Alzheimer’s disease (AD) is characterized by progressive cognitive deterioration and significant depression. However, the mechanisms linking depression to AD pathology remain unclear. Here, we investigated whether Notch2 signaling mediates depressionlike behaviors in presenilin-2 (PS2) N141I mutant mice, an early-onset AD model. PS2 wild-type (WT) and mutant (MT) mice aged 12-15 months were subjected to unpredictable chronic mild stress (UCMS) for 4 weeks, followed by sucrose preference, tail-hanging, and forced swimming tests. Behavioral assessments showed that UCMS exacerbated anhedonia and immobility only in PS2 MT mice. Molecular analysis revealed concomitant increases in plasma corticosterone, hippocampal γ-secretase activity, and Notch2 expression, and elevated total and phosphorylated glucocorticoid receptor levels in PS2 MT-UCMS mice. Gene expression profiling of human hippocampal datasets confirmed upregulation of NOTCH2 in Alzheimer’s disease and depression.Pharmacological inhibition of γ-secretase and Notch signaling with DAPT normalizes depressive behavior, reduces corticosterone release, attenuates GR phosphorylation, and inhibits Notch2 signaling in PS2 MT mice. These findings identify Notch2 as a pivotal mediator linking chronic stress to molecular changes associated with depression and AD, and suggest that targeting Notch2 signaling may provide therapeutic benefits for comorbid mood and neurodegenerative disorders.

Purpose: This study analyzed changes in body composition and physical fitness in men with testosterone deficiency (TD) after testosterone treatment (TT) and examined the correlations of body composition and physical fitness with serum testosterone levels and hypogonadal symptoms. Materials and Methods: Seventy patients with TD were divided into control (group I, n=23) and experimental (group II, n=47) groups. Patients in the experimental group were administered intramuscular testosterone enanthate (250 mg) for six months. The aging males symptom scale (AMS) score, international prostate symptom score (IPSS), body mass index, waist circumference, and serum laboratory values were measured at baseline and at the end of the study. Bioelectrical impedance analysis was used to assess the patients’ body composition. Seven types of basic exercise tests were used to evaluate the patients’ physical fitness. Results: After six months, there were no significant differences in group I, while group II had significantly improved IPSS and AMS scores; increased hemoglobin, hematocrit, prostate-specific antigen, and testosterone levels and skeletal muscle mass; and waist circumference, and body fat mass. All elements of the physical fitness test were significantly improved in group II, with the exceptions of flexibility and endurance. Decreased waist circumference was correlated with changes in testosterone levels in group II, and the IPSS, cardiorespiratory fitness, and agility were correlated with improved hypogonadal symptoms. Conclusions TT improved the hypogonadal and lower urinary tract symptoms in patients with TD and improved body composition, physical fitness, and metabolic syndrome parameters. Increased testosterone and improved hypogonadal symptoms were correlated with a decrease in waist circumference and an improvement in cardiorespiratory fitness and agility. As such, when implementing TT, we should consider whether these areas may be improved, as this can help to predict the effect.

BACKGROUND: Collagen is a key component of connective tissue and has been frequently used in the fabrication of medical devices for tissue regeneration. Human-originated collagen is particularly appealing due to its low immune response as an allograft biomaterial compared to xenografts and its ability to accelerate the regeneration process. Ethically and economically, adipose tissues available from liposuction clinics are a good resource to obtain human collagen.However, studies are still scarce on the extraction and characterization of human collagen, which originates from adipose tissue. The aim of this study is to establish a novel and simple method to extract collagen from human adipose tissue, characterize the collagen, and compare it with commercial-grade porcine collagen for tissue engineering applications. METHODS: We developed a method to extract the collagen from human adipose tissue under quasi-Good Manufacturing Practice (GMP) conditions, including freezing the tissue, blood removal, and ethanol-based purification. Various techniques, including protein quantification, decellularization assessment, SDS-PAGE, FTIR, and CD spectroscopy analysis, were used for characterization. Amino acid composition was compared with commercial collagen. Biocompatibility and cell proliferation tests were performed, and in vitro tests using collagen sponge scaffolds were conducted with statistical analysis. RESULTS: Our results showed that this human adipose-derived collagen was equivalent in quality to commercially available porcine collagen. In vitro testing demonstrated high cell attachment and the promotion of cell proliferation. CONCLUSION In conclusion, we developed a simple and novel method to extract and characterize collagen and extracellular matrix from human adipose tissue, offering a potential alternative to animal-derived collagen for xeno-free tissue engineering applications.

Background: Heterotopic ossification (HO) is difficult to characterize and classify on simple radiographs. Therefore, we attempted to evaluate intraobserver and interobserver reliability of simple radiography and computed tomography (CT) for detecting and classifying HO after reverse shoulder arthroplasty (RSA). It was hypothesized that CT would provide more reliable results than simple radiography. Methods: This retrospective study reviewed 30 patients who underwent RSA performed by a single surgeon. Patients were included if they had both postoperative simple radiographs and CT images taken immediately after surgery and at 1 year after surgery and if they had completed clinical assessment at least 1 year after surgery. We first evaluated the intraobserver and interobserver reliability for the detection of the presence of HO and Modified Brooker’s classification both on simple radiographs and CT scans with the use of Kappa statistics. Then, we analyzed the correlation of HO observed in simple radiographs and CT scans with clinical outcomes. All radiographic evaluations were performed by 2 independent reviewers in random orders with 3 weeks of intervals. Results: The intraobserver reliability outcomes of both reviewers in simple radiography and CT were almost perfect or perfect for the detection of HO and classification. However, CT images improved the interobserver reliability for the detection of HO (kappa value for simple radiographs [KXR ] = 0.6018 and kappa value for CT [KCT ] = 0.8316) and classification (KXR = 0.5300 and KCT = 0.6964).At a mean follow-up of 25 months (range, 12–54 months), clinical scores were not significantly different according to the presence of HO based on simple radiographs. However, when CT images were used, the University of California, Los Angeles score and physical component score of short-form 36-item health survey were significantly lower in patients with HO than in patients without HO (27.0 vs. 30.4, p = 0.045 and 57.6 vs. 70.7, p = 0.034, respectively). Conclusions Both simple radiography and CT provided excellent intraobserver reliability for detecting and classifying HO after RSA. Compared to simple radiography, CT tended to improve interobserver reliability and defined the presence and severity of HO more clearly.

We investigated whether endurance exercise training (EXT) ameliorates circadian rhythm (CR)-induced risk factors by improving skeletal muscle (SKM) mitochondrial biogenesis, reducing oxidative stress, and modulating apoptotic protein expression. We distinguished between regular and shift workers using the National Health and Nutrition Examination Survey (NHANES) and investigated the health problems caused by shift work (CR disturbance) and the potential therapeutic effects of exercise. In our animal study, 36 rats underwent 12 weeks of CR disturbance, divided into regular and irregular CR groups. These groups were further split into EXT (n = 12) and sedentary (n = 12) for an additional 8 weeks. We analyzed SKM tissue to understand the molecular changes induced by CR and EXT. NHANES data were analyzed using SAS 9.4 and Prism 8 software, while experimental animal data were analyzed using Prism 8 software. The statistical procedures used in each experiment are indicated in the figure legends. Our studies showed that CR disturbance increases dyslipidemia, alters circadian clock proteins (BMAL1, PER2), raises apoptotic protein levels, and reduces mitochondrial biogenesis in SKM. EXT improved LDL-C and HDLC levels without affecting muscle BMAL1 expression. It also enhanced mitochondrial biogenesis (AMPK, PGC-1α, Tfam, NADH-UO, COX-I), antioxidant levels (Catalase, SOD1, SOD2), and apoptotic protein (p53, Bax/Bcl2) expression or activity in SKM. We demonstrated that shift work-induced CR disturbance leads to dyslipidemia, diminished mitochondrial biogenesis, and reduced antioxidant capacity in SKM. However, EXT can counteract dyslipidemia under CR disturbance, potentially lowering the risk of cardiovascular disorders.

Purpose: This study aimed to determine whether micro-flow imaging (MFI) offers diagnostic performance comparable to that of contrast-enhanced ultrasonography (CEUS) in detecting segmental congestion among patients undergoing living donor liver transplantation (LDLT). Methods: Data from 63 patients who underwent LDLT between May and December 2022 were retrospectively analyzed. MFI and CEUS data collected on the first postoperative day were quantified. Segmental congestion was assessed based on imaging findings and laboratory data, including liver enzymes and total bilirubin levels. The reference standard was a postoperative contrast-enhanced computed tomography scan performed within 2 weeks of surgery. Additionally, a subgroup analysis examined patients who underwent reconstruction of the middle hepatic vein territory. Results: The sensitivity and specificity of MFI were 73.9% and 67.5%, respectively. In comparison, CEUS demonstrated a sensitivity of 78.3% and a specificity of 75.0%. These findings suggest comparable diagnostic performance, with no significant differences in sensitivity (P=0.655) or specificity (P=0.257) between the two modalities. Additionally, early postoperative laboratory values did not show significant differences between patients with and without congestion. The subgroup analysis also indicated similar diagnostic performance between MFI and CEUS. Conclusion MFI without contrast enhancement yielded results comparable to those of CEUS in detecting segmental congestion after LDLT. Therefore, MFI may be considered a viable alternative to CEUS.

Background: Heterotopic ossification (HO) is difficult to characterize and classify on simple radiographs. Therefore, we attempted to evaluate intraobserver and interobserver reliability of simple radiography and computed tomography (CT) for detecting and classifying HO after reverse shoulder arthroplasty (RSA). It was hypothesized that CT would provide more reliable results than simple radiography. Methods: This retrospective study reviewed 30 patients who underwent RSA performed by a single surgeon. Patients were included if they had both postoperative simple radiographs and CT images taken immediately after surgery and at 1 year after surgery and if they had completed clinical assessment at least 1 year after surgery. We first evaluated the intraobserver and interobserver reliability for the detection of the presence of HO and Modified Brooker’s classification both on simple radiographs and CT scans with the use of Kappa statistics. Then, we analyzed the correlation of HO observed in simple radiographs and CT scans with clinical outcomes. All radiographic evaluations were performed by 2 independent reviewers in random orders with 3 weeks of intervals. Results: The intraobserver reliability outcomes of both reviewers in simple radiography and CT were almost perfect or perfect for the detection of HO and classification. However, CT images improved the interobserver reliability for the detection of HO (kappa value for simple radiographs [KXR ] = 0.6018 and kappa value for CT [KCT ] = 0.8316) and classification (KXR = 0.5300 and KCT = 0.6964).At a mean follow-up of 25 months (range, 12–54 months), clinical scores were not significantly different according to the presence of HO based on simple radiographs. However, when CT images were used, the University of California, Los Angeles score and physical component score of short-form 36-item health survey were significantly lower in patients with HO than in patients without HO (27.0 vs. 30.4, p = 0.045 and 57.6 vs. 70.7, p = 0.034, respectively). Conclusions Both simple radiography and CT provided excellent intraobserver reliability for detecting and classifying HO after RSA. Compared to simple radiography, CT tended to improve interobserver reliability and defined the presence and severity of HO more clearly.

Purpose: This study aimed to determine whether micro-flow imaging (MFI) offers diagnostic performance comparable to that of contrast-enhanced ultrasonography (CEUS) in detecting segmental congestion among patients undergoing living donor liver transplantation (LDLT). Methods: Data from 63 patients who underwent LDLT between May and December 2022 were retrospectively analyzed. MFI and CEUS data collected on the first postoperative day were quantified. Segmental congestion was assessed based on imaging findings and laboratory data, including liver enzymes and total bilirubin levels. The reference standard was a postoperative contrast-enhanced computed tomography scan performed within 2 weeks of surgery. Additionally, a subgroup analysis examined patients who underwent reconstruction of the middle hepatic vein territory. Results: The sensitivity and specificity of MFI were 73.9% and 67.5%, respectively. In comparison, CEUS demonstrated a sensitivity of 78.3% and a specificity of 75.0%. These findings suggest comparable diagnostic performance, with no significant differences in sensitivity (P=0.655) or specificity (P=0.257) between the two modalities. Additionally, early postoperative laboratory values did not show significant differences between patients with and without congestion. The subgroup analysis also indicated similar diagnostic performance between MFI and CEUS. Conclusion MFI without contrast enhancement yielded results comparable to those of CEUS in detecting segmental congestion after LDLT. Therefore, MFI may be considered a viable alternative to CEUS.

Background: It is well known that a large number of patients with diabetes also have dyslipidemia, which significantly increases the risk of cardiovascular disease (CVD). This study aimed to evaluate the efficacy and safety of combination drugs consisting of metformin and atorvastatin, widely used as therapeutic agents for diabetes and dyslipidemia. Methods: This randomized, double-blind, placebo-controlled, parallel-group and phase III multicenter study included adults with glycosylated hemoglobin (HbA1c) levels >7.0% and <10.0%, low-density lipoprotein cholesterol (LDL-C) >100 and <250 mg/dL. One hundred eighty-five eligible subjects were randomized to the combination group (metformin+atorvastatin), metformin group (metformin+atorvastatin placebo), and atorvastatin group (atorvastatin+metformin placebo). The primary efficacy endpoints were the percent changes in HbA1c and LDL-C levels from baseline at the end of the treatment. Results: After 16 weeks of treatment compared to baseline, HbA1c showed a significant difference of 0.94% compared to the atorvastatin group in the combination group (0.35% vs. −0.58%, respectively; P<0.0001), whereas the proportion of patients with increased HbA1c was also 62% and 15%, respectively, showing a significant difference (P<0.001). The combination group also showed a significant decrease in LDL-C levels compared to the metformin group (−55.20% vs. −7.69%, P<0.001) without previously unknown adverse drug events. Conclusion The addition of atorvastatin to metformin improved HbA1c and LDL-C levels to a significant extent compared to metformin or atorvastatin alone in diabetes and dyslipidemia patients. This study also suggested metformin’s preventive effect on the glucose-elevating potential of atorvastatin in patients with type 2 diabetes mellitus and dyslipidemia, insufficiently controlled with exercise and diet. Metformin and atorvastatin combination might be an effective treatment in reducing the CVD risk in patients with both diabetes and dyslipidemia because of its lowering effect on LDL-C and glucose.

Background: Heterotopic ossification (HO) is difficult to characterize and classify on simple radiographs. Therefore, we attempted to evaluate intraobserver and interobserver reliability of simple radiography and computed tomography (CT) for detecting and classifying HO after reverse shoulder arthroplasty (RSA). It was hypothesized that CT would provide more reliable results than simple radiography. Methods: This retrospective study reviewed 30 patients who underwent RSA performed by a single surgeon. Patients were included if they had both postoperative simple radiographs and CT images taken immediately after surgery and at 1 year after surgery and if they had completed clinical assessment at least 1 year after surgery. We first evaluated the intraobserver and interobserver reliability for the detection of the presence of HO and Modified Brooker’s classification both on simple radiographs and CT scans with the use of Kappa statistics. Then, we analyzed the correlation of HO observed in simple radiographs and CT scans with clinical outcomes. All radiographic evaluations were performed by 2 independent reviewers in random orders with 3 weeks of intervals. Results: The intraobserver reliability outcomes of both reviewers in simple radiography and CT were almost perfect or perfect for the detection of HO and classification. However, CT images improved the interobserver reliability for the detection of HO (kappa value for simple radiographs [KXR ] = 0.6018 and kappa value for CT [KCT ] = 0.8316) and classification (KXR = 0.5300 and KCT = 0.6964).At a mean follow-up of 25 months (range, 12–54 months), clinical scores were not significantly different according to the presence of HO based on simple radiographs. However, when CT images were used, the University of California, Los Angeles score and physical component score of short-form 36-item health survey were significantly lower in patients with HO than in patients without HO (27.0 vs. 30.4, p = 0.045 and 57.6 vs. 70.7, p = 0.034, respectively). Conclusions Both simple radiography and CT provided excellent intraobserver reliability for detecting and classifying HO after RSA. Compared to simple radiography, CT tended to improve interobserver reliability and defined the presence and severity of HO more clearly.