Maslinic acid prevents IL-1ß-induced inflammatory response in osteoarthritis via PI3K/AKT/NF-κB pathways.

Osteoarthritis (OA) is a degenerative joint disease characterized by destruction of articular cartilage. The inflammatory response is the most important factor affecting the disease process. As interleukin-1ß (IL-1ß) stimulates several key mediators in the inflammatory response, it plays a major role in the pathogenesis of OA. Maslinic acid (MA) is a natural compound distributed in olive fruit. Previous studies have found that maslinic acid has an inhibitory effect on inflammation, but its specific role in the progression of OA disease has not been studied so far. In this study, we aim to assess the protective effect of MA on OA progression by in vitro and in vivo experiments. Our results indicate that, in IL-1ß-induced inflammatory response, MA is effective in attenuating some major inflammatory mediators such as nitric oxide (NO) and prostaglandin E2, and inhibits the expression of IL-6, inducible nitric oxide synthase, cyclooxygenase-2, and tumor necrosis factor-α (TNF-α) in a concentration-dependent manner. Also, MA downregulated the expression levels of thrombospondin motif 5 (ADAMTS5) and matrix metalloproteinase 13 in chondrocytes, resulting in reduced degradation of its extracellular matrix. Mechanistically, MA exhibits an anti-inflammatory effect by inactivating the PI3K/AKT/NF-κB pathway. In vivo, the protective effect of MA on OA development can be detected in a surgically induced mouse OA model. In summary, these findings suggest that MA can be used as a safe and effective potential OA therapeutic strategy.

Single-port thoracoscopic anatomic resection for chronic inflammatory lung disease.

BACKGROUND: It is challenging to proceed thoracoscopic anatomic resection when encountering severe pleural adhesion or calcified peribronchial lymphadenopathy. Compared with multiple-port video-assisted thoracoscopic surgery (MP-VATS), how to overcome these challenges in single-port (SP-) VATS is still an intractable problem. In the present study, we reported the surgical results of chronic inflammatory lung disease and shared some useful SP-VATS techniques. METHODS: We retrospectively assessed the surgical results of chronic inflammatory lung disease, primarily bronchiectasis, and mycobacterial infection, at our institution between 2010 and 2018. The patients who underwent SP-VATS anatomic resection were compared with those who underwent MP-VATS procedures. We analyzed the baseline characteristics, perioperative data, and postoperative outcomes, and illustrated four special techniques depending on the situation: flexible hook electrocautery, hilum-first technique, application of Satinsky vascular clamp, and staged closure of bronchial stump method. RESULTS: We classified 170 consecutive patients undergoing thoracoscopic anatomic resection into SP and MP groups, which had significant between-group differences in operation time and overall complication rate (P = 0.037 and 0.018, respectively). Compared to the MP-VATS group, the operation time of SP-VATS was shorter, and the conversion rate of SP-VATS was relatively lower (3.1% vs. 10.5%, P = 0.135). The most common complication was prolonged air leakage (SP-VATS, 10.8%; MP-VATS, 2.9%, P = 0.045). CONCLUSIONS: For chronic inflammatory lung disease, certain surgical techniques render SP-VATS anatomic resection feasible and safe with a lower conversion rate.

Opportunity Reboot: A Community-Based Evaluation Focused on Opportunity Youth.

The number of young people living in the margins of society reflects one of the most pressing social inequities of our time. Opportunity youth often face many complex challenges perpetrated by a range of systemic issues. These trajectories can be positively disrupted by surrounding youth with a cohesive web of relational and instrumental supports and spaces where their strengths and potential are seen. Opportunity Reboot, a technical assistance and program enhancement model, was developed to leverage the existing capacity and strengths of community programs to more effectively create pathways to school, career, and life success for opportunity youth. The impact of Opportunity Reboot was tested using a single-group, non-experimental design and a quasi-experimental design with propensity score matching. Findings established associations between opportunity youths' experiences of three core Opportunity Reboot features and growth in select positive identity, social-emotional competencies, and skills for systems navigation outcomes. Opportunity Reboot youth were also more likely, on average, than comparison youth to be employed in the four quarters after endline data collection; this finding was even stronger when comparing youth of color in the Opportunity Reboot and comparison groups. This evaluation strengthens the evidence that program enhancement models like Opportunity Reboot hold promise for positively disrupting the lives of opportunity youth.

Familial Transmission of Educational Plans and the Academic Self-Concept: A Three-Generation Longitudinal Study.

This research investigates the social reproduction of inequality by drawing on prospective longitudinal data from three generations of Youth Development Study respondents. It examines intergenerational influence on the relatively unexplored academic self-concept as well as educational plans, a critical component of the status attainment model. A structural equation model, based on 422 3-generation triads, finds evidence that the sources giving rise to the development of children's (Generation 3) achievement orientations do not only result from parental (G2) contemporaneous influence. Prior influences implicate grandparent (G1) educational attainment and income, grandparental expectations for the G2 adolescent, the G2 academic self-concept and educational plans measured more than twenty years earlier (in G2's adolescence), and G2 educational attainment. A familial culture emphasizing academic self-confidence and high educational expectations may be an important component of "family capital" that supports educational attainment and contributes to the maintenance of social class position in each successive generation.

The protective effects of icariin against testicular dysfunction in type 1 diabetic mice Via AMPK-mediated Nrf2 activation and NF-κB p65 inhibition.

BACKGROUND: Owing to the early suffering age and the rising incidence of type 1 diabetes (T1D), the resulting male reproductive dysfunction and fertility decline have become a disturbing reality worldwide, with no effective strategy being available. Icariin (ICA), a flavonoid extracted from Herba Epimedium, has been proved its promising application in improving diabetes-related complications including diabetic nephropathy, endothelial dysfunction and erectile dysfunction. Ensuring the future reproductive health of children and adolescents with T1D is crucial to improve global fertility. However, its roles in the treatment of T1D-induced testicular dysfunction and the potential mechanisms remain elusive. PURPOSE: The purpose of this present study was to investigate whether ICA ameliorates T1D-induced testicular dysfunction as well as its potential mechanisms. METHODS: T1D murine model was established by intraperitoneal injection of STZ with or without treated with ICA for eleven weeks. Morphological, pathological and serological experiments were used to determine the efficacy of ICA on male reproductive function of T1D mice. Western blotting, Immunohistochemistry analysis, qRT-PCR and kit determination were performed to investigated the underlying mechanisms. RESULTS: We found that replenishment of ICA alleviated testicular damage, promoted testosterone production and spermatogenesis, ameliorated apoptosis and blood testis barrier impairment in streptozotocin-induced T1D mice. Functionally, ICA treatment triggered adenosine monophosphate protein kinase (AMPK) activation, which in turn inhibited the nuclear translocation of nuclear factor kappa B p65 (NF-κB p65) to reduce inflammatory responses in the testis and activated nuclear factor erythroid 2-related factor 2(Nrf2), thereby enhancing testicular antioxidant capacity. Further studies revealed that supplementation with the AMPK antagonist Compound C or depletion of Nrf2 weakened the beneficial effects of ICA on testicular dysfunction of T1D mice. CONCLUSION: Collectively, these results demonstrate the feasibility of ICA in the treatment of T1D-induced testicular dysfunction, and reveal the important role of AMPK-mediated Nrf2 activation and NF-κB p65 inhibition in ICA-associated testicular protection during T1D.

Micheliolide ameliorates severe acute pancreatitis in mice through potentiating Nrf2-mediated anti-inflammation and anti-oxidation effects.

Severe acute pancreatitis (SAP) is an acute inflammatory injury disease with significant mortality rate and currently without effective strategy being available. Inflammation and oxidative stress play central roles in the etiology of SAP. Micheliolide (MCL), an active monomeric component isolated from Michelia champaca, has been proved its multiple therapeutic properties including anti-inflammatory, antioxidant and anti-cancer. Nevertheless, the therapeutic effect and underlying mechanism of MCL in SAP still remain unclear. Here, we found that caerulein with lipopolysaccharide (LPS)-induced SAP murine models exhibited severe pancreatic injury, including necrosis, edema, and vacuolation of acinar cells in the pancreas, elevated serum levels of amylase and lipase, and reduced number of the exocrine cells. As expected, MCL treatment alleviated these side effects. Mechanistically, MCL triggered nuclear factor erythroid 2-related factor 2 (Nrf2) activation, thereby activating Nrf2-regulated antioxidative pathways and inhibiting nuclear factor kappa B p65 (NF-κB p65)-mediated inflammatory response, resulting in protection against pancreatic injury in SAP mice. In addition, Nrf2 gene deficiency abolished the beneficial effects of MCL on SAP-induced pancreatic inflammation and oxidative stress and blocked the ability of MCL to alleviate the pancreatic injury in SAP mice. Collectively, these findings indicated that the suppression of SAP-induced pancreatic injury by MCL was at least in part due to Nrf2-mediated anti-oxidation effect and inhibition of inflammation.

Association of Cystic Periventricular Leukomalacia and Postnatal Epilepsy in Very Preterm Infants.

INTRODUCTION: Cystic periventricular leukomalacia (PVL) is the most common white matter injury and a common cause of cerebral palsy in preterm infants. Postnatal epilepsy may occur after cystic PVL, but their causal relationship remains uncertain. Our aim was to validate the contribution of cystic PVL to postnatal epilepsy in very preterm infants and demonstrate their seizure characteristics. METHODS: This prospective cohort study enrolled 1,342 preterm infants (birth weight <1,500 g and gestational age <32 weeks) from 2003 to 2015. Cystic PVL was diagnosed by serial cerebral ultrasound, and other comorbidities were recorded during hospitalization. Neurological developments and consequences, including epilepsy, were serially accessed until the age of 5. RESULTS: A total of 976 preterm infants completed a 5-year neurological follow-up; 47 (4.8%) had cystic PVL. Preterm infants with cystic PVL were commonly associated with other comorbidities, including necrotizing enterocolitis stage III, neonatal seizures, and intraventricular hemorrhage during hospitalization. At age 5, 14 of the 47 (29.8%) preterm infants with cystic PVL had postnatal epilepsy. After adjusting for gender, gestational age, and three common comorbidities, cystic PVL was an independent risk factor for postnatal epilepsy (adjust OR: 16.2; 95% CI: 6.8-38.4; p < 0.001). Postnatal epilepsy after cystic PVL was commonly the generalized type (13 of 14, 92.9%), not intractable and most occurred after 1 year of age. DISCUSSION/CONCLUSION: Cystic PVL would independently lead to postnatal epilepsy. Preterm infants with cystic PVL are at risk of postnatal epilepsy after age 1 in addition to cerebral palsy.

A Modified Small Intestinal Submucosa Patch with Multifunction to Promote Scarless Repair and Reinvigoration of Urethra.

To reconstruct and restore the functions of the male urethra is a challenging task for urologists. The acellular matrix graft currently used in the clinics is mono-functional and may cause a series of complications including stricture, fibrosis, and stone formation. As a result, such graft materials cannot meet the increasing demand for multifunctionality in the field of urethral tissue engineering. In this context, a multifunctional urethral patch is designed for the repair of urethral defects by mixing protocatechualdehyde (PCA) with small intestinal submucosa (SIS) under an alkalin condition to allow cross linking. As shown, the PCA/SIS patch possesses excellent biocompatibility, antioxidant activity, and anti-inflammatory property. More importantly, this patch can remarkably promote the adhesion, proliferation, and directional extension of rabbit bladder epithelial mucous cells (R-EMCs) as well as rabbit bladder smooth muscle cells (R-SMCs), and upregulate the expression of cytokeratin in the EMCs and contractile protein in the SMCs in vitro. In vivo experiments also confirm that the PCA/SIS patch can significantly enhance scarless repair of urethral defects in rabbits by facilitating smooth muscle regeneration, reducing excessive collagen deposition, and accelerating re-epithelialization and neovascularization. Taken together, the newly developed multifunctional PCA/SIS patch provides a promising candidate for urethral regeneration.

Application of mobile-based web app to enhance simple suturing skills of nurse practitioners.

BACKGROUND: Suturing is a crucial clinical skill for nurse practitioners (NPs), but the effectiveness of traditional training methods (e.g., physical suture kits combined with video content) is low. OBJECTIVE: This study compared the effectiveness and usability of a mobile-based web app (MoWa) developed for NPs to learn simple suturing skills with those of traditional instructional video-based training. METHODS: The MoWa system utilizes mobile devices to simulate hands-on suturing and provides learning guidance and feedback to support self-learning with a physical suturing kit. Fifty-four suturing novices (NPs) were recruited as participants, divided into an experimental group (EG: 28 participants) and a control group (CG: 26 participants), and instructed to self-learn for 3 weeks. Learning effectiveness and system usability were evaluated through a pretest and posttest. RESULTS: The EG exhibited significant improvements in learning outcomes, self-confidence, self-efficacy, and learning anxiety and expressed satisfaction with the MoWa system. Furthermore, the EG also considerably enhanced learning outcomes, self-efficacy, and learning anxiety compared to the CG, with no significant difference in self-confidence. CONCLUSION: The MoWa system combined with deliberate practice is an effective strategy for supporting suturing skills training.

Intra-practice Urologist-level Variation in Targeted Fusion Biopsy Outcomes.

OBJECTIVE: To examine the extent to which the urologist performing biopsy contributes to variation in prostate cancer detection during fusion-guided prostate biopsy. METHODS: All men in the Michigan Urological Surgery Improvement Collaborative (MUSIC) clinical registry who underwent fusion biopsy at Michigan Medicine from August 2017 to March 2019 were included. The primary outcomes were clinically significant cancer detection rate (defined as Gleason Grade ≥2) in targeted cores and clinically significant cancer detection on targeted cores stratified by PI-RADS score. Bivariate and multivariable logistic regression analyses were performed. RESULTS: A total of 1133 fusion biopsies performed by 5 providers were included. When adjusting for patient age, PSA, race, family history, prostate volume, clinical stage, and PI-RADS score, there was no significant difference in targeted clinically significant cancer detection rates across providers (range = 38.5%-46.9%, adjusted P-value = .575). Clinically significant cancer detection rates ranged from 11.1% to 16.7% in PI-RADS 3 (unadjusted P = .838), from 24.6% to 43.4% in PI-RADS 4 (adjusted P = .003), and from 69.4% to 78.8% in PI-RADS 5 (adjusted P = .766) lesions. CONCLUSION: There was a statistically significant difference in clinically significant prostate cancer detection in PI-RADS 4 lesions across providers. These findings suggest that even among experienced providers, variation at the urologist level may contribute to differences in clinically significant cancer detection rates within PI-RADS 4 lesions. However, the relative impact of biopsy technique, radiologist interpretation, and MR acquisition protocol requires further study.

Novel Variations in the KDM5C Gene Causing X-Linked Intellectual Disability.

BACKGROUND AND OBJECTIVES: To investigate the pathogenicity of 2 novel KDM5C variations, report the clinical and neuroimaging findings, and review the available literature. METHODS: Physical examinations, structural neuroimaging studies, and exome sequence analysis were performed. KDM5C constructs were used to study the effect of the variations in transfected cells. RESULTS: We identified 2 novel variations c.2233C>G and c.3392_3393delAG in the KDM5C gene harboring from 2 Chinese families with X-linked intellectual disability (ID). The affected male patients exhibited severe ID, short stature, and facial dysmorphism. The 1 with c.3392_3393delAG additionally had epilepsy and autistic spectrum disorder (ASD). Transiently transfected mutant KDM5C constructs both reduced protein expression and stability and decreased histone demethylase activities in cells. Reviewing the available literature, we found that the associated ASD tended to occur in patients with variations near the C-terminus of KDM5C. DISCUSSION: We report the clinical, molecular genetic, and pathologic features in patients with novel variations of KDM5C. The variability of the clinical phenotype in addition to an ID may associate with altered particular parts of KDM5C.

Living with Parkinson's disease: disease and medication experiences of patients and caregivers.

PURPOSE: Symptoms and medication use in patients with Parkinson's disease (PD) affect the quality of life of patients and caregivers, yet prior research seldom focused on their experiences with medications. This study explored comprehensive living and medication experience from patients with PD and their caregivers. METHODS: Patients diagnosed with PD for ≥2 years, with or without their caregivers, were recruited from an outpatient clinic in Taiwan. Semi-structured in-depth interviews were conducted based on the Common Sense Model. A qualitative content analysis was used to identify salient themes from verbatim transcripts. RESULTS: In total, 15 patients and eight caregivers were interviewed. Five themes were derived: (1) symptoms and help-seeking behaviours before a diagnosis, (2) emotional impacts and life adaptations after a PD diagnosis, (3) life affected by medications, (4) experiences of caregivers in taking care of PD patients, and (5) communication between doctors and patients. CONCLUSIONS: Patients frequently adjusted their daily schedules to live with PD and the medication side effects. Caregivers struggle to overcome caring burdens and to stay positive to support patients. More attention on providing medication information, mental support, and communication between stakeholders is needed to improve the quality of life of patients and caregivers.

Cause of Death During Renal Cell Carcinoma Survivorship: A Contemporary, Population-Based Analysis.

Background: As the survival rates of patients with renal cell carcinoma (RCC) continue to increase, noncancer causes of death cannot be ignored. The cause-specific mortality in patients with RCC is not well understood. Objective: Our study aimed to explore the mortality patterns of contemporary RCC survivors. Methods: We performed a retrospective cohort study involving patients with RCC from the Surveillance, Epidemiology, and End Results (SEER) database. We used standardized mortality ratios (SMRs) to compare the death rates in patients with RCC with those in the general population. Results: A total of 106,118 patients with RCC, including 39,630 who died (27%), were included in our study. Overall, compared with the general US population, noncancer SMRs were increased 1.25-fold (95% confidence intervals [CI], 1.22 to 1.27; observed, 11,235), 1.19-fold (95% CI, 1.14 to 1.24; observed, 2,014), and 2.24-fold (95% CI, 2.11 to 2.38; observed, 1,110) for stage I/II, III, and IV RCC, respectively. The proportion of noncancer causes of death increased with the extension of survival time. A total of 4,273 men with stage I/II disease (23.13%) died of RCC; however, patients who died from other causes were 3.2 times more likely to die from RCC (n = 14,203 [76.87%]). Heart disease was the most common noncancer cause of death (n = 3,718 [20.12%]; SMR, 1.23; 95% CI, 1.19-1.27). In patients with stage III disease, 3,912 (25.98%) died from RCC, and 2,014 (13.37%) died from noncancer causes. Most patients (94.99%) with stage IV RCC died within 5 years of initial diagnosis. Although RCC was the leading cause of death (n = 12,310 [84.65%]), patients with stage IV RCC also had a higher risk of noncancer death than the general population (2.24; 95% CI, 2.11-2.38). Conclusions: Non-RCC death causes account for more than 3/4 of RCC survivors among patients with stage I/II disease. Patients with stage IV are most likely to die of RCC; however, there is an increased risk of dying from septicemia, and suicide cannot be ignored. These data provide the latest and most comprehensive assessment of the causes of death in patients with RCC.

Small interfering RNA targeting N-cadherin regulates cell proliferation and migration in enzalutamide-resistant prostate cancer.

Enzalutamide is one of the options for treating patients with castration-resistant or metastatic prostate cancer. However, a substantial proportion of patients become resistant to enzalutamide after a period of treatment. Cells in these tumors typically exhibit increased proliferative and migratory capabilities, in which N-cadherin (CDH2) appear to serve an important role. In the present study, by up- and downregulating the expression of CDH2, the possible effects of CDH2 on the prostate cancer cell line LNCaP were investigated. Male sex hormone-sensitive LNCaP cells treated with 10 µM enzalutamide were named LNCaP enzalutamide-resistant (EnzaR) cells. Reverse transcription-PCR, western blotting and immunofluorescence staining were used to measure CDH2, E-cadherin, α-SMA, Snail and Slug expression. Transfection with the pCMV-CDH2 plasmid was performed for CDH2 upregulation, whilst transfection with small interfering RNA (siRNA)-CDH2 was performed for CDH2 downregulation. MTT and Cell Counting Kit-4 assays were used to evaluate the proportion of viable cancer cells. Subsequently, gap closure assay was performed to evaluate the migratory capability of both LNCaP and LNCaP EnzaR cell lines. CDH2 expression was found to be increased in LNCaP EnzaR cells compared with that in LNCaP cells. CDH2 overexpression increased cell viability and migration in both LNCaP and LNCaP EnzaR cell lines. By contrast, the opposite trend was observed after CDH2 expression was knocked down. CDH2 expression also showed a high association with that of four epithelial-mesenchymal transition markers, which was confirmed by western blotting. Based on these results, it was concluded that knocking down CDH2 expression using siRNA transfection mediated significant influence on LNCaP EnzaR cell physiology, which may be a potential therapeutic option for prostate cancer treatment.

A Case Series: Continuous Kidney Replacement Therapy in Neonates With Low Body Weight.

Emerging data indicate that acute kidney injury (AKI) may contribute to a worse prognosis in the infant population. Kidney replacement therapy (KRT) can be used to treat patients with AKI; however, this technique is challenging in patients in the neonatal intensive care units (NICUs) due to the low body weights and blood volumes in this population. Peritoneal dialysis (PD) is a potential modality since it is technically less challenging. However, PD has been associated with several disadvantages, including poor fluid status control, catheter-associated leakage, and peritonitis. Unfortunately, these complications can cause the temporary cessation of PD. Continuous kidney replacement therapy (CKRT) may represent a suitable alternative for PD. CKRT may be technically feasible in infants; however, little is known about the application of CKRT in neonates with low body weights. In this report, we discuss three cases of CKRT who were treated in the NICU at a tertiary medical center in southern Taiwan. We selected an adequate catheter diameter and achieved vascular access via an internal jugular vein or umbilical vein. The prescription of an appropriate dose of heparin was then used to prolong the circuit life of the CKRT. The maintenance of circuit durability in neonates with low body weight remains problematic. We hope that our experience can assist with the future clinical management of CKRT in neonates with low body weight.

Microbial Response to Fungal Infection in a Fungus-Growing Termite, Odontotermes formosanus (Shiraki).

The crosstalk between gut microbiota and host immunity has emerged as one of the research foci of microbiome studies in recent years. The purpose of this study was to determine how gut microbes respond to fungal infection in termites, given their reliance on gut symbionts for food intake as well as maintaining host health. Here, we used Metarhizium robertsii, an entomopathogenic fungus, to infect Odontotermes formosanus, a fungus-growing termite in the family Termitidae, and documented changes in host gut microbiota via a combination of bacterial 16S rDNA sequencing, metagenomic shotgun sequencing, and transmission electron microscopy. Our analyses found that when challenged with Metarhizium, the termite gut showed reduced microbial diversity within the first 12 h of fungal infection and then recovered and even surpassed pre-infection flora levels. These combined results shed light on the role of gut flora in maintaining homeostasis and immune homeostasis in the host, and the impact of gut flora dysbiosis on host susceptibility to infection.

Magnolol may contribute to barrier function improvement on imiquimod-induced psoriasis-like dermatitis animal model via the downregulation of interleukin-23.

Psoriasis is a chronic, recurrent, immune-mediated disease involving the skin and joints. Epidermal hyperproliferation, abnormal keratinocyte differentiation, angiogenesis with blood vessel dilatation, and excess T helper type-1 (Th-1) and Th-17 cell infiltration are the main histopathological features of psoriasis. Magnolol is a polyphenolic compound that exerts its biological properties through a variety of mechanisms such as the NF-κB/MAPK, Nrf2/HO-1 and PI3K/Akt pathways. Magnolol has been demonstrated to exert a number of therapeutic effects on dermatological processes, including acting as an anti-inflammation, antiproliferation and antioxidation agent. However, few studies have been published on the effect of magnolol on psoriasis. Therefore, the present study aimed to elucidate the mechanism of action of magnolol on psoriasis. BALB/c mice were treated topically with imiquimod (IMQ) to induce psoriasis-like dermatitis, and were randomly assigned to the control, vehicle control, low- and high-dose magnolol, and 0.25% desoximetasone ointment treatment groups in order to investigate skin barrier function, any changes in the levels of cytokines and for the histological assessment. High doses of magnolol were indicated to be able to improve the barrier function following IMQ-induced barrier disruption. Magnolol activated peroxisome proliferator-activated receptor-γ, and also significantly inhibited the protein expression of interleukin (IL)-23, IL-1ß, IL-6, tumor necrosis factor-α and interferon-γ. However, administering a high dose of magnolol did not lead to any improvement in the clinical and pathological features of the psoriasis severity Taken together, these results demonstrated that downregulation of IL-23 may contribute to barrier function improvement in a psoriatic skin model.