medications during the ‘delayed phase’ of 24–120 hours post-T-DXd administration. In addition, we define 120–504 hour as the ‘persistent phase’ and 0–504 hours as the ‘overall phase’ for secondary endpoint analysis. We have estimated that a total sample size of at least 156 patients is needed to allow a power of 80% at a one-sided significance level of 20% in this study. The target sample size is set to 166 to account for possible case exclusions.Ethics and dissemination The study protocol is approved by the West Japan Oncology Group protocol review committee and the SHOWA University Clinical Research Review Board. The study results will be presented at international conferences and published in a peer-reviewed journal.Trial registration number jRCTs031210410.

Abstract Aims/Introduction Recently, an increasing number of cohort studies have suggested using machine learning (ML) to predict type 2 diabetes mellitus. However, its predictive ability remains inconclusive. This meta‐analysis evaluated the current ability of ML algorithms for predicting incident type 2 diabetes mellitus. Materials and Methods We systematically searched longitudinal studies published from 1 January 1950 to 17 May 2020 using MEDLINE and EMBASE. Included studies had to compare ML’s classification with the actual incidence of type 2 diabetes mellitus, and present data on the number of true positives, false positives, true negatives and false negatives. The dataset for these four values was pooled with a hierarchical summary receiver operating characteristic and a bivariate random effects model. Results There were 12 eligible studies. The pooled sensitivity, specificity, positive likelihood ratio and negative likelihood ratio were 0.81 (95% confidence interval [CI] 0.67–0.90), 0.82 [95% CI 0.74–0.88], 4.55 [95% CI 3.07–6.75] and 0.23 [95% CI 0.13–0.42], respectively. The area under the summarized receiver operating characteristic curve was 0.88 (95% CI 0.85–0.91). Conclusions Current ML algorithms have sufficient ability to help clinicians determine whether individuals will develop type 2 diabetes mellitus in the future. However, persons should be cautious before changing their attitude toward future diabetes risk after learning the result of the diabetes prediction test using ML algorithms.

C-X-C motif chemokine receptor 3 (CXCR3) is an important receptor controlling the migration of leukocytes, although there is no report regarding its role in Neospora caninum infection. Herein, we investigated the relevance of CXCR3 in the resistance mechanism to N. caninum infection in mice. Wild-type (WT) C57BL/6 mice and CXCR3-knockout (CXCR3KO) mice were used in all experiments. WT mice displayed a high survival rate (100%), while 80% of CXCR3KO mice succumbed to N. caninum infection within 50 days. Compared with WT mice, CXCR3KO mice exhibited significantly lower body weights and higher clinical scores at the subacute stage of infection. Flow cytometric analysis revealed CXCR3KO mice as having significantly increased proportions and numbers of CD11c-positive cells compared with WT mice at 5 days post infection (dpi). However, levels of interleukin-6 and interferon-γ in serum and ascites were similar in all groups at 5 dpi. Furthermore, no differences in parasite load were detected in brain, spleen, lungs or liver tissue of CXCR3KO and WT mice at 5 and 21 dpi. mRNA analysis of brain tissue collected from infected mice at 30 dpi revealed no changes in expression levels of inflammatory response genes. Nevertheless, the brain tissue of infected CXCR3KO mice displayed significant necrosis and microglial activation compared with that of WT mice at 21 dpi. Interestingly, the brain tissue of CXCR3KO mice displayed significantly lower numbers of FoxP3+ cells compared with the brain tissue of WT mice at 30 dpi. Accordingly, our study suggests that the lack of active regulatory T cells in brain tissue of infected CXCR3KO mice is the main cause of these mice having severe necrosis and lower survival compared with WT mice. Thus, CXCR3+ regulatory T cells may play a crucial role in control of neosporosis.

Huntington’s disease (HD) is a progressive, neurodegenerative disease characterized by motor, cognitive, and psychiatric symptoms. To investigate the metabolic alterations that occur in HD, here we examined plasma and whole‐brain metabolomic profiles of the R6/2 mouse model of HD. Plasma and brain metabolomic analyses were conducted using capillary electrophoresis–mass spectrometry (CE‐MS). In addition, liquid chromatography–mass spectrometry (LC‐MS) was also applied to plasma metabolomic analyses, to cover the broad range of metabolites with various physical and chemical properties. Various metabolic alterations were identified in R6/2 mice. We report for the first time the perturbation of histidine metabolism in the brain of R6/2 mice, which was signaled by decreases in neuroprotective dipeptides and histamine metabolites, indicative of neurodegeneration and an altered histaminergic system. Other differential metabolites were related to arginine metabolism and cysteine and methionine metabolism, suggesting upregulation of the urea cycle, perturbation of energy homeostasis, and an increase in oxidative stress. In addition, remarkable changes in specific lipid classes are indicative of dysregulation of lipid metabolism. These findings provide a deeper insight into the metabolic alterations that occur in HD and provide a foundation for the future development of HD therapeutics.

Abstract Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently a serious public health concern worldwide. Notably, co-infection with other pathogens may worsen the severity of COVID-19 symptoms and increase fatality. Here, we show that co-infection with influenza A virus (IAV) causes more severe body weight loss and more severe and prolonged pneumonia in SARS-CoV-2-infected hamsters. Each virus can efficiently spread in the lungs without interference by the other. However, in immunohistochemical analyses, SARS-CoV-2 and IAV were not detected at the same sites in the respiratory organs of co-infected hamsters, suggesting that either the two viruses may have different cell tropisms in vivo or each virus may inhibit the infection and/or growth of the other within a cell or adjacent areas in the organs. Furthermore, a significant increase in IL-6 was detected in the sera of hamsters co-infected with SARS-CoV-2 and IAV at 7 and 10 days post-infection, suggesting that IL-6 may be involved in the increased severity of pneumonia. Our results strongly suggest that IAV co-infection with SARS-CoV-2 can have serious health risks and increased caution should be applied in such cases.

Cryptosporidium spp. are gastrointestinal opportunistic protozoan parasites that infect humans, domestic animals, and wild animals all over the world. Cryptosporidiosis is the second leading infectious diarrheal disease in infants less than 5 years old. Cryptosporidiosis is a common zoonotic disease associated with diarrhea in infants and immunocompromised individuals. Consequently, cryptosporidiosis is considered a serious economic, veterinary, and medical concern. The treatment options for cryptosporidiosis are limited. To address this problem, we screened a natural product library containing 87 compounds of Traditional Chinese Medicines for anti-Cryptosporidium compounds that could serve as novel drug leads and therapeutic targets against C. parvum. To examine the anti-Cryptosporidium activity and half-maximal inhibitory doses (EC50) of these compounds, we performed in vitro assays (Cryptosporidium growth inhibition assay and host cell viability assay) and in vivo experiments in mice. In these assays, the C. parvum HNJ-1 strain was used. Four of the 87 compounds (alisol-A, alisol-B, atropine sulfate, and bufotalin) showed strong anti-Cryptosporidium activity in vitro (EC50 values = 122.9±6.7, 79.58±13.8, 253.5±30.3, and 63.43±18.7 nM, respectively), and minimum host cell cytotoxicity (cell survival > 95%). Furthermore, atropine sulfate (200 mg/kg) and bufotalin (0.1 mg/kg) also showed in vivo inhibitory effects. Our findings demonstrate that atropine sulfate and bufotalin are effective against C. parvum infection both in vitro and in vivo. These compounds may, therefore, represent promising novel anti-Cryptosporidium drug leads for future medications against cryptosporidiosis.

Background: Endothelial dysfunction is an early pathophysiological feature and independent predictor of a poor prognosis in most forms of cardiovascular disease. We evaluated the effect of brown rice crackers (BR-C) on endothelial function. Methods: Effect of heat-moisture treated (HMT) -BR-C on postprandial flow-mediated dilation (FMD) in adults with mild endothelial dysfunction was compared with that of BR-C and white rice crackers (WR-C) in 12 adults with mild endothelial dysfunction (less than 7.0% of FMD) by a randomized, single-blind, three-treatment three-period crossover trial (UMIN 000034898). Since we considered that the FMD increase was associated with the treatment of HMT-BR-C, we examined the effect of three possible factors: postprandial glucose levels, polyphenol content, and polyphenol release from the food matrix. Results: Mean pre-intake baseline FMD values of HMT-BR-C, BR-C, and WR-C were 4.9%, 5.1%, and 4.9%, respectively, and those values 1 h post-intake were 6.3%, 5.1%, and 4.8%, respectively. There was no difference in intergroup comparisons of FMD using Dunnett's multiple comparison test. There was a significant increase in FMD only in HMT-BR-C in intragroup comparisons (P = 0.042 by paired-t test). In comparison with BR-C, no significant difference was noted in the postprandial glucose level nor in the content of total polyphenols and ferulic acid derivatives in HMT-BR-C. However, the 70% ethanol extracted from HMT-BR-C contained a significantly larger amount of free and bound ferulic acids than from BR-C. Conclusion: HMT-BR-C intake increased the postprandial FMD response.

Abstract To evaluate the characteristics of the spinopelvic parameters on radiography in patients with sacroiliac joint pain (SIJP). Two hundred fifty patients were included and divided into the SIJP group (those diagnosed with SIJP based on physical findings and response to analgesic periarticular injections; n = 53) and the non-SIJP group (those with low back pain [LBP] because of other reasons; n = 197). We compared their demographic characteristics and spinopelvic parameters using radiography. All differences found in the patients’ demographic characteristics and spinopelvic parameters were analyzed. More female participants experienced SIJP than male participants (P = 0.0179). Univariate analyses revealed significant differences in pelvic incidence (PI) (P = 0.0122), sacral slope (SS) (P = 0.0034), and lumbar lordosis (LL) (P = 0.0078) between the groups. The detection powers for PI, SS, and LL were 0.71, 0.84, and 0.66, respectively. Logistic regression analyses, after adjustment for age and sex, revealed significant differences in PI (P = 0.0308) and SS (P = 0.0153) between the groups, with odds ratios of 1.03 and 1.05, respectively. More female participants experienced SIJP than male participants. Higher PI and SS values were related to SIJP among LBP patients.

Abstract Notch signaling-modified human mesenchymal stem cell, SB623 cell, is a promising cell therapy product for ischemic stroke. With the aim to expand indications for their use for critical limb-threatening ischemia (CLTI), we hypothesized that SB623 cells improved tissue perfusion by inducing angiogenesis or arteriogenesis in a hindlimb ischemia model rat. In Sprague–Dawley rats, hindlimb ischemia was generated by femoral artery removal, then seven days after ischemic induction 1 × 105 SB623 cells or PBS was injected into the ischemic adductor muscle. As compared with the PBS group, tissue perfusion was significantly increased in the SB623 group. While capillary density did not vary between the groups, αSMA- and vWF-positive arterioles with a diameter > 15 μm were significantly increased in the SB623 group. Whole transcriptome analysis of endothelial cells co-cultured with SB623 cells showed upregulation of the Notch signaling pathway as well as several other pathways potentially leading to arteriogenesis. Furthermore, rat muscle treated with SB623 cells showed a trend for higher ephrin-B2 and significantly higher EphB4 expression, which are known as arteriogenic markers. In the hindlimb ischemia model, SB623 cells improved tissue perfusion by inducing arteriogenesis, suggesting a promising cell source for treatment of CLTI.

Abstract Despite mounting evidence of the positive relationship between diabetes mellitus (DM) and heart failure (HF), the entire context of the magnitude of risk for HF in relation to DM remains insufficiently understood. The principal reason is because new‐onset HF (HF occurring in participants without a history of HF) and recurrent HF (HF re‐occurring in patients with a history of HF) are not discriminated. This meta‐analysis aims to comprehensively and separately assess the risk of new‐onset and recurrent HF depending on the presence or absence of DM. We systematically searched cohort studies that examined the relationship between DM and new‐onset or recurrent HF using EMBASE and MEDLINE (from 1 Jan 1950 to 28 Jul 2019). The risk ratio (RR) for HF in individuals with DM compared with those without DM was pooled with a random‐effects model. Seventy‐four and 38 eligible studies presented data on RRs for new‐onset and recurrent HF, respectively. For new‐onset HF, the pooled RR [95% confidence interval (CI)] of 69 studies that examined HF as a whole [i.e. combining HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF)] was 2.14 (1.96–2.34). The large between‐study heterogeneity (I2 = 99.7%, P

Gene or cell therapy is currently not fully efficacious for arteriosclerosis obliterans (ASO). In this study, we determined whether YS-1402, a slow-release synthetic prostacyclin agonist, promoted neovascularization and skeletal muscle regeneration in a mouse model of critical limb ischemia (CLI). We ligated the femoral artery and its branches to obtain the CLI mouse model, administered saline (S group) or YS-1402 (YS group) to the thigh adductor 1 week after femoral artery occlusion, and evaluated tissue blood flow after surgery. After treatment, the leg muscle was obtained for histological, gene expression, and protein analyses to assess angiogenesis and skeletal muscle regeneration. Tissue blood flow improved in the YS group compared with that in the S group, and the number of CD31+/α-smooth muscle actin (αSMA)+ arterioles increased in the YS group. Prostacyclin receptor (IPR), stromal cell-derived factor-1, hepatocyte growth factor, and neural cell adhesion molecule expression levels were higher in the YS than in the S group. Skeletal muscle regeneration was detected based on PAX7- and Ki-67-positive satellite cells in the YS group. Myogenin and MyoD expression was higher in the YS than in the S group. Therefore, YS-1402 promoted functional angiogenesis and skeletal muscle regeneration in the CLI mouse model, suggesting a new therapy for ASO.

Airway foreign bodies are a medical emergency in children, as airway obstruction results in immediate respiratory distress. Common ingested foreign bodies differ among children from different social backgrounds, and metal foreign bodies, such as pins, coins, and dental appliances, are widely reported. Herein, we present the first case of a broken metal mesh foreign body ingested by an infant. An 11-month-old boy was found to be licking and biting the mesh cover of an electric lint remover. Part of the broken mesh was found in his mouth, but his mother could not remove it. The patient was referred to our hospital that same day. Although flexible laryngoscopy revealed no foreign bodies in the upper airway, computed tomography scan revealed high density foreign bodies in the left oropharynx. Two pieces of metal mesh that were buried in the left tonsillar fossa were removed under general anesthesia. The patient recovered uneventfully and was discharged the following day. This case suggests that thin metal mesh may be broken by infants with erupting deciduous teeth and become a pharyngeal foreign body.

Series of 1.0% Terbium (Tb)-doped rare-earth pyrosilicate single crystals including Lu2Si2O7 (LPS), Y2Si2O7 (YPS), Gd2Si2O7 (GPS), and La2Si2O7 (LaPS) have been prepared by the floating-zone method. After the phase confirmation by powder X-ray diffraction, the properties are measured on both photoluminescence and scintillation aspects, including the photoluminescence emission contour graph and decay times, X-ray induced scintillation spectra and decay times, afterglow profiles, and the recently developed pulse height spectra for scintillators with millisecond decay time. The results indicate the multiple emissions from Tb3+ 4f-4f transition with the dominant emission at 540 nm (5D4 → 7F5) on both ultraviolet and X-ray excitation with the decay time around 2.6–5.6 and 1.3–3.2 ms, respectively. Under the γ-ray irradiation from 137Cs, the Tb-doped LPS, YPS, GPS, and LaPS have presented scintillation light yields of 20,700, 29,600, 95,600, and 47,700 ph/MeV with ±10%, respectively, which considerably very high among the oxide scintillators.

Key message Abnormal anastomosis of peripheral pulmonary arteries is rare and resembles a pulmonary arteriovenous fistula; thus, when the inflow or outflow route cannot be clearly identified in a suspected pulmonary arteriovenous fistula, the possibility of peripheral pulmonary artery anastomosis should be considered. However, the final diagnosis requires a catheterization study.

Le Carbone (LC), a fiber-enriched activated charcoal dietary supplement, claimed to be effective against inflammation associated with colitis, trimethylaminuria, and sclerosis. The study aimed to investigate the underlying mechanisms of LC to protect liver damage and its progression in non-alcoholic steatohepatitis-hepatocellular carcinoma (NASH-HCC) mice. To induce this model, C57BL/6J male baby mice were injected with a low-dose of streptozotocin and fed with a high-fat diet (HFD) 32 during 4 weeks–16 weeks of age. The LC suspension was administered orally at a dose of 5 mg/mouse/day started at the age of 6 weeks and continued until 16 weeks of age along with HFD32 feeding. At the end of the experiment, serum and liver tissues were collected for the biochemical, histological, and molecular analysis. We found that LC suspension improved the histopathological changes, serum aminotransferases in NASH mice. The hepatic expression of metabolic proteins, p-AMPKα and sirtuin 1, and proteins responsible for β-oxidation of fatty acids, peroxisome proliferator-activated receptor (PPAR) γ coactivator-α, PPARα were significantly repressed in NASH mice. LC treatment markedly restored these expressions. LC treatment significantly reduced the hepatic proteins expressions of PPARγ, tissue inhibitor of metalloproteinases 4, p47phox, p-JNK, p-ERK1/2, glypican-3, and prothrombin in NASH mice. Our findings demonstrate that LC prevents the liver damage and progression of NASH, possibly by enhancing the AMPK-SIRT1 signaling pathway.

BackgroundPneumonia is a common cause of illness and death of the elderly in Japan. Its prevalence is escalating globally with the aging of population. To describe the latest trends in pneumonia hospitalizations, especially aspiration pneumonia (AP) cases, we assessed the clinical records of pneumonia patients admitted to core acute care hospitals in Miyagi prefecture, Japan.MethodsA retrospective multi-institutional joint research was conducted for hospitalized pneumonia patients aged ≥20 years from January 2019 to December 2019. Clinical data of patients were collected from the medical records of eight acute care hospitals.ResultsOut of the 1,800 patients included in this study, 79% of the hospitalized pneumonia patients were aged above 70 years. The most common age group was in the 80s. The ratio of AP to total pneumonia cases increased with age, and 692 out of 1,800 patients had AP. In univariate analysis, these patients had significantly older ages, lower body mass index (BMI), a lower ratio of normal diet intake and homestay before hospitalization, along with more AP recurrences and comorbidities. During hospitalization, AP patients had extended fasting periods, more swallowing assessments and interventions, longer hospitalization, and higher in-hospital mortality rate than non-AP patients. A total of 7% and 2% AP patients underwent video endoscopy and video fluorography respectively. In multivariate analysis, lower BMI, lower C-reactive protein, a lower ratio of homestay before hospitalization, a higher complication rate of cerebrovascular disease, dementia, and neuromuscular disease were noted as a characteristic of AP patients. Swallowing interventions were performed for 51% of the AP patients who had been hospitalized for more than two weeks. In univariate analysis, swallowing intervention improved in-hospital mortality. Lower AP recurrence before hospitalization and a lower ratio of homestay before hospitalization were indicated as characteristics of AP patients of the swallowing intervention group from multivariate analysis. Change in dietary pattern from normal to modified diet was observed more frequently in the swallowing intervention group.ConclusionAP accounts for 38.4% of all pneumonia cases in acute care hospitals in Northern Japan. The use of swallowing evaluations and interventions, which may reduce the risk of dysphagia and may associate with lowering mortality in AP patients, is still not widespread.

As it has been reported that type 2 diabetes mellitus increases the risk of Alzheimer’s disease, we investigated how to prevent type 2 diabetes and dementia using biofunctional boiled rice. We adopted unpolished super-hard rice (SHBR) for diabetes and wax-free unpolished black rice (WFBBR) for dementia and blended those with ordinary non-polished rice (KBR) (blending ratio 4:4:2), adding 2.5% waxy black rice bran (WBB) and 0.3% rice oil after high-pressure treatment (HPT) (WFBSK) to improve its palatability. This boiled rice is rich in dietary fiber, anthocyanin, free ferulic acid and β-secretase inhibitory activity. A randomized, parallel-group comparison study was conducted for 12 weeks with 24 subjects, using Cognitrax to evaluate their cognitive function primarily. Furthermore, as the secondary purpose, we performed a single-dose test for postprandial blood glucose and insulin secretion at the end of the human intervention test. After 12 weeks, consumers of the WFBSK rice exhibited significant improvement in language memory by cognitive test battery compared with those who consumed the control white rice (p < 0.05). Moreover, subjects who consumed the WFBSK rice had lower insulin secretion levels than those who consumed the control polished rice (p < 0.05).

The obligate intracellular parasite Toxoplasma gondii infects warm-blooded animals, including humans. We previously revealed through a whole-brain transcriptome analysis that infection with T. gondii in mice causes immune response-associated genes to be upregulated, for instance, chemokines and chemokine receptors such as CXC chemokine receptor 3 (CXCR3) and its ligand CXC chemokine ligand 10 (CXCL10). Here, we describe the effect of CXCR3 on responses against T. gondii infection in the mouse brain. In vivo assays using CXCR3-deficient mice showed that the absence of CXCR3 delayed the normal recovery of body weight and increased the brain parasite burden, suggesting that CXCR3 plays a role in the control of pathology in the brain, the site where chronic infection occurs. Therefore, to further analyze the function of CXCR3 in the brain, we profiled the gene expression patterns of primary astrocytes and microglia by RNA sequencing and subsequent analyses. CXCR3 deficiency impaired the normal upregulation of immune-related genes during T. gondii infection, in astrocytes and microglia alike. Collectively, our results suggest that the immune-related genes upregulated by CXCR3 perform a particular role in controlling pathology when the host is chronically infected with T. gondii in the brain.

Reportedly, the intake of koji amazake, a beverage made from steamed rice fermented by Aspergillus oryzae, improves defecation frequency. However, its functional ingredients and mechanism of action remain unclear. To compare the effects of koji amazake and a placebo beverage on defecation frequency and to identify the functional ingredients and mechanism of action, a randomized, placebo-controlled, double-blind parallel-group comparative trial was performed on two groups. The koji amazake had 302 ± 15.5 mg/118 g of A. oryzae cells, which was not in the placebo. Compared with the placebo group, the koji amazake group showed a significant increase in weekly defecation frequency at 2 weeks (5.09 days vs. 4.14 days), 3 weeks (5.41 days vs. 4.18 days), and 4 weeks (5.09 days vs. 3.95 days), along with an increase in the weekly fecal weight at 4 weeks (724 g vs. 501 g). The intake of koji amazake did not induce significant intergroup differences in the fecal SCFA concentration, whereas it significantly decreased the relative abundance of Blautia and significantly increased that of Bacteroides at 3 weeks. Therefore, koji amazake intake improved defecation frequency, and A. oryzae cells played potentially important roles as functional ingredients.

Abstract Background Laterality disorders of the abdominal organs include situs inversus totalis that mirrors the arrangements of all internal organs and heterotaxy syndrome (situs ambiguus) in which the thoracic or abdominal organs are abnormally arranged. Heterotaxy is often accompanied by multiple congenital malformations, and it generally comprises asplenia and polysplenia syndromes. To our knowledge, polysplenia syndrome has been reported in only three cattle, and computerized tomographic (CT) images of these animals were not obtained. Case presentation A six-month-old Holstein heifer had ruminal tympani and right abdominal distension. CT imaging showed that the rumen occupied the right side of the abdominal cavity, the omasum and abomasum occupied the left ventral side and the liver was positioned on the left. The colon and cecum were located at the left dorsum of the cavity, and the left kidney was located more cranially than the right. Postmortem findings revealed two spleens attached to the rumen. Significantly, the duodenum was too short to be divided into segments, except the cranial and descending parts, or flexures, except the cranial flexure, and the pancreas, which lacked a left lobe, was covered with mesojejunum. The liver comprised a relatively large right lobe and a small left lobe without quadrate and caudate lobes. The caudal vena cava that connected to the left azygous vein passed irregularly through the aortic hiatus of the diaphragm, and the common hepatic vein without the caudal vena cava passed through the caval foramen. Although the lungs and heart were morphologically normal, the right atrium received three major systemic veins. Polysplenia syndrome was diagnosed based on the CT and postmortem findings. Conclusion We defined the positions of the abdominal organs and morphological abnormalities in various organs of a calf with polysplenia syndrome based on CT and postmortem findings. These findings will improve understanding of the malpositioning and malformations that can occur in the organs of cattle with polysplenia syndrome.

ObjectiveTo determine the relationship between plaque composition and low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (Apo-B), and Apo-A1 using virtual-histology intravascular ultrasound (VH-IVUS).MethodsWe assessed plaque composition in patients with stable coronary artery disease (SCD) admitted to our hospital for percutaneous coronary intervention (PCI) between November 1, 2012, and March 10, 2015. Before PCI, fibrous (FI), fibrofatty (FF), necrotic core (NC), and dense calcium (DC) regions were evaluated using VH-IVUS, and the contributions of each to the culprit lesion volume were recorded. Plasma LDL-C, HDL-C, Apo-B, and Apo-A1 levels were assessed before PCI. The relationship between the regions on VH-IVUS and plasma lipid levels was assessed. Patients were categorized into low Apo-B (LAB) and high Apo-B (HAB) groups, based on the overall cohort median Apo-B level.ResultsWe enrolled 115 patients (median Apo-B, 91 mg/dL, male n = 88) with 57 and 58 patients in the LAB (Apo-B ≤ 90 mg/dL) and HAB (Apo-B ≥ 91 mg/dL) groups, respectively. Vessel, plaque, and %NC volumes were significantly greater in the HAB group than in the LAB group. The %FI, %FF, and %DC volumes were similar in both groups. In all 115 patients, the %NC volume correlated with LDL-C (r = 0.2353, P = 0.0114) and Apo-B (r = 0.2487, P = 0.0074) but not with HDL-C and Apo A-1. The high-sensitivity C-reactive protein level tended to be higher in the HAB group than in the LAB group. Multiple regression analysis showed that being male, Apo-A1, and Apo-B were significant predictors of %NC volume extent.ConclusionsElevated Apo-B level was related to the %NC in target coronary artery lesions in SCD patients, suggesting a role of Apo-B as a biomarker of unstable plaque in this population.

The vomeronasal organ (VNO) detects specific chemicals such as pheromones and kairomones. Hedgehogs (Eulipotyphla: Erinaceidae) have a well-developed accessory olfactory bulb that receives projections from the VNO, but little is known about the hedgehog VNO. Here, we studied the histological features of the VNO in five individual African pygmy hedgehogs by hematoxylin-eosin, periodic acid-Schiff, and Alcian blue stains. The hedgehog VNO comprises a hyaline cartilage capsule, soft tissue and epithelial lumen, and it branches from the site just before the incisive duct opening into the nasal cavity. The soft tissues contain several small mucous (or mucoserous) glands and a large serous gland, and many venous sinuses all around the lumen. The VNO lumen is round to oval throughout the hedgehog VNO, and the sensory epithelium lines almost the entire rostral part and medial wall of the middle part. These findings indicate that the VNO is functional and plays an important role in the hedgehog. Notably, the VNO apparently has a characteristic flushing mechanism with serous secretions like those of gustatory glands, which the hedgehog might frequently use to recognize the external environment.

Amyloid A (AA) amyloidosis is a condition in which amyloid fibrils characterized by a linear morphology and a cross-β structure accumulate and are deposited extracellularly in organs, resulting in chronic inflammatory diseases and infections. The incidence of AA amyloidosis is high in humans and several animal species. Serum amyloid A (SAA) is one of the most important precursor amyloid proteins and plays a vital step in AA amyloidosis. Amyloid enhancing factor (AEF) serves as a seed for fibril formation and shortens the onset of AA amyloidosis sharply. In this study, we examined whether AEFs extracted and purified from five animal species (camel, cat, cattle, goat, and mouse) could promote mouse SAA (mSAA) protein aggregation in vitro using quantum-dot (QD) nanoprobes to visualize the aggregation. The results showed that AEFs shortened and promoted mSAA aggregation. In addition, mouse and cat AEFs showed higher mSAA aggregation-promoting activity than the camel, cattle, and goat AEFs. Interestingly, homology analysis of SAA in these five animal species revealed a more similar amino acid sequence homology between mouse and cat than between other animal species. Furthermore, a detailed comparison of amino acid sequences suggested that it was important to mSAA aggregation-promoting activity that the 48th amino acid was a basic residue (Lys) and the 125th amino acid was an acidic residue (Asp or Glu). These data imply that AA amyloidosis exhibits higher transmission activity among animals carrying genetically homologous SAA gene, and may provide a new understanding of the pathogenesis of amyloidosis.

N-3 polyunsaturated fatty acids (PUFAs) are thought to have protective effects against cardiovascular disease. Here, we report the relationship between serum PUFA concentrations and plaque composition, as evaluated by virtual histology-intravascular ultrasound (VH-IVUS). Consecutive patients (n=61) who underwent percutaneous coronary intervention (PCI) were pre-operatively examined using VH-IVUS to assess the composition of culprit plaques. Gray-scale IVUS and VH-IVUS data of fibrous, fibro-fatty, necrotic core, and dense calcium regions of plaques were estimated at the minimal luminal area sites of culprit lesions. Serum levels of high-sensitivity C-reactive protein (hsCRP) and PUFAs, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA), were compared between patients with (ACS, n=27) and without acute coronary syndrome (non-ACS, n=34) before PCI. Multiple logistic regression analysis of the data showed that EPA/AA under the median was more highly associated with ACS than hsCRP over the median. In addition, EPA/AA was negatively correlated with the percentage of fibrous plaque regions and EPA/AA and DHA/AA were positively correlated with the percentage of dense calcium regions in plaques. Furthermore, the correlation index of EPA/AA was the most highly (R=0.513) correlated with the percentage of dense calcium regions in plaques. Keywords: N-3 polyunsaturated fatty acids, Eicosapentaenoic acid, Acute coronary syndrome, Stable coronary disease, Virtual histology-intravascular ultrasound

Serum amyloid A (SAA) is one of the most important precursor amyloid proteins and plays a vital step in AA amyloidosis, although the underlying aggregation mechanism has not been elucidated. Since SAA aggregation is a key step in this pathogenesis, inhibitors are useful to prevent and treat AA amyloidosis, serving as tools to investigate the pathogenic mechanism. In this study, we showed that rosmarinic acid (RA), which is a well-known inhibitor of the aggregation of amyloid β (Aβ), displayed inhibitory activity against SAA aggregation in vitro using a microliter-scale high-throughput screening (MSHTS) system with quantum-dot nanoprobes. Therefore, we evaluated the amyloid aggregation inhibitory activity of blood and the deposition of SAA in organs by feeding mice with Melissa officinalis extract (ME) containing RA as an active substance. Interestingly, the inhibitory activity of ME-fed mice sera for SAA and Aβ aggregation, measured with the MSHTS system, was higher than that of the control group. The amount of amyloid deposition in the organs of ME-fed mice was lower than that in the control group, suggesting that the SAA aggregation inhibitory activity of serum is associated with SAA deposition. These results suggest that dietary intake of RA-containing ME enhanced amyloid aggregation inhibitory activity of blood and suppressed SAA deposition in organs. This study also demonstrated that the MSHTS system could be applied to in vitro screening and to monitor comprehensive activity of metabolized foods adsorbed by blood.

Aging is a predominant risk factor for the development and progression of cardiovascular complications. Physiologically and anatomically, the heart undergoes numerous changes that result in poor cardiac function in the elderly population. Recently, several studies have provided promising results, confirming the ability of the senescence-accelerated mouse-prone 8 (SAMP8) model to accurately model age-related cardiovascular alterations. In this study, using a murine model of senescence, SAMP8, we aimed to investigate the effect of 3,4-dihydroxybenzalacetone (DBL), a catechol-containing phenylpropanoid derivative isolated from Inonotus obliquus (Chaga), on cardiac aging. DBL was administered at the doses of 10 mg/kg and 20 mg/kg by oral gavage to SAMP8 mice to examine aging-mediated cardiac changes, such as oxidative DNA damage, oxygen radical antioxidant capacity (ORAC) value, fibrosis, inflammation, and apoptosis. The treatment with DBL at both doses significantly reduced aging-mediated oxidative DNA damage, and simultaneously increased the ORAC value in the SAMP8 assay. Cardiac fibrosis was assessed with Azan-Mallory staining, and the number of cardiac remodeling markers was found to be significantly reduced after the treatment with DBL. We also observed a decrease in cardiomyocyte apoptosis as measured by the terminal transferase-mediated dUTP nick end labeling (TUNEL) staining method and the caspase-3 levels in SAMP8 mice compared with senescence-resistant control (SAMR1) mice. The findings from this study suggest that DBL has a potentially beneficial effect on aging-mediated myocardial alterations. Further studies are warranted to confirm the promising potential of this catechol compound against aging-associated myocardial dysfunction.

The purpose of this study was to determine whether blocking of G protein βγ (Gβγ) signaling halts heart failure (HF) progression by macrophage phenotype manipulation. Cardiac Gβγ signaling plays a crucial role in HF pathogenesis. Previous data suggested that inhibiting Gβγ signaling reprograms T helper cell 1 (Th1) and Th2 cytokines, suggesting that Gβγ might be a useful drug target for treating HF. We investigated the efficacy of a small molecule Gβγ inhibitor, gallein, in a clinically relevant, experimental autoimmune myocarditis (EAM) model of HF as well as in human macrophage phenotypes in vitro. In the myocardium of HF patients, we observed that G protein coupled receptor kinase (GRK)2 levels were down-regulated compared with healthy controls. In rat EAM, treatment with gallein effectively improved survival and cardiac function, suppressed cardiac remodeling, and further attenuated myocardial protein expression of GRK2 as well as high mobility group box (HMGB)1 and its cascade signaling proteins. Furthermore, gallein effectively inhibited M1 polarization and promoted M2 polarization in vivo in the EAM heart and in vitro in human monocyte-derived macrophages. Taken together, these data suggest that the small molecule Gβγ inhibitor, gallein, could be an important pharmacologic therapy for HF as it can switch the phenotypic reprogramming from M1 to M2 phenotype in a rat model of EAM heart and in human macrophages.

Induction of mucosal healing (MH) is an important treatment goal in inflammatory bowel disease (IBD). Although the molecular mechanisms underlying MH in IBD is not fully explored, local fibrosis would contribute to interfere mucosal repair. Carbohydrate sulfotransferase 15 (CHST15), which catalyzes sulfation of chondroitin sulfate to produce rare E-disaccharide units, is a novel mediator to create local fibrosis. Here we have used siRNA-based approach of silencing CHST15 in dextran sulfate sodium (DSS) induced colitis in mice, human colon fibroblasts and cancer cell lines. In a DSS-induced acute colitis model, CHST15 siRNA reduced CHST15 mRNA in the colon, serum IL-6, disease activity index (DAI) and accumulation of F4/80+ macrophages and ER-TR7+ fibroblasts, while increased Ki-67+ epithelial cells. In DSS-induced chronic colitis models, CHST15 siRNA reduced CHST15 mRNA in the colon, DAI, alpha-smooth muscle actin+ fibroblasts and collagen deposition, while enhanced MH as evidenced by reduced histological and endoscopic scores. We also found that endoscopic submucosal injection achieved effective pancolonic delivery of CHST15 siRNA in mice. In human CCD-18 Co cells, CHST15 siRNA inhibited the expression of CHST15 mRNA and selectively reduced E-units, a specific product biosynthesized by CHST15, in the culture supernatant. CHST15 siRNA significantly suppressed vimentin in both TGF-ß-stimulated CCD18-Co cells and HCT116 cells while up-regulated BMP7 and E-cadherin in HCT116 cells. The present study demonstrated that blockade CHST15 represses colonic fibrosis and enhances MH partly though reversing EMT pathway, illustrating a novel therapeutic opportunity to refractory and fibrotic lesions in IBD.

The aim of this study was to investigate the role of macrophage polarization in aging heart. Macrophage differentiation is pathogenically linked to many inflammatory and immune disorders. It is often preceded by myocardial inflammation, which is characterized by increased cardiac damage and pro-inflammatory cytokine levels. Therefore, we investigated the hypothesis that senescence accelerated-prone (SAMP8) mice cardiac tissue would develop macrophage polarization compared with senescence-resistant control (SAMR1) mice. Both SAMP8 and SAMR1 mice were sacrificed when they became six month old. We evaluated, histo-pathological changes and modifications in protein expression by Western blotting and immuno-histochemical staining for M1 and M2 macrophage markers, high mobility group protein (HMG)B1 and its cascade proteins, pro-inflammatory factors and inflammatory cytokines in cardiac tissue. We observed significant upregulation of HMGB1, toll-like receptor (TLR)2, TLR4, nuclear factor (NF)κB p65, tumor necrosis factor (TNF)α, cyclooxygenase (COX)2, interferon (IFN)γ, interleukin (IL)-1β, IL-6 and M1 like macrophage specific marker cluster of differentiation (CD)68 expressions in SAMP8 heart. In contrast, M2 macrophage specific marker CD36, and IL-10 expressions were down-regulated in SAMP8 mice. The results from the study demonstrated that, HMGB1-TLR2/TLR4 signaling cascade and induction of phenotypic switching to M1 macrophage polarization in SAMP8 mice heart would be one of the possible reasons behind the cardiac dysfunction and thus it could become an important therapeutic target to improve the age related cardiac dysfunction.

Although chronic sympathetic activation provides inotropic and chronotropic support to the failing heart, such activation may also have deleterious effects, including the direct cardiotoxic effects of catecholamines, activation of the renin-angiotensin-aldosterone system and an increase in myocardial oxygen demand. These observations indicate that β-blockade might be beneficial in the treatment of heart failure resulting from dilated cardiomyopathy or ischaemic heart disease. Carvedilol is a non-selective β-blocker acting on β1-, β2-, and α1-adrenoceptors. It possesses potent anti-oxidant and anti-apoptotic properties, along with neuroprotective, vasculoprotective, cardioprotective effects, and it has reduced overall mortality in patients with heart failure in controlled clinical trials. Its role in treating cardiomyopathy requires focus. The fact that anthracyclines are cardiotoxic seriously narrows their therapeutic index in cancer therapy. The cardiotoxic risk increases with the cumulative dose and may lead to congestive heart failure and dilated cardiomyopathy in adults and in children. This review focuses on recent research regarding the beneficial effects of carvedilol in the treatment of dilated cardiomyopathy and to revisit the available evidence on the cardioprotection of carvedilol when associated with anthracycline and to explain the mechanisms underlying the benefits of their co-administration.

Cardiotoxicity, which results from intense cardiac oxidative stress and inflammation, is the main limiting factor of the anthracyclines. Carvedilol, a beta blocker that is used as a multifunctional neurohormonal antagonist, has been shown to act not only as an anti-oxidant, but also as an anti-inflammatory drug. This study was designed to evaluate whether carvedilol exerts a protective role against inflammation-mediated cardiotoxicity in the daunorubicin (DNR)-induced rats. Carvedilol was administered orally to the rats every day for 6 weeks at a cumulative dose of 9 mg/kg body weight DNR. DNR significantly induced cardiac damage and worsened cardiac function as well as increased cardiac mast cell density, elevating the myocardial protein and mRNA expression levels of tumor necrosis factor-α, vascular cell adhesion molecule-1, inter-cellular adhesion molecule-1, nuclear factor kappa-B, cyclooxygenase-2, monocyte chemotactic protein -1 and interleukin -6 compared to that in the control group. Cotreatment with carvedilol significantly attenuated the myocardial protein and mRNA expression levels of these inflammatory markers, decreased cardiac mast cell density, improved histological cardiac damage and cardiac functions. In conclusion, inflammation plays a significant role in DNR-induced cardiotoxicity, and carvedilol contributes to cardioprotection against inflammation-mediated cardiotoxicity in DNR-induced rats through its anti-inflammatory mechanism.

The cold neutron imaging and diffraction instrument IMAT at the second target station of the pulsed neutron source ISIS is currently being commissioned and prepared for user operation. IMAT will enable white-beam neutron radiography and tomography. One of the benefits of operating on a pulsed source is to determine the neutron energy via a time of flight measurement, thus enabling energy-selective and energy-dispersive neutron imaging, for maximizing image contrasts between given materials and for mapping structure and microstructure properties. We survey the hardware and software components for data collection and image analysis on IMAT, and provide a step-by-step procedure for operating the instrument for energy-dispersive imaging using a two-phase metal test object as an example.

Diabetic cardiomyopathy and nephropathy induce endoplasmic reticulum stress (ERS) and ERS-initiated apoptosis. The primary function of 14-3-3 protein is to inhibit apoptosis, but the roles of this protein in protecting against cardiac ERS and apoptosis in the diabetic heart are largely unknown. In this study, we investigated the in vivo role of 14-3-3 protein in diabetic ERS and apoptosis using streptozotocin (STZ)-induced transgenic mice that showed cardiac-specific expression of a dominant negative (DN) 14-3-3η protein mutant. The expression levels of cardiac glucose-regulated protein (GRP) 78, inositol-requiring enzyme (Ire) 1α, and tumor necrosis factor receptor (TNFR)-associated factor (TRAF) 2 protein were significantly increased in the diabetic DN 14-3-3η mice compared with the diabetic wild-type. Moreover, cardiac apoptosis and the expression of CCAAT / enhancer binding protein homology protein (CHOP), caspase-12, and cleaved caspase-12 protein were significantly increased in the diabetic DN 14-3-3η mice. In conclusion, partial depletion of 14-3-3 protein in the diabetic heart exacerbates cardiac ERS and activates ERS-induced apoptosis pathways, at least in part, through the regulation of CHOP and caspase-12 via the Ire1α/TRAF2 pathway. The enhancement of 14-3-3 protein expression can be used as a novel protective therapy against ERS and ERS-initiated apoptosis in the diabetic heart. Keywords:: 14-3-3 protein, diabetes mellitus, endoplasmic reticulum stress, apoptosis, glucose-regulated protein (GRP) 78

Doxorubicin (Dox) is a highly effective antineoplastic drug. However, Dox-induced apoptosis in cardiomyocytes leads to irreversible degenerative cardiomyopathy, which limits Dox clinical application. Schisandrin B (Sch B), a dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis, has been shown to protect against oxidative damage in liver, heart and brain tissues in rodents. In current study, we investigated possible protective effects of Sch B against Dox-induced cardiomyopathy in mice. Mice received a single injection of Dox (20 mg/kg IP). Five days after Dox administration, left ventricular (LV) performance was significantly depressed and was improved by Sch B treatment. Sch B prevented the Dox-induced increase in lipid peroxidation, nitrotyrosine formation, and metalloproteinase activation in the heart. In addition, the increased expression of phospho-p38 MAPK and phospho-MAPK activated mitogen kinase 2 levels by Dox were significantly suppressed by Sch B treatment. Sch B also attenuated Dox-induced higher expression of LV proinflammatory cytokines, cardiomyocyte DNA damage, myocardial apoptosis, caspase-3 positive cells and phopho-p53 levels in mice. Moreover, LV expression of NADPH oxidase subunits and reactive oxygen species were significantly less in Sch B treatment mice after Dox injection. These findings suggest that Sch B attenuates Dox-induced cardiotoxicity via antioxidative and anti-inflammatory effects.

Amyloid β (Aβ)-induced neurotoxicity is a major pathological mechanism of Alzheimer's disease (AD). Our previous studies have demonstrated that schisandrin B (Sch B), an antioxidant lignan from Schisandra chinensis, could protect mouse brain against scopolamine- and cisplatin-induced neuronal dysfunction. In the present study, we examined the protective effect of Sch B against intracerebroventricular (ICV)-infused Aβ-induced neuronal dysfunction in rat cortex and explored the potential mechanism of its action. Our results showed that 26 days co-administration of Sch B significantly improved the behavioral performance of Aβ (1-40)-infused rats in step-through test. At the same time, Sch B attenuated Aβ-induced increases in oxidative and nitrosative stresses, inflammatory markers such as inducible nitric oxide syntheses, cyclooxygenase-2, interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α, and DNA damage. Several proteins such as receptor for advanced glycation end products (RAGE), nuclear factor-κB, mitogen-activated protein kinases, and apoptosis markers were over expressed in Aβ-infused rats but were significantly inhibited by Sch B treatment. Furthermore, Sch B negatively modulated the Aβ level with simultaneous up-regulation of HSP70 and beclin, autophagy markers in Aβ-infused rats. The aforementioned effects of Sch B suggest its protective role against Aβ-induced neurotoxicity through intervention in the negative cycle of RAGE-mediated Aβ accumulation during AD patho-physiology.

Poly(ether-ether-ketone) (PEEK)s are a group of polymeric biomaterials with excellent mechanical properties, chemical stability, and nonmagnetism. In the present study, we propose a novel self-initiated surface graft polymerization technique, using which we demonstrate the fabrication of a highly hydrophilic and biocompatible nanometer-scale layer on the surfaces of PEEK and carbon fiber-reinforced PEEK (CFR-PEEK) by the photoinduced graft polymerization of 2-methacryloyloxyethyl phosphorylcholine (MPC) without using any photoinitiators. The thus formed hydrophilic and smooth 100-nm-thick PMPC-grafted layer caused a significant reduction in the sliding friction of the bearing interface because the thin water film and hydrated PMPC layer acted as extremely efficient lubricants (so-called fluid-film lubrication or hydration lubrication). Fluid-film lubrication suppressed the direct contact of the counter-bearing surface with the PEEK substrate and thus reduced the frictional force. A PMPC-grafted layer is therefore expected to significantly increase bearing durability. Furthermore, the PMPC-grafted layer shows unique phenomena, e.g., it prevents damage of the metal counter surface regardless of the carbon fiber content of CFR-PEEK. Smart PEEK using the self-initiated surface graft polymerization of MPC should lead to development of novel orthopedic bearings. Keywords: poly(ether-ether-ketone), 2-methacryloyloxyethyl phosphorylcholine, surface modification, photopolymerization, joint replacement, wear mechanism

Metabolic compromise is crucial in aggravating age-associated chronic inflammation, oxidative stress, mitochondrial damage, increased LDL and triglycerides, and elevated blood pressure. Excessive adiposity, hyperglycemia, and insulin resistance due to aging are associated with elevated levels of damaging free radicals, inducing a proinflammatory state and hampering immune cell activity, leading to a malfunctioning cardiometabolic condition. The age-associated oxidative load and redox imbalance are contributing factors for cardiometabolic morbidities via vascular remodelling and endothelial damage. Recent evidence has claimed the importance of gut microbiota in maintaining regular metabolic activity, which declines with chronological aging and cardiometabolic comorbidities. Genetic mutations, polymorphic changes, and environmental factors strongly correlate with increased vulnerability to aberrant cardiometabolic changes by affecting key physiological pathways. Numerous studies have reported a robust link between biological aging and cardiometabolic dysfunction. This review outlines the scientific evidence exploring potential mechanisms behind the onset and development of cardiovascular and metabolic issues, particularly exacerbated with aging. [ABSTRACT FROM AUTHOR]

Background: Nonalcoholic steatohepatitis (NASH) is a common disease that may lead to hepatocellular carcinoma (HCC) through fatty liver and cirrhosis. Although the prevalence of NASH is increasing worldwide, there is no cure established thus far. Sake lees are a by-product of sake refining, with a known liver-protecting effect. Lactic acidfermented sake lees (FSL) are a food produced by lactic acid fermentation and dealcoholization of sake lees. This product is commercially available in Japan. Although FSL has been associated with numerous functions, thus far, studies have not investigated its hepatoprotective effect. Objectives: The objectives of this study are to evaluate the hepatoprotective effects of lactic acid-fermented sake lees (FSL) in a mouse model of NASH-HCC, to assess the impact of FSL supplementation on blood glucose levels in mice with NASH, to analyze the expression of inflammatory markers in FSL-fed mice compared to controls, and to determine the overall efficacy of FSL in inhibiting the progression of NASH. Methods: For this study, we established a mouse model of NASH-HCC. Mice were placed on a high-fat diet supplemented with FSL from 10 to 14 weeks of age. We assessed the diet's efficacy in halting NASH progression compared to a control group. Results: The group fed with FSL exhibited a significant suppression in blood glucose levels and a notable inhibition of NASH progression compared to the control group. Protein analysis revealed a reduction in the expression of inflammatory markers in the FSL-fed group compared to controls. Conclusion: Ingestion of FSL may exert anti-inflammatory and blood glucose-lowering effects and inhibit NASH progression. [ABSTRACT FROM AUTHOR]