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Background: Canine corneal disease is a common condition encountered in daily practice. If the depth of corneal damage is limited to the epithelial layer, healing is often straightforward; however, if it extends into the epithelial basement membrane or corneal parenchyma, surgical treatment is the treatment of choice. Moreover, in cases where there is underlying disease or where the owner refuses surgical treatment, treatment options are often limited to eye drop treatment, which may be inadequate. Case Description: Dogs aged 10 and 14 years were admitted to the hospital with eye injuries. Based on the examination findings, the owner believed that surgical treatment would be effective; however, this could not be performed owing to the underlying condition of the cases. Hyaluronic acid and antibiotic eye drops were administered, but there was no improvement in the eye damage. The eye-drop treatment prolonged without any improvement, and in the meantime the patients' weakness became apparent. In parallel with the eye-drop treatment, the patients were given a supplement containing equine placental extract to help restore their physical fitness. Consequently, in addition to the recovery of physical fitness, a film gradually formed over the eye damage area and injuries improved eventually. Conclusion: Based on these cases, supplementation with equine placenta extract may be an effective treatment option for ocular conditions that are difficult to treat surgically. [Open Vet J 2024; 14(6.000): 1503-1508]

The motivating question for this study is determining whether electrical muscle stimulation (EMS)-induced movements can extend the user’s ability without reducing the sense of agency. Moreover, it is crucial to find the timing of the EMS application that is robust against individual differences and environmental changes. Previous studies have reported that the user-specific EMS-application timings, determined through explicit measures of sense of agency, would effectively shorten their reaction time in a push task while maintaining their sense of agency. However, no study has investigated EMS-application timings in relation to implicit measures of sense of agency. Intentional binding, an example of an implicit measure, refers to the phenomenon whereby the interval between an intentional action and the subsequent perceptual outcome is typically perceived to be shorter than the actual interval. By measuring this perceptual shift using a Libet clock, we have identified an EMS-application timing that accelerates the users’ push action while maintaining their sense of agency. First, to conduct the EMS-application experiment while appropriately maintaining the intentional binding effect, we designed a new push task such that a pre-action, as the base timing of the EMS-application trigger, always occurs just before the push movement. (1) We showed the difference between the action-binding effect of EMS-induced involuntary movements and voluntary push movements. Subsequently, (2) we identified the EMS application timing that significantly shifted judgments of action tasks while accelerating voluntary movements. Additionally, (3) we demonstrated that the EMS application could accelerate user pushing movement while maintaining the sense of agency at this specific application time. The proposed EMS in the novel pushing setup was found to be robustly effective against individual and environmental changes.

BackgroundSatralizumab, a monoclonal antibody that recognizes interleukin-6 receptors, is known to reduce the relapse rate in neuromyelitis optica spectrum disorder (NMOSD), but its safety during pregnancy has not been established. We present the case of an NMOSD patient who safely completed pregnancy, parturition, and breastfeeding under satralizumab treatment. Importantly, satralizumab transfer to umbilical cord blood, infant serum, or breast milk was not observed.Case presentationA 37-year-old Japanese female developed anti-aquaporin 4 antibody-positive NMOSD with left optic neuritis. Despite responding to steroid and azathioprine therapy, she experienced moon face and weight gain and desired the prompt reduction of the steroid dosage. She also wanted to conceive a child with a safe and preferably early pregnancy and parturition. Because pregnancy and parturition after the onset of NMOSD elevate the risk of relapse and miscarriage, treatment with satralizumab was initiated with the patient's consent. She experienced normal parturition and continued with satralizumab, steroid, and azathioprine treatments while breastfeeding without experiencing any relapses. Concentrations of satralizumab in the umbilical cord blood, infant serum, and breast milk were below the detection sensitivity.ConclusionThese findings suggest that satralizumab may be safe and effective for the perinatal management of NMOSD, especially when there are concerns about continuing pregnancy and the risk of relapse after parturition.

ABSTRACT: The presentation range and position that could not be obtained using conventional side and rear mirrors can be obtained using the camera monitor system (CMS). Studies have proposed the effectiveness of a side–rear wide-view monitor that covers a wide angle from left to right. However, placing such a monitor in the same position as a conventional rear mirror creates an incongruent spatial relation problem because the driver seated on the right seat is forced to shift their gaze point to the left to perceive the right side. Thus, this study clarifies the effects of placing a side-rear wide-view monitor at the driver-centered (front of the driver) position on the drivers’ cognitive load, mental stress, and rearward visual behavior. Based on a driving simulator, the proposed side–rear wide-view monitor was set at three positions: the same position as a conventional rear mirror (vehicle-centered), in front of the driver (driver-centered), and in front of the driver and raised upward (driver-centered-up). Under the driver-centered condition, the oxygenated hemoglobin in the prefrontal cortex and the heart rate decreased and the eye movement became more frequent compared with the other conditions. By placing the side–rear wide-view monitor at the driver-centered position, the driver’s cognitive load and mental stress decreased and the rearward visual behavior was closer to that of skilled drivers. Placing the side–rear wide-view monitor at the driver-centered position shows some benefits for support of rearward recognition in perspective of the effects on cognitive load.

The establishment of the legume-rhizobia symbiosis, termed the root-nodule symbiosis (RNS), requires elaborate interactions at the molecular level. The host plant–derived transcription factor NODULE INCEPTION (NIN) is known to be crucial for RNS, regulating associated processes such as alteration of root hair morphology, infection thread formation, and cell division during nodulation. This emphasizes the importance of the precise spatiotemporal regulation of NIN expression for the establishment of RNS; however, the detailed role of NIN promoter sequences in this process remains unclear. The daphne mutant, a nin mutant allele containing a chromosomal translocation approximately 7 kb upstream of the start codon, does not form nodules but does form infection threads, indicating that the region within 7 kb of the NIN start codon contributes to NIN expression during infection thread formation. CYCLOPS binds to a CYCLOPS response element (CYC-RE) in the NIN promoter, and cyclops mutants are defective in infection thread formation. Here, we performed complementation analysis in nin mutants, using various truncated forms of the NIN promoter, and found that the CYC-RE is important for infection thread formation. Additionally, the CYC-RE deletion mutant, generated through CRISPR/Cas9 technology, displayed a significant reduction in infection thread formation, indicating that the CYC-RE is important for the fine-tuning of NIN expression during this process. However, the fact that infection thread formation is not completely abolished in the CYC-RE deletion mutant suggests that cis and trans factors other than CYCLOPS and the CYC-RE may cooperatively regulate NIN expression for the induction of infection thread formation. [Graphic: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Abstract Melanocortin 4 receptor gene-knockout (MC4R-KO) mice are known to develop obesity with a high-fat diet. Meanwhile, daisaikoto, one of Kampo medicines, is a drug that is expected to have therapeutic effects on obesity. Here, we report the efficacy of daisaikoto in MC4R-KO mice. Eight-week-old MC4R-KO male mice (n = 12) were divided into three groups as follows: the SD group, which is fed with a standard diet; the HFD group, fed a high-fat diet; and the DSK group, fed with a high-fat diet containing 10% of daisaikoto. After the four-week observation period, mice in each group were sacrificed and samples were collected. The body weights at 12 weeks were significantly higher in the HFD group than in the other groups, indicating that daisaikoto significantly reduced body weight gain and fat deposition of the liver. The metabolome analysis indicated that degradation of triglycerides and fatty acid oxidation in the liver were enhanced by daisaikoto administration. In MC4R-KO mice, the cytoplasm and uncoupling protein 1 expression of brown adipose tissue was decreased; however, it was reversed in the DSK group. In conclusion, daisaikoto has potentially improved fatty liver and obesity, making it a useful therapeutic agent for obesity and fatty liver.

BackgroundTo investigate whether ivermectin inhibits SARS-CoV-2 proliferation in patients with mild-to-moderate COVID-19 using time to a negative COVID-19 reverse transcription-polymerase chain reaction (RT-PCR) test.MethodsCORVETTE-01 was a double-blind, randomized, placebo-controlled study (August 2020–October 2021) conducted in Japan. Overall, 248 patients diagnosed with COVID-19 using RT-PCR were assessed for eligibility. A single oral dose of ivermectin (200 μg/kg) or placebo was administered under fasting. The primary outcome was time to a negative COVID-19 RT-PCR test result for SARS-CoV-2 nucleic acid, assessed using stratified log-rank test and Cox regression models.ResultsOverall, 112 and 109 patients were randomized to ivermectin and placebo, respectively; 106 patients from each group were included in the full analysis set (male [%], mean age: 68.9%, 47.9 years [ivermectin]; 62.3%, 47.5 years [placebo]). No significant difference was observed in the occurrence of negative RT-PCR tests between the groups (hazard ratio, 0.96; 95% confidence interval [CI] 0.70–1.32; p = 0.785). Median (95% CI) time to a negative RT-PCR test was 14.0 (13.0–16.0) and 14.0 (12.0–16.0) days for ivermectin and placebo, respectively; 82.1% and 84% of patients achieved negative RT-PCR tests, respectively.ConclusionIn patients with COVID-19, single-dose ivermectin was ineffective in decreasing the time to a negative RT-PCR test.Clinical Trial RegistrationClinicalTrials.gov, NCT04703205.

A 33-year-old woman visited our hospital due to visual loss. Her BP was 280/150 mm Hg and pulse rate was 111 beats per minute. A urinalysis showed protein in urine, suggesting kidney injury. A transthoracic echocardiography showed left ventricular hypertrophy. A Cardiac magnetic resonance imaging suggested left ventricular endocardial edema or inflammation. Ophthalmoscopy showed optic disc edema and hard exudates in both eyes. A brain MRI showed multiple high-intensity areas at the pons and white matter of the cerebrum and cerebellum. Although the patient had malignant hypertension, she was successfully treated by medication.

Background: Liver cirrhosis is an end-stage multiple liver disease. Mesenchymal stem cells (MSCs) are an attractive cell source for reducing liver damage and regressing fibrosis; additional therapies accompanying MSCs can potentially enhance their therapeutic effects. Kampo medicines exhibit anti-inflammatory and anti-oxidative effects. Here, we investigated the therapeutic effect of MSCs combined with the Kampo medicine Juzentaihoto (JTT) as a combination therapy in a carbon tetrachloride (CCl4)-induced cirrhosis mouse model. Methods: C57BL/6 mice were administered JTT (orally) and/or MSCs (one time, intravenously). The levels of liver proteins were measured in the sera. Sirius Red staining and hydroxyproline quantitation of hepatic tissues and immune cells were conducted, and their associated properties were evaluated. Liver metabolomics of liver tissues was performed. Results: JTT monotherapy attenuated liver damage and increased serum albumin level, but it did not effectively induce fibrolysis. JTT rapidly reduced liver damage, in a dose-dependent manner, after a single-dose CCl4 administration. Furthermore, JTT-MSC combination therapy attenuated liver damage, improved liver function, and regressed liver fibrosis. The combination increased the CD4+/CD8+ ratio. JTT had stronger effects on NK and regulatory T cell induction, whereas MSCs more strongly induced anti-inflammatory macrophages. The combination therapy further induced anti-inflammatory macrophages. JTT normalized lipid mediators, and tricarboxylic acid cycle- and urea cycle-related mediators effectively. Conclusions: The addition of JTT enhanced the therapeutic effects of MSCs; this combination could be a potential treatment option for cirrhosis.

Abstract Gastric cancer (GC) is one of the most lethal malignant tumors. To improve the prognosis of GC, the identification of novel driver genes as therapeutic targets is in urgent need. Here, we aimed to identify novel driver genes and clarify their roles in gastric cancer. OSBPL3 was identified as a candidate driver gene by in silico analysis of public genomic datasets. OSBPL3 expression was analyzed by RT-qPCR and immunohistochemistry in GC cells and tissues. The biological functions and mechanisms of OSBPL3 in GC were examined in vitro and in vivo using GC cells. The association between OSBPL3 expression and clinical outcome in GC patients was also evaluated. Overexpression of OSBPL3 was detected in GC cells with OSBPL3 DNA copy number gains and promoter hypomethylation. OSBPL3-knockdown reduced GC cell growth in vitro and in vivo by inhibiting cell cycle progression. Moreover, an active Ras pull-down assay and western blotting demonstrated that OSBPL3 activates the R-Ras/Akt signaling pathway in GC cells. In a clinical analysis of two GC datasets, high OSBPL3 expression was predictive of a poor prognosis. Our findings suggest that OSBPL3 is a novel driver gene stimulating the R-Ras/Akt signaling pathway and a potential therapeutic target in GC patients.

A 13-year-old castrated male Toy Poodle presented with an acute vestibular disorder. Magnetic resonance imaging and computed tomography revealed a large oval space-occupying mass with skull destruction located from the subcutaneous tissue to the posterior fossa region. Histopathologically, the mass was a bundled growth of spindle-shaped mesenchymal tumor cells between the myofibrillar and collagen bundles. The cells were moderately irregular in size and had eosinophilic stained cytoplasm. The cells were highly atypical and had rare mitotic figures. Neoplastic cells were immunoreactive for S100, GFAP, Olig-2, SOX10 and immunonegative for NF, E-cadherin, and Claudin-1. Collective findings were presumptive with a diagnosis of malignant peripheral nerve sheath tumor.

Abstract Chronic undernutrition contributes to the increase in frailty observed among elderly adults, which is a pressing issue in the sector of health care for older people worldwide. Autophagy, an intracellular recycling system, is closely associated with age-related pathologies. Therefore, decreased autophagy in aging could be involved in the disruption of energy homeostasis that occurs during undernutrition; however, the physiological mechanisms underlying this process remain unknown. Here, we showed that 70% daily food restriction (FR) induced fatal hypoglycemia in 23–26-month-old (aged) mice, which exhibited significantly lower hepatic autophagy than 9-week-old (young) mice. The liver expressions of Bcl-2, an autophagy-negative regulator, and Beclin1–Bcl-2 binding, were increased in aged mice compared with young mice. The autophagy inducer Tat-Beclin1 D11, not the mTOR inhibitor rapamycin, decreased the plasma levels of the glucogenic amino acid and restored the blood glucose levels in aged FR mice. Decreased liver gluconeogenesis, body temperature, physical activity, amino acid metabolism, and hepatic mitochondrial dynamics were observed in the aged FR mice. These changes were restored by treatment with hochuekkito that is a herbal formula containing several autophagy-activating ingredients. Our results indicate that Bcl-2 upregulation in the liver during the aging process disturbs autophagy activation, which increases the vulnerability to undernutrition. The promotion of liver autophagy may offer clinical therapeutic benefits to frail elderly patients.

The technique most widely used to quantitatively measure leg edema is only a pitting edema method. It has recently become possible to digitize B-mode ultrasound images and accurately quantify their brightness using an image-analysis software program. The purpose of this study was to find new indices of the grade of leg skin, to study whether or not analyses of the subcutaneous layer of leg skin on ultrasound images using image-editing software program can be used to evaluate it and to digitize it. Images of 282 subcutaneous layers of leg skin in 141 pregnant women were obtained using a B-scan portable ultrasound device. Rectangular photographs (vertical: skin thickness; horizontal: width of probe) were obtained using an image-editing program, and the luminous intensity (pixel grayscale: 0–255) and thickness of the skin were calculated using a histogram. We investigated the correlation between these parameters and the grade of pitting edema (0–3). There was a significant positive correlation between the grade of pitting edema and the average luminous intensity value, its standard deviation, and the skin thickness (ρ = 0.36, ρ = 0.22, ρ = 0.51, p < 0.0001, respectively). In particular, there was strong positive correlation between the grade of pitting edema and both the total number of pixels in a rectangle × (multiplied by) the average luminous intensity value and the total number of pixels in a rectangle × the standard deviation of the average luminous intensity value (ρ = 0.58 and ρ = 0.59, p < 0.0001, respectively). We could quantitatively evaluate the grade of leg edema by analyzing ultrasound photographs of the subcutaneous layer of the leg skin using an image-editing software program and found new indices to digitize it.

A number of food components, such as polyphenols and phytonutrients, have immunomodulatory effects. Collagen has various bioactivities, such as antioxidative effects, the promotion of wound healing, and relieving symptoms of bone/joint disease. Collagen is digested into dipeptides and amino acids in the gastrointestinal tract and subsequently absorbed. However, the difference in immunomodulatory effects between collagen-derived dipeptides and amino acids is unknown. To investigate such differences, we incubated M1 macrophages or peripheral blood mononuclear cells (PBMC) with collagen-derived dipeptides (hydroxyproline-glycine (Hyp-Gly) and proline-hydroxyproline (Pro-Hyp)) and amino acids (proline (Pro), hydroxyproline (Hyp), and glycine (Gly)). We first investigated the dose dependency of Hyp-Gly on cytokine secretion. Hyp-Gly modulates cytokine secretion from M1 macrophages at 100 µM, but not at 10 µM and 1 µM. We then compared immunomodulatory effects between dipeptides and mixtures of amino acids on M1 macrophages and PBMC. There was, however, no difference in cytokine secretion between dipeptides and their respective amino acids. We conclude that collagen-derived dipeptides and amino acids have immunomodulatory effects on M1-differentiated RAW264.7 cells and PBMC and that there is no difference in the immunomodulatory effects between dipeptides and amino acids.

Malnutrition impairs basic daily activities and leads to physical frailty, which is aggravated in the elderly compared with young adults. It is also well-known that the elderly are more vulnerable to metabolic stress. Therefore, in this study, using a food restricted (FR) mouse, we aimed to evaluate the effect of aging on locomotor activity and liver metabolic function. Further, we also investigated the involvement of hepatic mitochondria in liver metabolic function during aging, as well as the therapeutic benefit of the traditional Japanese medicine, hochuekkito (HET). Our findings indicated that following food restriction provided as 30% of ad libitum intake for 5 days, the locomotor activity was lower in 23–26-month-old (aged) mice than in 9-week-old (young) mice. Further, compared with young mice, aged mice exhibited significant decreases in the levels of metabolites related to the urea cycle, mitochondrial function, and anti-oxidative stress. The livers of the aged mice also showed a greater decrease in mitochondrial DNA copy number than young mice. Furthermore, the gene expression levels of sirtuin 1 (SIRT1) and mitochondrial biogenesis-related regulators were attenuated in aged mice. However, these changes were partially restored by HET treatment, which also improved locomotor activity, and combined treatment with alanine resulted in more significant effects in this regard. Therefore, our findings suggested that the decrease in locomotor activity in aged FR mice was associated with a decline in the metabolic function of hepatic mitochondria via decreased SIRT1 expression, which was restored by HET treatment. This implies that enhancing the metabolic function of liver mitochondria can contribute to alleviating energy deficiency in the elderly.

A 27-year-old man visited our hospital after experiencing palpitations. His 12-lead electrocardiogram and chest radiograph were unremarkable. Blood test results showed normal plasma brain natriuretic peptide level (

This study aimed to use quantitative and qualitative evaluations based on micro-tensile bond strength (μTBS) to clarify the appropriate immediate dentin sealing (IDS) approach for improving the bonding of CAD/CAM ceramic crown restorations. Forty-eight extracted human molars were prepared to obtain standardized abutment specimens and divided into three groups: no IDS (group C: control), IDS performed by a single application of an all-in-one adhesive system (group A), and IDS performed by the combined application of an adhesive system and a flowable resin composite (group F). All specimens were restored with a ceramic crown fabricated by a chair-side CAD/CAM system and were divided into no-stress and stressed groups. After cyclic loading (78.5 N; total, 3 × 105 cycles; 90 cycles/min) on the specimens in the stressed group, all specimens were sectioned. The μTBS values for the occlusal and mesioaxial walls were measured (n = 16) and analyzed statistically. The quantitative bonding performance of groups A and F were superior to that of group C, regardless of the cyclic loading and abutment wall conditions. Group F showed the maximum bond strength and the highest bond durability in the qualitative bonding performance even under the cyclic loading condition simulating clinical mastication.

Background: One of the most common treatments for leg edema during pregnancy is the use of compression stockings. The purpose of this study was to evaluate the objective effectiveness in pregnant women, by measuring the changes of skin thickness using ultrasonography. Methods: Pregnant women were diagnosed with leg edema using the pitting edema method at 36 weeks of gestation. Twenty-four pregnant women (48 legs) with leg edema spent time without wearing elastic stockings at 36–37 weeks of gestation. Then, they wore elastic stockings for one week at 37–38 weeks of gestation. We measured the grade of edema (from 0 to 3) and the skin thickness of the lower leg by portable ultrasonography at 36, 37, and 38 weeks of gestation (a before-and-after study). Results: In 24 pregnant women, thigh edema was not detected in any of the 48 legs before or after the use of elastic stockings. All 48 legs in 24 pregnant women had physiological lower leg edema, but not thigh edema. The average grade of pitting edema in each lower leg significantly decreased after using the stockings (36 weeks, 1.77 ± 0.85; 37 weeks, 1.79 ± 0.77; 38 weeks, 1.04 ± 0.74, p < 0.0001). In addition, the skin thickness of the lower legs was significantly decreased after the use of elastic stockings (36 weeks, 7.47 ± 2.45 mm; 37 weeks, 7.93 ± 2.83 mm; 38 weeks, 7.15 ± 2.35 mm, p < 0.0001). Conclusions: The wearing of elastic compression stockings on the lower legs is objectively effective for improving leg edema in pregnant women.

(1) Background: A mouth-free interface is required for functional electrical stimulation (FES) in people with spinal cord injuries. We developed a novel system for clenching the human metacarpophalangeal (MP) joint using an earphone-type ear canal movement sensor. Experiments to control joint angle and joint stiffness were performed using the developed system. (2) Methods: The proposed FES used an equilibrium point control signal and stiffness control signal: electrical agonist–antagonist ratio and electrical agonist–antagonist sum. An angle sensor was used to acquire the joint angle, and system identification was utilized to measure joint stiffness using the external force of a robot arm. Each experiment included six and five subjects, respectively. (3) Results: While the joint angle could be controlled well by clenching with some hysteresis and delay in three subjects, it could not be controlled relatively well after hyperextension in the other subjects, which revealed a calibration problem and a change in the characteristics of the human MP joint caused by hyperextension. The joint stiffness increased with the clenching amplitude in five subjects. In addition, the results indicated that viscosity can be controlled. (4) Conclusions: The developed system can control joint angle and stiffness. In future research, we will develop a method to show that this system can control the equilibrium point and stiffness simultaneously.