RNA sequencing provides novel insights into the pathogenesis of naturally occurring myxomatous mitral valve disease stage B1 in beagle dogs.

Myxomatous mitral valve disease (MMVD) is the most common cardiovascular disorder in dogs with a high prevalence, accounting for approximately 75% of all canine heart disease cases. MMVD is a complex disease and shows variable progression from mild valve leakage to severe regurgitation, potentially leading to heart failure. However, the molecular mechanisms and age-related changes that govern disease progression, especially at the early stage (B1) before the development of discernable clinical signs, remain poorly understood. In this prospective study, we aimed to compare gene expression differences between blood samples of aged beagle dogs with stage B1 MMVD and those of healthy controls using RNA sequencing. Clinical evaluation was also conducted, which revealed minimal differences in radiographic and echocardiographic measurements despite distinct biomarker variations between the two groups. Comparative transcriptomics revealed differentially expressed genes associated with extracellular matrix remodeling, prostaglandin metabolism, immune modulation, and interferon-related pathways, which bear functional relevance for MMVD. In particular, the top 10 over- and under-expressed genes represent promising candidates for influencing pathogenic changes in MMVD stage B1. Our research findings, which include identified variations in clinical markers and gene expression, enhance our understanding of MMVD. Furthermore, they underscore the need for further research into early diagnosis and treatment strategies, as, to the best of our knowledge, no prior studies have explored the precise molecular mechanisms of stage B1 in MMVD through total RNA sequencing.

Investigating the Impact of Mechanical Properties and Cell-Collagen Interaction on NIH3T3 Function: A Comparative Study on Different Substrates and Culture Environments.

This study investigates the intricate dynamics of matrix stiffness, substrate composition, and cell-cell interactions and elucidates their cumulative effects on fibroblast behavior in different culture contexts. Three primary substrate types were examined: non-coated, collagen-coated, and collagen hydrogel, within both two-dimensional (2D) monolayer and three-dimensional (3D) spheroid cultures. The research provides several key insights. First, 3D spheroid culture, which promotes robust cell-cell interactions, emerges as a critical factor in maintaining fibroblast functionality. Second, substrate stiffness significantly influences results, with the soft collagen hydrogel showing superior support for fibroblast function. Notably, fibroblasts cultured on collagen hydrogel in 2D exhibit comparable functionality to those in 3D, highlighting the importance of substrate mechanical properties. Third, surface composition, as exemplified by collagen coating, showed a limited effect compared to the other factors studied. These findings provide a basis for innovative applications in regenerative medicine, tissue engineering, and drug testing models, and offer valuable insights into harnessing the potential of fibroblasts and advancing biomedical sciences.

Mortality and causes of death in patients with Parkinson's disease: a nationwide population-based cohort study.

Objective: Parkinson's disease (PD) is a neurodegenerative disease involving multiple systems that can affect mortality. This study aimed to compare all-cause and cause-specific mortality between people with PD and without PD. Methods: This population-based prospective cohort study is based on Korean National Health Insurance Service data. The primary outcome was the hazard ratio (HR) of all-cause and cause-specific mortality for PD from 2010 to 2019. Cox proportional hazards regression was applied to calculate HRs under crude and three adjusted models with epidemiologic variables. Results: A total of 8,220 PD patients and 41,100 age- and sex-matched controls without PD were registered. Ten-year mortality was 47.9% in PD patients and 20.3% in non-PD controls. The mortality rate was higher among older and male participants. The leading cause of death in PD was nervous system diseases (38.73%), and 97.1% of those were extrapyramidal and movement disorders, followed by circulatory diseases (15.33%), respiratory diseases (12.56%), and neoplasms (9.7%). PD contributed to an increased risk of all-cause death with an HR of 2.96 (95% CI = 2.84-3.08). HRs of death for PD were 3.07 (95% CI = 2.74-3.45) from respiratory diseases, 1.93 (95% CI = 1.75-2.13) from circulatory diseases, 2.35 (95% CI = 2.00-2.77) from external causes, and 2.69 (95% CI = 2.10-3.43) from infectious diseases. Conclusion: These results showed that PD was related to a higher risk of mortality in all ages and sexes. The leading causes of death in PD were nervous, circulatory, respiratory, infectious diseases, and external causes.

Low Muscle and High Fat Percentages Are Associated with Low Natural Killer Cell Activity: A Cross-Sectional Study.

This study aimed to investigate whether body fat and muscle percentages are associated with natural killer cell activity (NKA). This was a cross-sectional study, conducted on 8058 subjects in a medical center in Korea. The association between the muscle and fat percentage tertiles and a low NKA, defined as an interferon-gamma level lower than 500 pg/mL, was assessed. In both men and women, the muscle mass and muscle percentage were significantly low in participants with a low NKA, whereas the fat percentage, white blood cell count, and C-reactive protein (CRP) level were significantly high in those with a low NKA. Compared with the lowest muscle percentage tertile as a reference, the fully adjusted odd ratios (ORs) (95% confidence intervals (CIs)) for a low NKA were significantly lower in T2 (OR: 0.69; 95% CI: 0.55-0.86) and T3 (OR: 0.74; 95% CI: 0.57-0.95) of men, and T3 (OR: 0.76; 95% CI: 0.59-0.99) of women. Compared with the lowest fat percentage tertile as a reference, the fully adjusted OR was significantly higher in T3 of men (OR: 1.31; 95% CI: 1.01-1.69). A high muscle percentage was significantly inversely associated with a low NKA in men and women, whereas a high fat percentage was significantly associated with a low NKA in men.

Clinical Significance of Physical Frailty in Subjects With Subjective Cognitive Decline: A Prospective Study With Amyloid PET Data.

BACKGROUND AND PURPOSE: Physical frailty is known to be closely associated with cognitive impairment and to be an early sign of Alzheimer's disease. We aimed to understand the characteristics of physical frailty and define factors associated with physical frailty in subjects with subjective cognitive decline (SCD) by analyzing amyloid data. METHODS: We prospectively enrolled subjects with SCD from a cohort study to identify predictors for the clinical progression to mild cognitive impairment or dementia from SCD (CoSCo). All of the subjects underwent brain magnetic resonance imaging, and brain amyloid positron-emission tomography (PET) to detect amyloid beta plaques. Self-reported exhaustion, handgrip strength, and gait speed were used to measure physical frailty. RESULTS: Of 120 subjects with SCD, 26 (21.7%) were amyloid-positive in PET. Female (odds ratio [OR]=3.79, p=0.002) and amyloid-PET-positive (OR=3.80, p=0.008) subjects with SCD were at high risks of self-reported exhaustion. Amyloid PET positivity (OR=3.22, p=0.047) and high burden from periventricular white-matter hyperintensity (OR=3.34, 95% confidence interval=1.18-9.46, p=0.023) were significantly associated with a weaker handgrip. The subjects with SCD with self-reported exhaustion and weaker handgrip presented with lower cognitive performance in neuropsychological tests, especially for information processing speed and executive function. Subjects with a slower gait performed worse in visual memory function tests. CONCLUSIONS: Amyloid PET positivity was associated with a higher risk of self-reported exhaustion and weaker handgrip in subjects with SCD. The subjects with SCD and physical frailty also performed worse in neuropsychological tests.

Relationship between Serum Cortisol, Dehydroepiandrosterone Sulfate (DHEAS) Levels, and Natural Killer Cell Activity: A Cross-Sectional Study.

The adrenal steroid hormones, cortisol and dehydroepiandrosterone sulfate (DHEAS), are associated with the immune system in opposite actions. This study aimed to investigate the relationship between cortisol and DHEAS serum concentrations, their ratio (CDR), and natural killer cell activity (NKA). This cross-sectional study included 2275 subjects without current infection or inflammation in the final analyses. NKA was estimated by measuring the amount of interferon-gamma (IFN-γ) released by activated natural killer cells; low NKA was defined as IFN-γ level < 500 pg/mL. Cortisol, DHEAS levels, and CDRs were categorized by quartiles in men, premenopausal women, and postmenopausal women. Compared with the lowest quartile as reference, the adjusted odd ratios (ORs) and 95% confidence intervals (CIs) for low NKA of the highest cortisol and CDR group were 1.66 (1.09-2.51) and 1.68 (1.11-2.55) in men, 1.58 (1.07-2.33) and 2.33 (1.58-3.46) in premenopausal women, and 2.23 (1.28-3.87) and 1.85 (1.07-3.21) in postmenopausal women. Only in premenopausal women, the highest DHEAS group showed significantly lower risk of low NKA (OR: 0.51, 95% CI: 0.35-0.76). HPA axis activation indicated as high cortisol level, CDR was significantly associated with low NKA, while high DHEAS levels were inversely associated with low NKA in premenopausal women.

Oxidative balance score is inversely associated with the incidence of non-alcoholic fatty liver disease.

BACKGROUND & AIMS: The contribution of the balance between overall oxidative stress and antioxidant status in non-alcoholic fatty liver disease (NAFLD) is unclear. The oxidative balance score (OBS) comprises dietary and lifestyle pro- and antioxidant components that indicate the overall oxidative stress burden. We investigated the association between OBS and the incidence of NAFLD in middle-aged and older Korean adults. METHODS: Among the 10,030 participants of the Korean Genome and Epidemiology Study_Ansan and Ansung cohort, 5065 without NAFLD at baseline were selected for secondary analysis. OBS was categorized into quartiles. Multiple Cox proportional hazard regression analyses were performed to estimate the hazard ratio (HR) and 95% confidence interval (CI) for NAFLD incidence by sex-specific OBS quartile groups after adjusting for confounders. RESULTS: During the follow-up period (median 13.4 years), 913 (43.2%) men and 1288 (43.9%) women were newly diagnosed with NAFLD. Compared with that of the lowest quartile (Q1) group, the adjusted HR (95% CI) for NAFLD incidence in Q2, Q3, and Q4 groups was 0.85 (0.71-1.00), 0.65 (0.54-0.78), and 0.50 (0.40-0.62) in men, and 0.85 (0.73-0.99), 0.66 (0.56-0.77), and 0.48 (0.40-0.59) in women, respectively, and for NAFLD incidence, per incremental change in OBS, was 0.90 (0.87-0.92) in men and 0.88 (0.86-0.90) in women. CONCLUSIONS: A higher OBS was significantly associated with a lower risk for NAFLD incidence. Maintaining a healthy lifestyle and an antioxidant-rich diet is a potentially viable strategy for preventing NAFLD.

Multi-organ metastases of primary chondrosarcoma of the mammary gland of a spayed Toy Poodle.

We report the clinical and histopathological findings associated with multi-organ metastases of primary mammary chondrosarcoma in a 12-year-old spayed female Toy Poodle. At post-mortem examination, multifocal, sharply demarcated, grey-white to bright brown, round nodules of variable size were randomly distributed in the lungs, myocardium, liver, pancreas, spleen, intestinal tract and kidneys. Histologically, immature cartilage structures and primitive mesenchymal cells were seen in these organs. Neoplastic cells located in the cartilaginous basophilic extracellular matrix had cytoplasmic vacuolation and round vesicular nuclei and were stained with Safranin O and Alcian blue. To the best of our knowledge, this is the first report of a multi-organ metastatic chondrosarcoma that originated in the mammary gland of a dog.

Clinical characteristics of acute kidney injury in patients with glyphosate surfactant herbicide poisoning.

BACKGROUND: In this study, we investigated the clinical characteristics of acute kidney injury (AKI) in patients with glyphosate surfactant herbicide (GSH) poisoning. METHODS: This study was performed between 2008 and 2021 and included 184 patients categorized into the AKI (n = 82) and nonAKI (n = 102) groups. The incidence, clinical characteristics, and severity of AKI were compared between the groups based on the Risk of renal dysfunction, Injury to the kidney, Failure or Loss of kidney function, and End-stage kidney disease (RIFLE) classification. RESULTS: The incidence of AKI was 44.5%, of which 25.0%, 6.5%, and 13.0% of patients were classified into the Risk, Injury, and Failure categories, respectively. Patients in the AKI group were older (63.3 ± 16.2 years vs. 57.4 ± 17.5 years, p = 0.02) than those in the non-AKI group. The length of hospitalization was longer (10.7 ± 12.1 days vs. 6.5 ± 8.1 days, p = 0.004) and hypotensive episodes occurred more frequently in the AKI group (45.1% vs. 8.8%, p < 0.001). Electrocardiographic (ECG) abnormalities on admission were more frequently observed in the AKI group than in the non-AKI group (80.5% vs. 47.1%, p < 0.001). Patients in the AKI group had poorer renal function (estimated glomerular filtration rate at the time of admission, 62.2 ± 22.9 mL/min/1.73 m2 vs. 88.9 ± 26.1 mL/min/1.73 m2 , p < 0.001) on admission. The mortality rate was higher in the AKI group than in the non-AKI group (18.3% vs. 1.0%, p < 0.001). Multiple logistic regression analysis showed that hypotension and ECG abnormalities upon admission were significant predictors of AKI in patients with GSH poisoning. CONCLUSION: The presence of hypotension on admission may be a useful predictor of AKI in patients with GSH intoxication.

A National Referral Service for Paediatric Brachytherapy: An Evolving Practice and Outcomes Over 13 Years.

AIMS: Most children requiring radiotherapy receive external beam treatment and few have tumours suitable for brachytherapy. No paediatric radiotherapy centre will treat enough patients from its own normal catchment population for expertise in brachytherapy to be developed and sustained. Following discussion and agreement in the national paediatric radiotherapy group, a service for paediatric brachytherapy in the UK has been developed. We report the process that has evolved over more than 10 years, with survival and functional outcome results. MATERIALS AND METHODS: Since 2009, potential patients have been referred to the central paediatric oncology multidisciplinary team meeting, where imaging, pathology and treatment options are discussed. Since 2013, the National Soft Tissue Sarcoma Advisory Panel has also reviewed most patients, with the principal aim of advising on the most suitable primary tumour management for complex patients. Clinical assessment and examination under anaesthetic with biopsies may be undertaken to confirm the appropriateness of brachytherapy, either alone or following conservative surgery. Fractionated high dose rate brachytherapy was delivered to a computed tomography planned volume after implantation of catheters under ultrasound imaging guidance. Since 2019, follow-up has been in a dedicated multidisciplinary clinic. RESULTS: From 2009 to 2021 inclusive, 35 patients (16 female, 19 male, aged 8 months to 17 years 6 months) have been treated. Histology was soft-tissue sarcoma in 33 patients and carcinoma in two. The treated site was pelvic in 31 patients and head and neck in four. With a median follow-up of 5 years, the local control and overall survival rates are 100%. Complications have been few, and functional outcome is good. CONCLUSION: Brachytherapy is effective for selected paediatric patients, resulting in excellent tumour control and good functional results. It is feasible to deliver paediatric brachytherapy at a single centre within a national referral service.

Self-directed learning quotient and common learning types of pre-medical students in Korea by the Multi-Dimensional Learning Strategy Test 2nd edition: a descriptive study.

This study aimed to find the self-directed learning quotient and common learning types of pre-medical students through the confirmation of 4 characteristics of learning strategies, including personality, motivation, emotion, and behavior. The response data were collected from 277 out of 294 target first-year pre-medical students from 2019 to 2021, using the Multi-Dimensional Learning Strategy Test 2nd edition. The most common learning type was a self-directed type (44.0%), stagnant type (33.9%), latent type (14.4%), and conscientiousness type (7.6%). The self-directed learning index was high (29.2%), moderate (24.6%), somewhat high (21.7%), somewhat low (14.4%), and low (10.1%). This study confirmed that many students lacked self-directed learning capabilities for learning strategies. In addition, it was found that the difficulties experienced by each student were different, and the variables resulting in difficulties were also diverse. It may provide insights into how to develop programs that can help students increase their self-directed learning capability.

Dynamic Changes of Carotid Atherosclerosis and Their Relation with Stroke Recurrence in Patients with Stroke or Transient Ischemic Attack.

BACKGROUND AND PURPOSE: The purpose of this study was to show dynamic changes in carotid and vertebral artery using carotid Doppler ultrasonography (DUS) through a long-term follow- up exam, and determine their associations with stroke recurrence. METHODS: We consecutively enrolled stroke or transient ischemic attack (TIA) patients who had undergone DUS more than twice with intervals of three months or more. Stroke recurrence during follow-up was also investigated by reviewing medical records. Progress or regress of plaque was defined as more than 0.1 mm change from the initial scan with a semi-quantitative measurement. The development of new plaque was also regarded as plaque progress. Increased intima-media thickness and plaque presence were interpreted at the initial and follow-up scans. Factors related to progression or regression were analyzed. The relationship between plaque change and stroke recurrence was investigated. RESULTS: A total of 201 patients were enrolled (186 ischemic stroke patients and 15 TIA patients). There were 61 (30.3%) females. Their mean age was 64.2 ± 9.9 years. During a follow-up of 35.0 ± 22.6 (mean ± SD) months, plaque progress was observed in 92 (45.8%) and plaque regress in 13 (6.5%). Stroke recurred in 18 patients. Plaque progression showed no significant association with age, risk factors, statin use, or subtype. After adjustment of age, sex, diabetes, and stroke subtype, multiple logistic regression showed a significant association of plaque progression with stroke recurrence (odds ratio: 3.8, 95% confidence interval: 1.1 to 13.1, p = 0.034). Patients with plaque regress were significantly younger than those without plaque regress (57.8 years vs. 64.6 years, p = 0.041). CONCLUSION: Plaque progression occurred in 46% of stroke or TIA patients. Plaque progression was significantly associated with clinical stroke recurrence. Plaque regressed in 6.5% of patients. Patients with regression were younger than those without.

Effects of Single Nucleotide Polymorphisms and Mediterranean Diet in Overweight or Obese Postmenopausal Women With Breast Cancer Receiving Adjuvant Hormone Therapy: A Pilot Randomized Controlled Trial.

Background and Aims: Weight management is recommended in overweight or obese breast cancer patients, as they have an increased risk of cancer recurrence and poor prognosis. Furthermore, identifying the relationships between genetic factors and nutrition could help suggest possible individualized nutritional solutions in weight management. The objective of this pilot randomized controlled trial was to investigate the influence of two obesity-associated single nucleotide polymorphisms and the Mediterranean diet intervention on weight loss and modification of nutrient intake and metabolic parameters in overweight or obese, postmenopausal, breast cancer patients receiving adjuvant hormone therapy. Methods: Seventy-eight breast cancer patients were randomly assigned to the Mediterranean diet (MeDiet) group or control group, and seventy-one were finally analyzed. Body composition, nutrient intake, and metabolic parameters were assessed at baseline and after the 8-week intervention. Fat mass and obesity-associated (FTO) rs7185735 and melanocortin-4 receptor (MC4R) rs476828 variants were genotyped. Results: We found that both variants did not influence weight loss or improvement of metabolic parameters within the Mediterranean diet intervention. Intake of saturated fatty acid (SFA) and trans fat was significantly increased in C carriers compared with the TT genotype of MC4R rs476828 only in the control group (p = 0.002 for SFA; p = 0.016 for trans fat), whereas no significant difference was observed between genotypes in the MeDiet group. There were statistically significant interactions between MC4R rs476828 and dietary intervention for changes in SFA intake (p = 0.009) and trans fat intake (p = 0.049). Conclusion: Our data suggest that considering the effects of genotype may be more necessary when the Mediterranean diet is not followed and that this diet may have a protective role against the effects of certain genotypes. Further studies are required to determine the potential mechanism of the observed gene-diet interaction. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT04045392].

RNF43 R117fs mutant positively regulates Wnt/ß-catenin signaling by failing to internalize FZD expressed on the cell surface.

RING finger protein 43 (RNF43) encodes the transmembrane E3 ubiquitin ligase, which targets the Wnt receptor Frizzled (FZD). RNF43 mutations have been discovered in various human cancers including colon, pancreatic, stomach, ovarian, and liver cancers. Functional studies on RNF43 missense mutations have shown that they negatively regulate Wnt signaling; however, there are few functional studies on RNF43 frameshift mutations. In this study, we showed that R117fs and P441fs mutants enhanced Wnt/ß-catenin signaling, whereas Q409fs and G659fs mutants retained the ability to suppress Wnt/ß-catenin signaling. Specifically, R117fs was unable to ubiquitinate FZD5 due to lack of the RING domain, although it was able to interact with FZD5. Immunofluorescence showed that R117fs failed to internalize FZD5 expressed on the cell surface. We also showed that LGK974, a potent Wnt inhibitor, decreased the Wnt/ß-catenin activity by R117fs and P441fs mutations. Together, these results demonstrate that RNF43 frameshift mutations retain normal functionality; thus, targeted anti-cancer therapy can be developed according to the mutation type of RNF43.

A Rare Case of Spinal Epidural Abscess Following Urinary Tract Infection Caused by Escherichia coli in a Patient with Pre-existing Stress Fractures of the Lumbar Spine.

Spinal epidural abscess (SEA) caused by Escherichia coli is an uncommon condition. It usually occurs secondary to urinary tract infection (UTI), following hematogenous propagation. Disruption of spinal anatomic barriers increases susceptibility to SEA. Although rarely, such disruption can take the form of lumbar spine stress fractures, which can result from even innocuous activity. Here, we describe a case of SEA secondary to UTI in a patient with pre-existing stress fractures of the lumbar spine, following use of an automated massage chair. Successful treatment of SEA consisted of surgical debridement and a six-month course of antibiotic therapy.

Serum Low-Density Lipoprotein Cholesterol Levels and Depressive Mood in Korean Adults: A Nationwide Population-Based Study.

BACKGROUND: The association between serum cholesterol levels and depression has been studied extensively; however, results are inconsistent. This study aimed to investigate the association between low-density lipoprotein cholesterol (LDL-C) levels and depressive symptoms among Korean adults. METHODS: This cross-sectional study used data obtained from the 2007-2015 Korea National Health and Nutrition Examination Survey. In total, 40,904 adults were included in the final analysis. Participants were categorized into five groups according to their LDL-C levels, using the Korean guidelines for dyslipidemia. Symptoms of depression were evaluated using a self-reported questionnaire. Weighted logistic regression was used to examine the relationship between LDL-C levels and self-reported depressive symptoms. RESULTS: Compared with the intermediate category, the lowest (<70 mg/dL) and highest (≥160 mg/dL) LDL-C categories were associated with depressive symptoms, after adjusting for potential confounding factors (odds ratio [OR], 1.191; 95% confidence interval [CI], 1.008-1.409; OR, 1.241; 95% CI, 1.073-1.435, respectively). The highest LDL-C category was positively associated with depressive symptoms in those who were middle-aged, female, had a low body mass index, and taking or not taking dyslipidemia medications. CONCLUSION: A U-shaped association was identified between LDL-C categories and self-reported depressive symptoms. Our findings suggest that LDL-C levels that are too low or too high are associated with self-reported depressive symptoms. Further prospective studies are needed to determine the causal relationship of this association.

Effects of Natural Polyphenols on Oxidative Stress-Mediated Blood-Brain Barrier Dysfunction.

The blood-brain barrier (BBB), which consists mainly of brain microvascular endothelial cells and astrocytes connected by tight junctions (TJs) and adhesion molecules (AMs), maintains the homeostatic balance between brain parenchyma and extracellular fluid. Accumulating evidence shows that BBB dysfunction is a common feature of neurodegenerative diseases, including stroke, traumatic brain injury, and Alzheimer's disease. Among the various pathological pathways of BBB dysfunction, reactive oxygen species (ROS) are known to play a key role in inducing BBB disruption mediated via TJ modification, AM induction, cytoskeletal reorganization, and matrix metalloproteinase activation. Thus, antioxidants have been suggested to exert beneficial effects on BBB dysfunction-associated brain diseases. In this review, we summarized the sources of ROS production in multiple cells that constitute or surround the BBB, such as BBB endothelial cells, astrocytes, microglia, and neutrophils. We also reviewed various pathological mechanisms by which BBB disruption is caused by ROS in these cells. Finally, we summarized the effects of various natural polyphenols on BBB dysfunction to suggest a therapeutic strategy for BBB disruption-related brain diseases.