Human Neuralized is a novel tumour suppressor targeting Wnt/ß-catenin signalling in colon cancer.

While there is growing evidence that many epigenetically silenced genes in cancer are tumour suppressor candidates, their significance in cancer biology remains unclear. Here, we identify human Neuralized (NEURL), which acts as a novel tumour suppressor targeting oncogenic Wnt/ß-catenin signalling in human cancers. The expression of NEURL is epigenetically regulated and markedly suppressed in human colorectal cancer. We, therefore, considered NEURL to be a bona fide tumour suppressor in colorectal cancer and demonstrate that this tumour suppressive function depends on NEURL-mediated oncogenic ß-catenin degradation. We find that NEURL acts as an E3 ubiquitin ligase, interacting directly with oncogenic ß-catenin, and reducing its cytoplasmic levels in a GSK3ß- and ß-TrCP-independent manner, indicating that NEURL-ß-catenin interactions can lead to a disruption of the canonical Wnt/ß-catenin pathway. This study suggests that NEURL is a therapeutic target against human cancers and that it acts by regulating oncogenic Wnt/ß-catenin signalling.

Metabolomic Characteristics of Nontuberculous Mycobacterial Pulmonary Disease.

BACKGROUND: The therapeutic challenges posed by nontuberculous mycobacterial pulmonary disease (NTM-PD) contribute to an unmet medical need. In this study, we aimed to investigate NTM-PD-specific metabolic pathways using serum metabolomics to understand disease pathogenesis. METHODS: Mass spectrometry-based untargeted metabolomic profiling of serum from patients with NTM-PD (n = 50), patients with bronchiectasis (n = 50), and healthy controls (n = 60) was performed. Selected metabolites were validated by an independent cohort and subjected to pathway analysis and classification modeling. RESULTS: Leucine, tyrosine, inosine, proline, 5-oxoproline, and hypoxanthine levels increased in the NTM-PD group compared with the healthy control group. Furthermore, levels of antioxidant metabolites (ferulic acid, α-lipoic acid, biotin, and 2,8-phenazinediamine) decreased in patients with NTM-PD. These changes were associated with arginine- and proline-related metabolism, leading to generation of reactive oxygen species. Interestingly, the observed metabolic changes in the NTM-PD group overlapped with those in the bronchiectasis group. CONCLUSION: In NTM-PD, 11 metabolites linked to increased oxidative stress were significantly altered from those in healthy controls. Our findings enhance a comprehensive understanding of NTM-PD pathogenesis and provide insights for novel treatment approaches.

Improvement in Health-Related Quality of Life Following Antibiotic Treatment in Nontuberculous Mycobacterial Pulmonary Disease: Initial Analysis of the NTM-KOREA Cohort.

BACKGROUND: Improving health-related quality of life (HRQOL) has emerged as a priority in the management of nontuberculous mycobacterial pulmonary disease (NTM-PD). We aimed to evaluate HRQOL and its changes after 6 months' treatment in patients with NTM-PD. METHODS: The NTM-KOREA is a nationwide prospective cohort enrolling patients initiating treatment for NTM-PD in 8 institutions across South Korea. We conducted the Quality of Life-Bronchiectasis (QOL-B) at 6-month intervals and evaluated baseline scores (higher scores indicate better quality of life) and changes after 6 months' treatment. Multivariate logistic regression was performed to identify factors associated with improvement in the QOL-B physical functioning and respiratory symptoms domains. RESULTS: Between February 2022 and August 2023, 411 patients were included in the analysis. Baseline scores (95% confidence interval [CI]) for physical functioning and respiratory symptoms were 66.7 (46.7-86.7) and 81.5 (70.4-92.6), respectively. Among 228 patients who completed the QOL-B after 6 months' treatment, improvements in physical functioning and respiratory symptoms were observed in 61 (26.8%) and 71 (31.1%) patients, respectively. A lower score (adjusted odds ratio; 95% CI) for physical functioning (0.93; 0.91-0.96) and respiratory symptoms (0.92; 0.89-0.95) at treatment initiation was associated with a greater likelihood of physical functioning and respiratory symptom improvement, respectively; achieving culture conversion was not associated with improvement in physical functioning (0.62; 0.28-1.39) or respiratory symptoms (1.30; 0.62-2.74). CONCLUSIONS: After 6 months of antibiotic treatment for NTM-PD, HRQOL improved in almost one-third, especially in patients with severe initial symptoms, regardless of culture conversion. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier: NCT03934034.

Protective effects of tauroursodeoxycholate against radiation-induced intestinal injury in a mouse model.

In patients with high-level radiation exposure, gastrointestinal injury is the main cause of death. Despite the severity of damage to the gastrointestinal tract, no specific therapeutic option is available. Tauroursodeoxycholic acid (TUDCA) is a conjugated form of ursodeoxycholic acid that suppresses endoplasmic reticulum (ER) stress and regulates various cell-signaling pathways. We investigated the effect of TUDCA premedication in alleviating intestinal damage and enhancing the survival of C57BL/6 mice administered a lethal dose (15Gy) of focal abdominal irradiation. TUDCA was administered to mice 1 h before radiation exposure, and reduced apoptosis of the jejunal crypts 12 h after irradiation. At later timepoint (3.5 days), irradiated mice manifested intestinal morphological changes that were detected via histological examination. TUDCA decreased the inflammatory cytokine levels and attenuated the decrease in serum citrulline levels after radiation exposure. Although radiation induced ER stress, TUDCA pretreatment decreased ER stress in the irradiated intestinal cells. The effect of TUDCA indicates the possibility of radiation therapy for cancer in tumor cells. TUDCA did not affect cell proliferation and apoptosis in the intestinal epithelium. TUDCA decreased the invasive ability of the CT26 metastatic colon cancer cell line. Reduced invasion after TUDCA treatment was associated with decreased matrix metalloproteinase (MMP)-7 and MMP-13 expression, which play important roles in invasion and metastasis. This study shows a potential role of TUDCA in protecting against radiation-induced intestinal damage and inhibiting tumor cell migration without any radiation and radiation therapy effect.

Breast cancer malignancy is governed by regulation of the macroH2A2/TM4SF1 axis, the AKT/NF-κB pathway, and elevated MMP13 expression.

The histone variant, macroH2A (mH2A) influences gene expression through epigenetic regulation. Tumor suppressive function of mH2A isoforms has been reported in various cancer types, but few studies have investigated the functional role of mH2A2 in breast cancer pathophysiology. This study aimed to determine the significance of mH2A2 in breast cancer development and progression by exploring its downstream regulatory mechanisms. Knockdown of mH2A2 facilitated the migration and invasion of breast cancer cells, whereas its overexpression exhibited the opposite effect. In vivo experiments revealed that augmenting mH2A2 expression reduced tumor growth and lung metastasis. Microarray analysis showed that TM4SF1 emerged as a likely target linked to mH2A2 owing to its significant suppression in breast cancer cell lines where mH2A2 was overexpressed among the genes that exhibited over twofold upregulation upon mH2A2 knockdown. Suppressing TM4SF1 reduced the migration, invasion, tumor growth, and metastasis of breast cancer cells in vitro and in vivo. TM4SF1 depletion reversed the increased aggressiveness triggered by mH2A2 knockdown, suggesting a close interplay between mH2A2 and TM4SF1. Our findings also highlight the role of the mH2A2/TM4SF1 axis in activating the AKT/NF-κB pathway. Consequently, activated NF-κB signaling leads to increased expression and secretion of MMP13, a potent promoter of metastasis. In summary, we propose that the orchestrated regulation of the mH2A2/TM4SF1 axis in conjunction with the AKT/NF-κB pathway and the subsequent elevation in MMP13 expression constitute pivotal factors governing the malignancy of breast cancer.

The Sexual Health Clinic Role in Vaccine and Treatment Access During the 2022 Mpox Outbreak in King County, Washington.

BACKGROUND: Sexual health clinics were frontline providers in the 2022 US mpox public health response, though data on clinic-based mpox vaccine scale-up, diagnoses, and treatment are limited. We describe the role of a public health sexual health clinic (SHC) in King County's mpox response, between 5/23/22-10/31/22. METHODS: In July 2022, the SHC implemented a dedicated vaccine clinic and presumptive tecovirimat treatment (prior to laboratory confirmation) with on-site dispensation. We describe SHC's vaccine scale-up and contribution to clinical care by calculating the weekly number of vaccines administered by SHC and the total number of patients diagnosed and treated for mpox within SHC, and comparing to countywide data. We calculated time from symptom onset to testing and time from testing to treatment, and assessed temporal changes in these metrics using linear regression. RESULTS: The SHC provided ≥1 vaccine doses to 7,442 individuals (10,295 doses), administering 42% of the 24,409 vaccine doses provided countywide, with the greatest contribution in the first week of August (n = 1,562, 58% of countywide vaccinations that week). Of 598 patients evaluated for mpox and tested, 178 (30%) tested positive (37% of countywide cases), and 152 (85% of SHC patients with mpox) received tecovirimat (46% of treatment countywide). Median time from symptom onset to testing decreased from 12 to 6 days (p = 0.045); time from testing to treatment decreased from 4.5 days to 0 days (p < 0.001). CONCLUSION: The SHC was central to mpox vaccination and treatment scale-up, particularly in the first months of the 2022 epidemic.

Pulse versus non-pulse corticosteroid therapy in patients with acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Corticosteroids are commonly used for the treatment of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF); however, the optimal initial dose of corticosteroids remains uncertain due to a lack of sufficient evidence. We evaluated whether the administration of a pulse dose of corticosteroids resulted in improved survival outcomes compared with conventional non-pulse dose of corticosteroids. METHODS: We retrospectively analysed 238 patients with AE-IPF treated with corticosteroids at a tertiary referral hospital between January 2013 and December 2021. Based on whether a pulse dose of corticosteroids (methylprednisolone of ≥250 mg/day or equivalent) was administered within 7 days of hospitalization for AE-IPF, the patients were divided into the pulse and non-pulse regimen groups. The survival outcomes were compared between the two groups using multivariable regression and propensity score-matched analyses. RESULTS: Among the 238 patients, 59 patients received pulse dose of corticosteroids, whereas 179 patients received conventional non-pulse dose of corticosteroids. After adjusting for the confounding factors related to the baseline clinical and radiographic severity, compared with the conventional non-pulse regimen, the pulse regimen of corticosteroids did not reduce the risk of mortality at the 3-month (aHR 0.84, 95% CI 0.45-1.38) or 12-month (aHR 0.96, 95% CI 0.60-1.25) follow-ups. Propensity score-matched analysis revealed similar results. CONCLUSION: The survival outcomes of patients with AE-IPF who received a pulse dose of corticosteroids did not differ from those of patients who received conventional non-pulse dose of corticosteroids. Further prospective studies are required to establish the optimal initial dose of corticosteroids for the treatment of AE-IPF.

Comparative Morphology of Island and Inland Agastache rugosa and Their Gastroprotective Effects in EtOH/HCl-Induced Gastric Mucosal Gastritis.

Agastache rugosa Kuntze (Lamiaceae; Labiatae), a medicinal and functional herb used to treat gastrointestinal diseases, grows well both on islands and inland areas in South Korea. Thus, we aimed to reveal the morphological and micromorphological differences between A. rugosa grown on island and inland areas and their pharmacological effects on gastritis in an animal model by combining morphological and mass spectrophotometric analyses. Morphological analysis showed that island A. rugosa had slightly smaller plants and leaves than inland plants; however, the density of all types of trichomes on the leaves, petioles, and stems of island A. rugosa was significantly higher than that of inland plants. The essential oil component analysis revealed that pulegone levels were substantially higher in island A. rugosa than in inland A. rugosa. Despite the differences between island and inland A. rugosa, treatment with both island and inland A. rugosa reduced gastric damages by more than 40% compared to the gastritis induction group. In addition, expression of inflammatory protein was reduced by about 30% by treatment of island and inland A. rugosa. The present study demonstrates quantitative differences in morphology and volatile components between island and inland plants; significant differences were not observed between the gastritis-inhibitory effects of island and inland A. rugosa, and the efficacy of island A. rugosa was found to be similar to that of A. rugosa grown in inland areas.

Pre-Sepsis Length of Hospital Stay and Mortality: A Nationwide Multicenter Cohort Study.

BACKGROUND: Prolonged length of hospital stay (LOS) is associated with an increased risk of hospital-acquired conditions and worse outcomes. We conducted a nationwide, multicenter, retrospective cohort study to determine whether prolonged hospitalization before developing sepsis has a negative impact on its prognosis. METHODS: We analyzed data from 19 tertiary referral or university-affiliated hospitals between September 2019 and December 2020. Adult patients with confirmed sepsis during hospitalization were included. In-hospital mortality was the primary outcome. The patients were divided into two groups according to their LOS before the diagnosis of sepsis: early- (< 5 days) and late-onset groups (≥ 5 days). Conditional multivariable logistic regression for propensity score matched-pair analysis was employed to assess the association between late-onset sepsis and the primary outcome. RESULTS: A total of 1,395 patients were included (median age, 68.0 years; women, 36.3%). The early- and late-onset sepsis groups comprised 668 (47.9%) and 727 (52.1%) patients. Propensity score-matched analysis showed an increased risk of in-hospital mortality in the late-onset group (adjusted odds ratio [aOR], 3.00; 95% confidence interval [CI], 1.69-5.34). The same trend was observed in the entire study population (aOR, 1.85; 95% CI, 1.37-2.50). When patients were divided into LOS quartile groups, an increasing trend of mortality risk was observed in the higher quartiles (P for trend < 0.001). CONCLUSION: Extended LOS before developing sepsis is associated with higher in-hospital mortality. More careful management is required when sepsis occurs in patients hospitalized for ≥ 5 days.

Integrated Genome-Wide Analysis of DNA Methylation and Gene Expression in the Hippocampi of 5xFAD Alzheimer's Disease Mouse Model.

BACKGROUND: DNA methylation forms 5-methylcytosine and its regulation in the hippocampus is critical for learning and memory. Indeed, dysregulation of DNA methylation is associated with neurological diseases. Alzheimer's disease (AD) is the predominant of dementia and a neurodegenerative disorder. METHODS: We examined the learning and memory function in 3- and 9-month-old wild-type and 5xfamiliar Alzheimer's disease (5xFAD) transgenic mice by performing the object recognition memory and Y-maze tests, and identified the hippocampal amyloid beta burden. To investigate the epigenetically regulated genes involved in the development or neuropathology of AD, we performed genome-wide DNA methylation sequencing and RNA sequencing analyses in the hippocampus of 9-month-old wild-type and 5xFAD tg mice. To validate the genes inversely regulated by epigenetics, we confirmed their methylation status and mRNA levels. RESULTS: At 9 months of age, 5xFAD tg mice showed significant cognitive impairment and amyloid-beta plaques in the hippocampus. DNA methylation sequencing identified a total of 13,777 differentially methylated regions, including 4484 of hyper- and 9293 of hypomethylated regions, that are associated with several gene ontology (GO) terms including 'nervous system development' and 'axon guidance'. In RNA sequencing analysis, we confirmed a total of 101 differentially expressed genes, including 52 up- and 49 downregulated genes, associated with GO functions such as 'positive regulation of synaptic transmission, glutamatergic' and 'actin filament organization'. Through further integrated analysis of DNA methylation and RNA sequencing, three epigenetically regulated genes were selected: thymus cell antigen 1, theta (Thy1), myosin VI (Myo6), and filamin A-interacting protein 1-like (Filip1l). The methylation level of Thy1 decreased and its mRNA levels increased, whereas that of Myo6 and Filip1l increased and their mRNA levels decreased. The common functions of these three genes may be associated with the neural cytoskeleton and synaptic plasticity. CONCLUSIONS: We suggest that the candidate genes epigenetically play a role in AD-associated neuropathology (i.e., amyloid-beta plaques) and memory deficit by influencing neural structure and synaptic plasticity. Furthermore, counteracting dysregulated epigenetic changes may delay or ameliorate AD onset or symptoms.

Antiepileptic and Neuroprotective Effects of Rheum tanguticum Root Extract on Trimethyltin-Induced Epilepsy and Neurodegeneration: In Vivo and in Silico Analyses.

BACKGROUND: Rheum tanguticum root, cataloged as "Daehwang" in the Korean Pharmacopeia, is rich in various anthraquinones known for their anti-inflammatory and antioxidant properties. Formulations containing Daehwang are traditionally employed for treating neurological conditions. This study aimed to substantiate the antiepileptic and neuroprotective efficacy of R. tanguticum root extract (RTE) against trimethyltin (TMT)-induced epileptic seizures and hippocampal neurodegeneration. METHODS: The constituents of RTE were identified by ultra-performance liquid chromatography (UPLC). Experimental animals were grouped into the following five categories: control, TMT, and three TMT+RTE groups with dosages of 10, 30, and 100 mg/kg. Seizure severity was assessed daily for comparison between the groups. Brain tissue samples were examined to determine the extent of neurodegeneration and neuroinflammation using histological and molecular biology techniques. Network pharmacology analysis involved extracting herbal targets for Daehwang and disease targets for epilepsy from multiple databases. A protein-protein interaction network was built using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, and pivotal targets were determined by topological analysis. Enrichment analysis was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) tool to elucidate the underlying mechanisms. RESULTS: The RTE formulation was found to contain sennoside A, sennoside B, chrysophanol, emodin, physcion, (+)-catechin, and quercetin-3-O-glucuronoid. RTE effectively inhibited TMT-induced seizures at 10, 30, and 100 mg/kg dosages and attenuated hippocampal neuronal decay and neuroinflammation at 30 and 100 mg/kg dosages. Furthermore, RTE significantly reduced mRNA levels of tumor necrosis factor (TNF-α), glial fibrillary acidic protein (GFAP), and c-fos in hippocampal tissues. Network analysis revealed TNF, Interleukin-1 beta (IL-1ß), Interleukin-6 (IL-6), Protein c-fos (FOS), RAC-alpha serine/threonine-protein kinase (AKT1), and Mammalian target of rapamycin (mTOR) as the core targets. Enrichment analysis demonstrated significant involvement of R. tanguticum components in neurodegeneration (p = 4.35 × 10-5) and TNF signaling pathway (p = 9.94 × 10-5). CONCLUSIONS: The in vivo and in silico analyses performed in this study suggests that RTE can potentially modulate TMT-induced epileptic seizures and neurodegeneration. Therefore, R. tanguticum root is a promising herbal treatment option for antiepileptic and neuroprotective applications.

Functional alignment maximises advantages of robotic arm-assisted total knee arthroplasty with better patient-reported outcomes compared to mechanical alignment.

PURPOSE: Robotic arm-assisted total knee arthroplasty (RTKA) enables adjustment of implant position to achieve the surgeon's preferred alignment. However, the alignment concept that most effectively enhances patient satisfaction remains unclear. This study compares the clinical outcomes of patients who underwent functionally aligned RTKA (FA-RTKA), mechanically aligned conventional TKA (MA-CTKA) and mechanically aligned RTKA (MA-RTKA). METHODS: A prospectively collected database was retrospectively reviewed for patients who underwent primary TKA for knee osteoarthritis. One hundred and forty-seven knees were performed with MA-CTKA, followed by 72 consecutive knees performed with MA-RTKA, and subsequently, 70 consecutive knees performed with FA-RTKA were enrolled. After 1:1 propensity score matching of patient demographics, 70 knees were finally included in each group. The extent of additional soft tissue release during surgery was identified, and the Coronal Plane Alignment of the Knee classification was utilised to categorise the alignment. At the 1-year follow-up, patient-reported outcomes, including the pain Visual Analogue Scale, Knee Society Score, Western Ontario and McMaster Universities Arthritis Index and Forgotten Joint Score-12, were also compared among the groups. RESULTS: The FA-RTKA group showed significantly less additional soft tissue release than the MA-CTKA and MA-RTKA groups (15.7%, 38.6% and 35.7%, respectively; p = 0.006). Statistically significant differences in functional scores were observed in the postoperative 1-year clinical outcomes in favour of the FA-RTKA group, which had a significantly larger percentage of knees that maintained constitutional alignment and joint line obliquity than those of the other groups. CONCLUSIONS: Functionally aligned TKA showed superior 1-year postoperative patient-reported outcomes compared with those of conventional and robotic arm-assisted mechanically aligned TKA. Therefore, the advantage of RTKA is maximised when the implant positioning is based on functional alignment. The application of RTKA with mechanical alignment has been proven ineffective in improving the clinical outcomes of patients. LEVEL OF EVIDENCE: Level III.

Robotic-assisted medial unicompartmental knee arthroplasty restored prearthritic alignment and led to superior functional outcomes compared with conventional techniques.

PURPOSE: Robotic-assisted medial unicompartmental knee arthroplasty (UKA) can ensure precise preoperative planning, minimise soft tissue damage and restore native coronal alignment. However, few studies have investigated how these advantages translate into differences in early postoperative outcomes. This study aimed to compare differences in early outcomes between conventional UKA (C-UKA) and robotic-assisted UKA (R-UKA). METHODS: This retrospective study investigated two groups of patients who underwent medial UKA: C-UKA group (n = 35) and R-UKA group (n = 35). We assessed (1) serum indicators (hemoglobin, creatine kinase and C-reactive protein) and pain visual analogue scale (VAS) at postoperative days (PODs) 1, 2, 4 and 6; (2) radiologic parameters including joint line height change and arithmetic and mechanical hip-knee-ankle angle (aHKA and mHKA); (3) patient-reported outcomes including Knee Society Scores, Western Ontario and Mcmaster Universities Arthritis Index (WOMAC) and Forgotten Joint Score-12 (FJS-12) at 1-year follow-up. RESULTS: Despite similar serum indicator results, pain VAS was lower in the R-UKA group than in the C-UKA group at PODs 2 (2.5 ± 1.3 vs. 3.6 ± 1.2, p = 0.02), 4 (2.4 ± 0.9 vs. 3.3 ± 1.0, p = 0.03) and 6 (1.9 ± 1.1 vs. 3.1 ± 1.1, p < 0.01). The joint line height change was significantly lower in the R-UKA group than in the C-UKA group (0.9 mm ± 0.6 mm vs. 2.0 mm ± 1.3 mm, p = 0.02). The equivalence test for preoperative aHKA and postoperative mHKA revealed equivalence in only the R-UKA group (p < 0.01). The R-UKA group showed better WOMAC and FJS-12 compared to C-UKA group at 1-year follow-up. CONCLUSION: R-UKA led to lower pain VAS in the early postoperative period compared with C-UKA. Additionally, R-UKA effectively restored the joint line and prearthritic lower limb alignment, resulting in superior functional outcomes at 1-year follow-up compared with C-UKA. LEVEL OF EVIDENCE: Level III.

Integrated Analysis of DNA Methylation and Gene Expression Profiles in a Rat Model of Osteoarthritis.

Osteoarthritis (OA) is common and affected by several factors, such as age, weight, sex, and genetics. The pathogenesis of OA remains unclear. Therefore, using a rat model of monosodium iodoacetate (MIA)-induced OA, we examined genomic-wide DNA methylation using methyl-seq and characterized the transcriptome using RNA-seq in the articular cartilage tissue from a negative control (NC) and MIA-induced rats. We identified 170 genes (100 hypomethylated and upregulated genes and 70 hypermethylated and downregulated genes) regulated by DNA methylation in OA. DNA methylation-regulated genes were enriched in functions related to focal adhesion, extracellular matrix (ECM)-receptor interaction and the PI3K-Akt and Hippo signaling pathways. Functions related to extracellular matrix organization, extracellular matrix proteoglycans, and collagen formation were involved in OA. A molecular and protein-protein network was constructed using methylated expression-correlated genes. Erk1/2 was a downstream target of OA-induced changes in DNA methylation and RNA expression. We found that the integrin subunit alpha 2 (ITGA2) gene is important in focal adhesion, alpha6-beta4 integrin signaling, and the inflammatory response pathway in OA. Overall, gene expression changes because DNA methylation influences OA pathogenesis. ITGA2, whose gene expression changes are regulated by DNA methylation during OA onset, is a candidate gene. Our findings provide insights into the epigenetic targets of OA processes in rats.

The effects of Pycnogenol, a pine bark extract on pulmonary inflammation by Asian sand dust in mice.

Asian sand dust (ASD), also called China dust or yellow dust, mainly occurs in East Asia during spring and autumn. Because ASD enters the body mainly through the respiratory system, it can cause respiratory disorders or worsen underlying diseases. Because of this, it has become an important health concern that threatens the well-being of humans and animals. In this study, we investigated the effects of 15 and 30 mg/kg of Pycnogenol (PYC15 and 30 groups), a pine bark extract, on ASD-induced pulmonary inflammation in mice. We evaluated the inflammatory cell counts, inflammatory cytokines, and matrix-metalloproteinase (MMP)-9 expression in animal models. PYC administration significantly decreased inflammatory cell infiltration into lung tissue; this was accompanied by a reduction in the levels of proinflammatory mediators including interleukin (IL)-1ß (P < 0.01), IL-6 (P < 0.01) and tumour necrosis factor-α (P < 0.01) in bronchoalveolar lavage fluids of ASD-exposed mice (ASD group). Histological analysis revealed that PYC suppressed ASD-induced pulmonary inflammation. Moreover, PYC suppressed the levels of matrix-metalloproteinase (MMP)-9 in the lung tissue of ASD-exposed mice, indicating that PYC reduced ASD-induced pulmonary inflammation by suppressing MMP-9. Together, these results indicate that PYC as the potential to treat ASD-driven pulmonary inflammation.

Impact of Treatment on Long-Term Survival of Patients With Mycobacterium avium Complex Pulmonary Disease.

BACKGROUND: Whether antimicrobial treatment improves long-term survival in patients with Mycobacterium avium complex pulmonary disease (MAC-PD) is unclear. METHODS: We analyzed survival in patients aged ≥18 years who were treated for MAC-PD at a tertiary referral center in South Korea between 1 January 2009 and 31 December 2020. Treatment exposure was divided into 4 time intervals: <6, ≥6 to <12, ≥12 to <18, and ≥18 months. Time-varying multivariable Cox proportional hazards models were used to calculate the all-cause mortality risk in each time interval. The model was adjusted for major clinical factors related to mortality including age, sex, body mass index, presence of cavities, erythrocyte sedimentation rate, positive acid-fast bacilli (AFB) smear, clarithromycin resistance, and comorbid conditions. RESULTS: A total of 486 patients treated for MAC-PD were included in the analysis. A significant inverse correlation was observed between mortality and duration of treatment (P for trend = .007). Long-term treatment (≥18 months) was significantly associated with reduced mortality (adjusted hazard ratio, 0.32 [95% confidence interval, .15-.71]). In subgroup analyses, patients with cavitary lesions (adjusted hazard ratio, 0.17 [95% confidence interval, .05-.57]) or positive AFB smears (0.13 [.02-.84]) at baseline maintained this significant inverse relationship between treatment duration and mortality. CONCLUSIONS: Long-term antimicrobial treatment should be actively considered in patients with progressive MAC-PD, especially in the presence of cavities or positive AFB smears indicative of high mycobacterial burden.

Obstructive Sleep Apnea and Striatal Dopamine Availability in Parkinson's Disease.

BACKGROUND: Sleep disorders are frequently associated with Parkinson's disease. Obstructive sleep apnea syndrome is one of these sleep disorders and is associated with the severity of motor symptoms in Parkinson's disease. Obstructive sleep apnea can lead to dopaminergic neuronal cell degeneration and may impair the clearance of α-synuclein in Parkinson's disease. Striatal dopamine uptake is a surrogate marker of nigral dopaminergic cell damage. OBJECTIVE: We aimed to investigate the differences in striatal dopamine availability between Parkinson's disease patients with or without obstructive sleep apnea. METHODS: A total of 85 de novo and nonmedicated Parkinson's disease patients were enrolled. Full-night polysomnography was performed for all patients, and obstructive sleep apnea was diagnosed as apnea/hypopnea index ≥5. Positron emission tomography was performed with 18 F-N-(3-fluoropropyl)-2ß-carbon ethoxy-3ß-(4-iodophenyl) nortropane, and the regional standardized-uptake values were analyzed using a volume-of-interest template and compared between groups with or without obstructive sleep apnea. RESULTS: Dopamine availability in the caudate nucleus of the obstructive sleep apnea group was significantly lower than that of the nonobstructive sleep apnea group. On subgroup analysis, such association was found in female but not in male patients. In other structures (putamen, globus pallidus, and thalamus), dopamine availability did not differ between the two groups. CONCLUSION: This study supports the proposition that obstructive sleep apnea can contribute to reduced striatal dopamine transporter availability in Parkinson's disease. Additional studies are needed to assess the causal association between obstructive sleep apnea and the neurodegenerative process in Parkinson's disease. © 2023 International Parkinson and Movement Disorder Society.

Human embryonic stem cell-specific role of YAP in maintenance of self-renewal and survival.

Human embryonic stem cells (hESCs) have unique characteristics, such as self-renewal and pluripotency, which are distinct from those of other cell types. These characteristics of hESCs are tightly regulated by complex signaling mechanisms. In this study, we demonstrate that yes-associated protein (YAP) functions in an hESC-specific manner to maintain self-renewal and survival in hESCs. hESCs were highly sensitive to YAP downregulation to promote cell survival. Interestingly, hESCs displayed dynamic changes in YAP expression in response to YAP downregulation. YAP was critical for the maintenance of self-renewal. Additionally, the function of YAP in maintenance of self-renewal and cell survival was hESC-specific. Doxycycline upregulated YAP in hESCs and attenuated the decreased cell survival induced by YAP downregulation. However, decreased expression of self-renewal markers triggered by YAP downregulation and neural/cardiac differentiation were affected by doxycycline treatment. Collectively, the results reveal the mechanism underlying the role of YAP and the novel function of doxycycline in hESCs.

Prognostic serum biomarkers in non-tuberculous mycobacterial pulmonary disease.

Increased serum C-reactive protein (CRP) levels at the time of diagnosis predicted worse prognosis in patients with non-tuberculous mycobacterial pulmonary disease (NTM-PD). Approximately one-quarter of the patients with NTM-PD had higher than normal CRP levels, and this elevation led to a higher risk of death.

Learning curve of robot-assisted total knee arthroplasty and its effects on implant position in asian patients: a prospective study.

BACKGROUND: Robot-assisted total knee arthroplasty (r-TKA) can reportedly achieve more accurate implant positioning than conventional total knee arthroplasty (c-TKA), although its learning curve is controversial. Moreover, few studies have investigated r-TKA in Asians, who have different anatomical characteristics. This study aimed to determine the learning curve for r-TKA and compare implant positions between r-TKA and c-TKA according to the learning curve in Asian patients. METHODS: This prospective study included 50 consecutive c-TKAs (group C), followed by 50 consecutive r-TKAs conducted using the MAKO robotic system (Stryker, USA). Cumulative summation analyses were performed to assess the learning curve for operative time in r-TKA. Accordingly, the r-TKA cases were divided into the initial (group I) and proficiency cases (group P). The femoral and tibial component positions in the coronal, sagittal, and axial planes and lower limb alignment were compared among the three groups. RESULTS: r-TKA was associated with a learning curve for operative time in 18 cases. The operative time was significantly shorter in groups C and P than that in group I, with no significant difference between groups C and P. Groups I and P demonstrated fewer outliers with respect to lower limb alignment, femoral component coronal position, axial position, and tibial component sagittal position than those in group C, with no significant difference between groups I and P. CONCLUSION: The operative time did not differ significantly between r-TKA and c-TKA after the learning curve. Surgeons could expect more accurate and reproducible lower limb alignment and implant positioning with r-TKA in Asian patients, irrespective of the learning curve.