Intra-articular Histone Deacetylase Inhibitor Microcarrier Delivery to Reduce Osteoarthritis.

The histone deacetylase inhibitor (HDACi) was a milestone in the treatment of refractory T-cell lymphoma. However, the beneficial effects of HDACi have not been appreciated in osteoarthritis (OA). Herein, we implemented a microcarrier system because of the outstanding advantages of controlled and sustained release, biodegradability, and biocompatibility. The poly(d,l-lactide-co-glycolide) (PLGA) microcapsules have a regulated and sustained release profile with a reduced initial burst release, which can improve the encapsulation efficiency of the Chidamide. The emulsion solvent evaporation strategy was used to encapsulate Chidamide in PLGA microcapsules. The encapsulation of Chidamide was established by UV-vis spectra and scanning electron microscopy. Additionally, the inhibition of Tnnt3 and immune stimulation by Chidamide helped to inhibit cartilage destruction and prevent articular cartilage degeneration. Based on the results, the Chidamide in PLGA microcapsules provides a transformative therapeutic strategy for the treatment of osteoarthritis patients to relieve symptoms and protect against cartilage degeneration.

Effects of refined nursing interventions in the operating room on surgical-site wound infection in patients with lung cancer: A meta-analysis.

In this study, a meta-analysis was conducted to assess the effect of refined nursing interventions in the operating room on the incidence of surgical-site wound infections in patients undergoing lung cancer surgery to provide an evidence base for the prevention and management of nosocomial infections. A computerised literature search was used to identify randomised controlled trials (RCTs) on the application of refined nursing interventions in the operating room in patients undergoing lung cancer surgery published in the PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), VIP and Wanfang databases from their inception until July 2023. The literature screening, data extraction and quality assessment of the included studies were performed independently by two researchers. RevMan 5.4 software was used for the meta-analysis. Twenty-eight studies were included in the analysis, with a total of 2406 patients, including 1210 patients in the refined nursing intervention group and 1196 patients in the control group. The results of the meta-analysis showed that the refined nursing interventions in the operating room significantly reduced the incidence of surgical-site wound infections in patients undergoing lung cancer surgery, compared with the control group (1.82% vs. 6.52%, odds ratio: 0.30, 95% CI: 0.19-0.47, p < 0.001), and shortened the length of hospital stay (standardised mean difference: -1.51 days, 95% CI: -1.92 to -1.11 days, p < 0.001). Current evidence suggests that the application of refined nursing interventions in the operating room is effective at reducing the incidence of surgical-site wound infections and shortening the length of hospital stay in patients undergoing lung cancer surgery. However, owing to the small number and low quality of the studies, more high-quality RCTs with large sample sizes are needed to confirm these results.

Molecular basis for substrate recognition by the bacterial nucleoside transporter NupG.

Nucleoside homeostasis, which is mediated by transporters and channels, is essential for all life on Earth. In Escherichia coli, NupG mediates the transport of nucleosides and was deemed to be the prototype of the nucleoside proton symporter (NHS) family and the major facilitator superfamily. To date, the substrate recognition and transport mechanisms of NHS transporters are still elusive. Here, we report two crystal structures of NupG (WT and D323A NupG) resolved at 3.0 Å. Both structures reveal an identical inward-open conformation. Together with molecular docking and molecular dynamics simulations and in vitro uridine-binding assays, we found that the uridine binding site, which locates in the central cavity between N and C domains of NupG, is constituted by R136, T140, F143, Q225, N228, Q261, E264, Y318, and F322. Moreover, we found that D323 is very important for substrate binding via in vitro uridine-binding assays using D323 mutations, although it does not have a direct contact with uridine. Our structural and biochemical data therefore provide an important framework for the mechanistic understanding of nucleoside transporters of the NHS family.

Superoxide dismutase 3 facilitates the chondrogenesis of bone marrow-derived mesenchymal stem cells.

Articular cartilage defects are considered a major clinical problem because they cannot heal by themselves. To date, bone marrow-derived mesenchymal stem cells (BMSCs)-based therapy has been widely applied for cartilage repair. However, fibrocartilage was often generated after BMSC therapy; therefore, there is an urgent need to stimulate and maintain BMSCs chondrogenic differentiation. The specific role of superoxide dismutase 3 (SOD3) in chondrogenesis is unknown; therefore, the present study aimed to clarify whether SOD3 could facilitate the chondrogenic differentiation of BMSCs. We first evaluated SOD3 protein levels during chondrogenesis of BMSCs using plate cultures. We then tested whether SOD3 could facilitate chondrogenesis of BMSCs using knockdown or overexpression experiments. Increased SOD3 protein levels were observed during BMSCs chondrogenesis. SOD3 knockdown inhibited collagen type II alpha 1 chain (COL2A1), aggrecan (ACAN), and SRY-box 9 (SOX9) expression. Overexpression of SOD3 increased the levels of chondrogenesis markers (COL2A1, ACAN, and SOX9). Elevated superoxide anions were observed when SOD3 was knocked down. We concluded that SOD3 could facilitate chondrogenesis of BMSCs to improve cartilage regeneration.

Quadriceps-sparing versus traditional medial parapatellar approaches for total knee arthroplasty: a meta-analysis.

BACKGROUND: There is still controversy regarding whether Quadriceps-sparing (QS) approach for total knee arthroplasty (TKA) lead to better earlier recovery as well as compromising low limb alignment and prosthesis position compared with conventional medial parapatellar (MP) approach. To overcome the shortcomings and inaccuracies of single studies, the clinical outcomes and radiographic assessments of QS approach and MP approach were evaluated through meta-analysis. METHODS: We performed this meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. A literature search was conducted in the PubMed, EMBase, Cochrane Collaboration Library and Web of Science databases. Our search strategy followed the requirements of the Cochrane Library Handbook. The study selection, data extraction and assessment of methodological quality were independently completed by four authors. And subgroup analysis and publication bias were also performed in the study. RESULTS: Eight prospective randomized controlled trials (RCTs) and eight retrospective studies were identified. Overall meta-analysis and subgroup meta-analysis of RCTs identified the QS approach mainly was associated with increased Knee Society function score beyond 24 months postoperatively (weighted mean difference [WMD] 1.78, P = 0.0004) (WMD 1.86, P = 0.0002), and improved range of motion 1-2 weeks postoperatively (WMD 5.84, P < 0.00001) (WMD 4.87, P = 0.002). Besides, lower visual analogue scale on postoperative day 1 (WMD -0.91, P = 0.02), shorter hospital stay (WMD -0.88, P = 0.02) and shorter incision (extension) (WMD -4.62, P < 0.00001) were indicated in overall meta-analysis. However, surgical and tourniquet time was significantly longer in QS group by both overall and subgroup meta-analysis. CONCLUSIONS: QS approach may accelerate early recovery without increasing the risk of malalignment of low limb and malposition of prosthesis.

Tumor-derived high-mobility group box 1 and thymic stromal lymphopoietin are involved in modulating dendritic cells to activate T regulatory cells in a mouse model.

High-mobility group box 1 (HMGB1) is involved in the tumor-associated activation of regulatory T cells (Treg), but the mechanisms remain unknown. In a mouse tumor model, silencing HMGB1 in tumor cells or inhibiting tumor-derived HMGB1 not only dampened the capacity of tumor cells to produce thymic stromal lymphopoietin (TSLP), but also aborted the tumor-associated modulation of Treg-activating DC. Tumor-derived HMGB1 triggered the production of TSLP by tumor cells. Importantly, both tumor-derived HMGB1 and TSLP were necessary for modulating DC to activate Treg in a TSLP receptor (TSLPR)-dependent manner. In the therapeutic model, intratumorally inhibiting tumor-derived HMGB1 (causing downstream loss of TSLP production) attenuated Treg activation, unleashed tumor-specific CD8 T cell responses, and elicited CD8α+/CD103+DC- and T cell-dependent antitumor activity. These results suggest a new pathway for the activation of Treg involving in tumor-derived HMGB1 and TSLP, and have important implications for incorporating HMGB1 inhibitors into cancer immunotherapy.

Genetic vaccines to potentiate the effective CD103+ dendritic cell-mediated cross-priming of antitumor immunity.

The development of effective cancer vaccines remains an urgent, but as yet unmet, clinical need. This deficiency is in part due to an incomplete understanding of how to best invoke dendritic cells (DC) that are crucial for the induction of tumor-specific CD8(+) T cells capable of mediating durable protective immunity. In this regard, elevated expression of the transcription factor X box-binding protein 1 (XBP1) in DC appears to play a decisive role in promoting the ability of DC to cross-present Ags to CD8(+) T cells in the therapeutic setting. Delivery of DNA vaccines encoding XBP1 and tumor Ag to skin DC resulted in increased IFN-α production by plasmacytoid DC (pDC) from skin/tumor draining lymph nodes and the cross-priming of Ag-specific CD8(+) T cell responses associated with therapeutic benefit. Antitumor protection was dependent on cross-presenting Batf3(+) DC, pDC, and CD8(+) T cells. CD103(+) DC from the skin/tumor draining lymph nodes of the immunized mice appeared responsible for activation of Ag-specific naive CD8(+) T cells, but were dependent on pDC for optimal effectiveness. Similarly, human XBP1 improved the capacity of human blood- and skin-derived DC to activate human T cells. These data support an important intrinsic role for XBP1 in DC for effective cross-priming and orchestration of Batf3(+) DC-pDC interactions, thereby enabling effective vaccine induction of protective antitumor immunity.

The roles of metabolic thermogenesis in body fat regulation in striped hamsters fed high-fat diet at different temperatures.

The metabolic thermogenesis plays important roles in thermoregulation, and it may be also involved in body fat regulation. The thermogenesis of brown adipose tissue (BAT) is largely affected by ambient temperature, but it is unclear if the roles in body fat regulation are dependent on the temperature. In the present study, uncoupling protein 1 (ucp1)-based BAT thermogenesis, energy budget and body fat content were examined in the striped hamsters fed high fat diet (HF) at cold (5°C) and warm (30°C) temperatures. The effect of 2, 4-dinitrophenol (DNP), a chemical uncoupler, on body fat was also examined. The striped hamsters showed a notable increase in body fat following the HF feeding at 21°C. The increased body fat was markedly elevated at 30°C, but was significantly attenuated at 5°C compared to that at 21°C. The hamsters significantly increased energy intake at 5°C, but consumed less food at 30°C relative to those at 21°C. Metabolic thermogenesis, indicated by basal metabolic rate, UCP1 expression and/or serum triiodothyronine levels, significantly increased at 5°C, but decreased at 30°C compared to that at 21°C. A significant decrease in body fat content was observed in DNP-treated hamsters relative to the controls. These findings suggest that the roles of metabolic thermogenesis in body fat regulation largely depend on ambient temperature. The cold-induced enhancement of BAT thermogenesis may contribute the decreased body fat, resulting in a lean mass. Instead, the attenuation of BAT thermogenesis at the warm may result in notable obesity.

Risk of total/subtotal meniscectomy for respective medial and lateral meniscus injury: correlation with tear type, duration of complaint, age, gender and ACL rupture in 6034 Asian patients.

BACKGROUND: To evaluate the risk factor associated with total or subtotal meniscectomy for respective medial and lateral meniscus injury. METHODS: The data of all the meniscus injured patients undergoing arthroscopy in our institute between January 15th, 2000 and December 31st, 2008 was collected and 6034 patients with 7241 injured menisci met the inclusion criteria. The mean patient age was 33.6 ± 14.9 years and there were 4785 males and 2456 females with 3568 medial and 3673 lateral menisci. The decision tree approach was applied to investigate the correlation of the tear type, the duration of complaint, age, gender, ACL rupture and total/subtotal meniscectomy for respective medial and lateral meniscus. RESULTS: The tear type was associated with both medial (χ2 = 70.901, P < 0.001) and lateral (χ2 = 268.019, P < 0.001) total/subtotal meniscectomy. The strongest risk of total/subtotal meniscectomy of both medial and lateral meniscus tear was shown for the complex tear followed by the longitudinal, oblique, horizontal and radial tear of the medial meniscus and followed by horizontal, longitudinal, radial and oblique tear of the lateral meniscus. The risk of total/subtotal medial meniscectomy was significantly elevated for the patients with complex tear and the age of ≤40 years old (χ2 = 21.028, P < 0.001) and those with the oblique, horizontal or radial tear accompanied by ACL rupture (χ2 = 6.631, P = 0.01). Besides, the duration of complaint was also associated with total/subtotal meniscectomy of the medial longitudinal tear with ACL rupture (χ2 = 17.155, P < 0.001). On the other side, the risk of total/subtotal lateral meniscectomy was significantly elevated for the complex tear of the female patients (χ2 = 5.877, P = 0.015) with no ACL rupture (χ2 = 50.501, P < 0.001). The ACL rupture was associated with a decreased risk of total/subtotal meniscectomy for all the types of the lateral meniscus (complex: χ2 = 50.501, P < 0.001; horizontal: χ2 = 20.897, P < 0.001; oblique: χ2 = 27.413, P < 0.001; longitudinal and radial: χ2 = 110.85, P < 0.001). CONCLUSION: Analyzing data from a big sample available in an Asian patient database, we found different risk factors associated with total/subtotal meniscectomy for respective medial and lateral meniscus. Identifying patients at high risk for total/subtotal meniscectomy may allow for interventions after meniscus injury.

Plasticity in gastrointestinal morphology and enzyme activity in lactating striped hamsters (Cricetulus barabensis).

In small mammals, marked phenotypic plasticity of digestive physiology has been shown to make it easier for them to cope with energetically stressful periods, such as lactation. It has been proposed that the capacity of the gut to digest and absorb food is not the limiting factor to sustained energy intake (SusEI) during peak lactation. In this study, plasticity in energy intake and gastrointestinal morphology was examined in striped hamsters at different stages of reproduction and when raising litters of different sizes. Mechanisms associated with digestive enzymes and neuroendocrine hormones underpinning the plasticity were also examined. Females significantly increased energy intake, digestibility, digestive tract mass and the activity of stomach pepsin and small intestine maltase, sucrase and aminopeptidase in peak lactation compared with the non-productive and post-lactating periods. Further, females raising large litters significantly increased energy intake, digestibility, gastrointestinal mass and activity of digestive enzymes, and weaned heavier offspring compared with those nursing small and medium litters, indicating that the significant plasticity of digestive physiology increased reproductive performance. Agouti-related protein (AgRP) mRNA expression in the hypothalamus was up-regulated significantly in females raising large litters relative to those raising small litters. Serum leptin levels, and mRNA expression of hypothalamus neuropeptide Y (NPY) and the anorexigenic neuropeptides pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) did not differ among females raising small, medium and large litters. Leptin levels in lactation may only reflect a state of energy balance rather than being the prime driver of hyperphagia. Some hypothalamic neuropeptides, such as NPY, POMC and CART, may be involved in the limits to the SusEI during lactation.

Intraoperative anthropomorphic study of anterior femoral condyles compared with sizing of femoral arthroplasty.

PURPOSE: The present study was designed to compare the dimensions of the anterior femoral condyle with those of the anterior component flange using intraoperative morphological data. METHODS: Overall, 1227 knees in 962 patients were included in this study. The height of the anterior lateral/medial condylar height (ALCH/AMCH) was measured and compared between men and women. These morphological data were compared with the dimensions of the chosen component for each patient. The lateral/medial anterior femoral offset was calculated, and the over-/understuffing rates were compared between men and women. RESULTS: The median ALCH in men was 8.5 mm (6.5, 10.0 mm) versus 7.0 mm (6.0, 9.0 mm) in women. The median AMCH in men was 4.0 mm (2.5, 6.0 mm) versus 3.5 mm (2.5, 6.0 mm) in women. There was a significant difference between the genders with respect to ALCH (p < 0.05). When the dimensions of the component were compared with those of the native knee, the anterior lateral flange height was smaller than the native knees (1.3 mm in male, 0.7 mm in female), but the anterior medial flange height was larger than the corresponding condyle (1.8 mm in male, 1.8 mm in female). A significant difference was observed between the genders with respect to the ideal fit rate of ALCH (p < 0.01). CONCLUSION: The results demonstrate that gender differences exist in the anterior lateral condyles of knees. The anterior flange of component is not designed to precisely reproduce normal trochlear anatomy. LEVEL OF EVIDENCE: II.

Food restriction attenuates oxidative stress in brown adipose tissue of striped hamsters acclimated to a warm temperature.

It has been suggested that the up-regulation of uncoupling proteins (UCPs) decreases reactive oxygen species (ROS) production, in which case there should be a negative relationship between UCPs expression and ROS levels. In this study, the effects of temperature and food restriction on ROS levels and metabolic rate, UCP1 mRNA expression and antioxidant levels were examined in the brown adipose tissue (BAT) of the striped hamsters (Cricetulus barabensis). The metabolic rate and food intake of hamsters which had been restricted to 80% of ad libitum food intake, and acclimated to a warm temperature (30°C), decreased significantly compared to a control group. Hydrogen peroxide (H2O2) levels were 42.9% lower in food restricted hamsters than in the control. Malonadialdehyde (MDA) levels of hamsters acclimated to 30°C that were fed ad libitum were significantly higher than those of the control group, but 60.1% lower than hamsters that had been acclimated to the same temperature but subject to food restriction. There were significantly positive correlations between H2O2 and, MDA levels, catalase activity, and total antioxidant capacity. Cytochrome c oxidase activity and UCP1 mRNA expression significantly decreased in food restricted hamsters compared to the control. These results suggest that warmer temperatures increase oxidative stress in BAT by causing the down-regulation of UCP1 expression and decreased antioxidant activity, but food restriction may attenuate the effects.

Optimal patellar alignment with minimally invasive approaches in total knee arthroplasty after a minimum five year follow-up.

PURPOSE: Patellofemoral syndrome is still a common complication after total knee arthroplasty (TKA). However, the effects of specific surgical approaches on patellar tracking and alignment remain incompletely understood. In this study, we compared patellar alignment in patients who underwent TKA via three different techniques. METHODS: A total of 96 patients who completed a minimum follow-up of five years were involved in three groups: 30 patients were treated with the traditional medial parapatellar approach (MPP group), 35 patients were treated with the mini-medial parapatellar approach (MMP group) and 31 were treated with a quadriceps-sparing approach (QS group). Radiographic data for patellar alignment and clinical results were compared. RESULTS: Patellar tilt and patellar displacement at the final follow-up evaluation differed significantly among the three groups [P < 0.01, analysis of variance (ANOVA)]. The MMP and QS groups exhibited more proper patellar alignment than the MPP group. The clinical results did not differ significantly among the groups (P > 0.05, ANOVA). In addition, there were no correlations between postoperative patellar alignment and clinical scores. CONCLUSIONS: The results of this study indicate that TKA performed using minimally invasive approaches yields superior patellar alignment compared to the traditional MPP approach.

Different tenogenic differentiation capacities of different mesenchymal stem cells in the presence of BMP-12.

BACKGROUND: Mesenchymal stem cells (MSCs) are regarded as a promising cell-based therapeutic tool for tendon repair. This study aimed to compare the different tenogenic differentiation capacities of the three types of MSCs in the presence of bone morphogenic protein 12 (BMP-12). METHODS: MSCs were isolated from rat bone marrow (BM), inguinal adipose tissue (AD), and synovium (SM) from the knee joint. MSCs were characterized by morphology, proliferation, trilineage differentiation, and surface marker analysis. Tenogenic differentiation potential was initially assessed using real-time polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay in vitro. Histological assessments were also performed after subcutaneous implantation of BMP-12 recombinant adenovirus-infected MSCs in nude mice in vivo. RESULTS: The three types of MSCs exhibited similar fibroblast-like morphology and surface markers but different differentiation potentials toward adipogenic, osteogenic, and chondrogenic lineage fates. Bone marrow-derived MSCs (BM-MSCs) showed the most superior in vitro tenogenic differentiation capacity, followed by synovial membrane-derived MSCs (SM-MSCs) and then adipose-derived MSCs (AD-MSCs). After implantation, all three types of MSC masses infected with BMP-12 recombinant adenovirus emerged in the form of fiber-like matrix, especially in 6-week specimens, compared with the control MSCs in vivo. BM-MSCs and SM-MSCs revealed more intense staining for collagen type I (Col I) compared with AD-MSCs. Differences were not observed between BM-MSCs and SM-MSCs. However, SM-MSCs demonstrated higher proliferation capacity than BM-MSCs. CONCLUSION: BM-MSCs exhibited the most superior tenogenic differentiation capacity, followed by SM-MSCs. By contrast, AD-MSCs demonstrated the inferior capacity among the three types of MSCs in the presence of BMP-12 both in vivo and in vitro.

Repair of articular cartilage defects in the knee with autologous iliac crest cartilage in a rabbit model.

PURPOSE: To demonstrate that iliac crest cartilage may be used to repair articular cartilage defects in the knees of rabbits. METHODS: Full-thickness cartilage defects were created in the medial femoral condyle on both knees of 36 New Zealand white rabbits. The 72 defects were randomly assigned to be repaired with ipsilateral iliac crest cartilage (Group I), osteochondral tissues removed at defect creation (Group II), or no treatment (negative control, Group III). Animals were killed at 6, 12, and 24 weeks post-operatively. The repaired tissues were harvested for magnetic resonance imaging (MRI), histological studies (haematoxylin and eosin and immunohistochemical staining), and mechanical testing. RESULTS: At 6 weeks, the iliac crest cartilage graft was not yet well integrated with the surrounding articular cartilage, but at 12 weeks, the graft deep zone had partial ossification. By 24 weeks, the hyaline cartilage-like tissue was completely integrated with the surrounding articular cartilage. Osteochondral autografts showed more rapid healing than Group I at 6 weeks and complete healing at 12 weeks. Untreated defects were concave or partly filled with fibrous tissue throughout the study. MRI showed that Group I had slower integration with surrounding normal cartilage compared with Group II. The mechanical properties of Group I were significantly lower than those of Group II at 12 weeks, but this difference was not significant at 24 weeks. CONCLUSION: Iliac crest cartilage autografts were able to repair knee cartilage defects with hyaline cartilage and showed comparable results with osteochondral autografts in the rabbit model.

[Comparison of clinical results between middle-aged patients and young patients after anterior cruciate ligament reconstruction].

OBJECTIVE: To compare the outcomes of anterior cruciate ligament (ACL) reconstruction in patients aged over 40 years and under 25 years at least 24 months follow-up after operation. METHODS: Fifty-seven patients who underwent ACL reconstruction for ACL rupture in Institute of Sports Medicine, Peking University Third Hospital, from October 2010 to December 2012 were selected for this retrospective study.The patients aged over 40 years consisted of 13 men and 15 women with an average age of 46.5 years (range, 41 to 63 years). The patients younger than 25 years consisted of 19 men and 10 women with an average age of 21.0 years (range, 18 to 24 years). The average follow-up time was 26.0 months (range, 24 to 45 months). Clinical functional evaluation for all patients was performed according to Lysholm, Tegner and IKDC scores both before and after surgery.In addition, a pre- and post-operative arthrometric evaluation was also performed with KT-2000. RESULTS: The average postoperative Lysholm, Tegner and IKDC scores in patients aged over 40 years and under 25 years were 89 (74 to 100), 5 (3 to 6), 90 (70 to 100) and 94 (79 to 100), 5 (4 to 7), 93 (74 to 100) respectively.The average postoperative KT-2000 arthrometer anterior laxity in 30° and 90° in both groups was 2 mm (0 to 4 mm), 1 mm (-1 to 4 mm) and 2 mm (0 to 4 mm), 1 mm (0 to 4 mm) respectively.The postoperative functional scores and side-to-side difference improved more significantly than preoperative values, with no significant difference in both groups. CONCLUSION: ACL reconstruction provides the comparable clinical outcomes between middle-aged patients and young patients.

Exogenous IFN-beta regulates the RANKL-c-Fos-IFN-beta signaling pathway in the collagen antibody-induced arthritis model.

BACKGROUND: Although a variety of drugs have been used to treat the symptoms of rheumatoid arthritis (RA), none of them are able to cure the disease. Interferon ß (IFN-ß) has pleiotropic effects on RA, but whether it can be used to treat RA remains globally controversial. Thus, in this study we tested the effects of IFN-ß on RA patients and on collagen antibody-induced arthritis (CAIA) model mice. METHODS: The cytokine and auto-antibody expression profiles in the serum and synovial fluid (SF) from RA patients were assessed using enzyme-linked immunosorbent assay (ELISA) and compared with the results from osteoarthritis (OA) patients. Exogenous IFN-ß was administered to RA patients and CAIA model mice, and the therapeutic effects were evaluated. Endogenous IFN-ß expression in the joint bones of CAIA model mice was evaluated by quantitative real-time PCR (qRT-PCR). The effects of exogenous IFN-ß on CAIA model mice were assessed using a clinical scoring system, hematoxylin eosin and safranin-O with fast green counterstain histology, molybdenum target X-ray, and tartrate-resistant acid phosphatase (TRAP) staining. The RANKL-RANK signaling pathway was analyzed using qRT-PCR. The RAW 264.7 cell line was differentiated into osteoclasts with RANKL stimulation and then treated with exogenous IFN-ß. RESULTS: The expression of inflammatory cytokines (IFN-γ, IL-17, MMP-3, and RANKL) and auto-antibodies (CII antibodies, RF-IgM, and anti-CCP/GPI) were significantly higher in RA compared with OA patients. After IFN-ß intervention, some clinical symptoms in RA patients were partially alleviated, and the expression of IFN-γ, IL-17, MMP-3, and OPG) returned to normal levels. In the CAIA model, the expression of endogenous IFN-ß in the joint bones was decreased. After IFN-ß administration, the arthritis scores were decreased; synovial inflammation, cartilage, and bone destruction were clearly attenuated; and the expression of c-Fos and NFATc1 were reduced, while RANKL and TRAF6 expression was unchanged. In addition, exogenous IFN-ß directly inhibited RANKL-induced osteoclastogenesis. CONCLUSIONS: Exogenous IFN-ß administration immunomodulates CAIA, may reduce joint inflammation and, perhaps more importantly, bone destruction by inhibiting the RANKL-c-Fos signaling pathway. Exogenous IFN-ß intervention should be selectively used on RA patients because it may only be useful for RA patients with low endogenous IFN-ß expression.

Inhibiting T-Cell-Mediated Rejection of the Porcine Meniscus Through Freeze-Thawing and Downregulating Porcine Xenoreactive Antigen Genes.

Immune rejection presents a significant challenge in xenogenic meniscal transplantation. Pigs are widely regarded as an advantageous tissue source for such transplants, with porcine GGTA1, CMAH, and B4GALNT2 being among the most common xenoreactive antigen (Ag) genes. While some studies have suggested that allogeneic meniscus (AM) transplants may exhibit immunoprivileged properties, our study observed slight immunological rejection has been observed following contact between human meniscal cells (HMCs) and human peripheral blood mononuclear cells (PBMCs). Given the limited systematic research on immune responses following xenograft meniscus transplantation, we established porcine meniscus transplantation (PMT) models to comprehensively assess the immunogenicity of porcine meniscus (PM) from both innate and adaptive immune perspectives. Our investigations confirmed that PMT beneath the epidermis led to innate cell infiltration into the xenografts and T-cell activation in local lymph nodes. T-cell activation upregulated the interleukin (IL)-17 signaling pathway, disrupting collagen organization and metabolic processes, thereby hindering PM regeneration. Using freeze-thaw treatment on PM alleviated T-cell activation post-transplantation by eliminating xenogenic DNA. In vitro findings demonstrated that gene editing in porcine meniscal cells (PMCs) suppressed human T-cell activation by downregulating the expression of xenoreactive Ag genes. These results suggest that GGTA1/CMAH/B4GALNT2 knockout (KO) pigs hold significant promise for advancing the field of meniscal transplantation.

Construction and validation of a postoperative hypothermia prediction model in elderly patients undergoing colorectal surgery.

Background: Postoperative hypothermia (POH) is a common issue in colorectal surgery patients, leading to complications. This study aimed to develop and validate a predictive model for identifying POH in colorectal surgery patients. Methods: A retrospective analysis of 1,316 patients who underwent colorectal surgery between June 2020 and September 2022 was conducted using institutional medical records. Intraoperative core temperatures and potential influencing factors were collected, and regression analysis was used to identify risk factors for POH and create a model. The model's performance was evaluated using the receiver operating characteristic curve analysis. Results: Intraoperative hypothermia occurred in 51.5 % of patients. Significant predictors of POH included gender, alcohol consumption, surgery duration, platelet count, and age. The constructed model included factors like fluid intake, platelets, cigarette use, alcohol consumption, surgery type, muscle relaxants, age, ABSI, and gender. The model showed good predictive performance with an area under the ROC curve of 0.981 and a Hosmer-Lemeshow test p-value of 0.676. The Youden index, sensitivity, specificity, and practical application rate were 0.602, 0.790, 0.812, and 98.81 %, respectively. Conclusion: This study developed a predictive model for POH in colorectal surgery patients, considering individual factors and exploring underlying causes. Understanding risk factors and consequences of POH is crucial for nurses and perioperative professionals in clinical practice.

Functional meniscus reconstruction with biological and biomechanical heterogeneities through topological self-induction of stem cells.

Meniscus injury is one of the most common sports injuries within the knee joint, which is also a crucial pathogenic factor for osteoarthritis (OA). The current meniscus substitution products are far from able to restore meniscal biofunctions due to the inability to reconstruct the gradient heterogeneity of natural meniscus from biological and biomechanical perspectives. Here, inspired by the topology self-induced effect and native meniscus microstructure, we present an innovative tissue-engineered meniscus (TEM) with a unique gradient-sized diamond-pored microstructure (GSDP-TEM) through dual-stage temperature control 3D-printing system based on the mechanical/biocompatibility compatible high Mw poly(ε-caprolactone) (PCL). Biologically, the unique gradient microtopology allows the seeded mesenchymal stem cells with spatially heterogeneous differentiation, triggering gradient transition of the extracellular matrix (ECM) from the inside out. Biomechanically, GSDP-TEM presents excellent circumferential tensile modulus and load transmission ability similar to the natural meniscus. After implantation in rabbit knee, GSDP-TEM induces the regeneration of biomimetic heterogeneous neomeniscus and efficiently alleviates joint degeneration. This study provides an innovative strategy for functional meniscus reconstruction. Topological self-induced cell differentiation and biomechanical property also provides a simple and effective solution for other complex heterogeneous structure reconstructions in the human body and possesses high clinical translational potential.