Associations between immune cells signatures and osteoarthritis: An integrated analysis of bidirectional Mendelian randomization and Bayesian colocalization.

BACKGROUND: Previous investigations have explored the associations between immune cell signatures and osteoarthritis (OA); however, causality remains unclear. This study employs an integrated analysis, combining bidirectional Mendelian randomization (MR) and Bayesian colocalization (Coloc), to investigate causal relationships between 731 immune cells signatures and OA, identifying shared causal variants. METHODS: Utilizing publicly available summary data, this study primarily employs inverse variance weighting (IVW). Supplementary methods include MR-Egger regression, weighted median, weight mode, and simple mode. Various sensitivity tests, including Cochran's Q test, MR pleiotropy Residual Sum and Outlier, and leave-one-out tests, were conducted to assess the robustness of the analysis results. Coloc was employed to identify shared causal genetic variants among potential associations. RESULTS: IVW analysis revealed 196 immune cell signatures potentially linked to OA across diverse subtypes. Reverse MR analyses indicated the causal impact of OA on the levels of 140 immune cell signatures, with subtype-specific variations. Notably, several specific associations, including CD64 on CD14-CD16 + monocyte for Hip OA (OR = 1.0593, 95 % CI: 1.0260-1.0938, P = 0.0004), HLA-DR on CD14 + CD16- monocyte (OR = 0.9664, 95 % CI: 0.9497-0.9834, P = 0.0001), HLA-DR on CD14 + monocyte (OR = 0.9680, 95 % CI: 0.9509-0.9853, P = 0.0003) in the Knee or Hip OA, PDL-1 on CD14-CD16 + monocyte by All OA (OR = 1.7091, 95 %CI:1.2494-2.3378, P = 0.0008), and herpesvirus entry mediator on effector memory CD4 + T cell by Spine OA (OR = 0.5200, 95 %CI:0.3577-0.7561, P = 0.0006) remained significant post-Bonferroni correction. Sensitivity tests validated the credibility of the IVW analysis. Additionally, Coloc revealed several potential associations among shared genetic variants, including rs115328872, rs1800973, and rs317667. CONCLUSIONS: Our findings provide evidence for the potential involvement of immune cell signatures in OA development, revealing avenues for early prevention and innovative therapeutic strategies.

Brachial plexus injury after clavicle fracture operation: a case report and literature review.

BACKGROUND: Open reduction and internal fixation (ORIF) is the preferred choice for treating clavicle fractures. The brachial plexus injury caused by ORIF of a clavicle fracture is very rare. If it is not treated in time, the function of the brachial plexus will be challenging to recover, which will eventually lead to upper limb dysfunction and seriously affect the patient's quality of life. Our team recently used ORIF to treat a patient with a clavicle fracture, who developed brachial plexus injury symptoms after surgery. CASE PRESENTATION: A 34-year-old female patient was admitted to the hospital for 13 h due to the right shoulder movement restriction after a fall. Due to the significant displacement of the fracture, we used ORIF to treat the fracture. The surgery went well. When the anaesthesia effect subsided 12 h after the operation, the patient developed right brachial plexus injury symptoms, decreased right upper limb muscle strength, dysfunction, and hypoesthesia. Symptomatic treatments, such as nourishing nerve and electrical stimulation, were given immediately. Sixty days after the operation, the patient's brachial plexus injury symptoms disappeared, and the function of the right upper limb returned to the preoperative state. CONCLUSIONS: Patients with clavicle fractures usually need to undergo a careful physical examination before surgery to determine whether symptoms of brachial plexus injury have occurred. Anaesthesia puncture requires ultrasound guidance to avoid direct damage to the brachial plexus. When the fracture end is sharp, reset should be careful to prevent nerve stump stabbed. When using an electric drill to drill holes, a depth limiter should be installed in advance to prevent the drill from damaging the subclavian nerve and blood vessels. When measuring the screw depth, the measuring instrument should be close to the bone surface and sink slowly to avoid intense hooks and damage to the brachial plexus. Try to avoid unipolar electrosurgical units to prevent heat conduction from damaging nerves, and bipolar electrocoagulation should be used instead. If symptoms of brachial plexus injury occur after surgery, initial symptomatic treatment is drugs and functional exercise, and if necessary, perform surgical exploration.

The role of serum interleukins in Cancer: A Multi-center Mendelian Randomization study.

The occurrence of cancer is often accompanied by immune evasion and tumor-promoting inflammation, with interleukins (IL) playing a pivotal role in the immune-inflammatory mechanism. However, the precise contribution of serum interleukins in cancer remains elusive. We obtained GWAS summary data for 35 interleukins from eight independent large-scale serum proteome studies of European ancestry populations and for 23 common cancers from the FinnGen Consortium. We then conducted a multicenter Mendelian Randomization (MR) study to explore the relationship between systemic inflammatory status and cancers. 24 causal associations between interleukins and cancers were supported by multicenter data, 18 of which were reported for the first time. Our results indicated that IL-1α (Hodgkin lymphoma), IL-5 (bladder cancer), IL-7 (prostate cancer), IL-11 (bone malignant tumor), IL-16 (lung cancer), IL-17A (pancreatic cancer), IL-20 (bladder cancer), IL-22 (lymphocytic leukemia), IL-34 (breast cancer), IL-36ß (prostate cancer), and IL-36γ (liver cancer) were risk factors for related cancers. Conversely, IL-9 (malignant neoplasms of the corpus uteri), IL-17C (liver cancer), and IL-31 (colorectal cancer, bladder cancer, pancreatic cancer, and cutaneous melanoma) exhibited protective effects against related cancers. Notably, the dual effects of serum interleukins were also observed. IL-18 acted as a risk factor for prostate cancer, however, was a protective factor against laryngeal cancer. Similarly, IL-19 promoted the development of lung cancer and myeloid leukemia, while conferring protection against Breast, cervical, and thyroid cancers. Our study confirmed the genetic association between multiple serum interleukins and cancers. Immune and anti-inflammatory strategies targeting these associations provide opportunities for prevention and treatment.

Causal associations between rheumatoid arthritis, cataract and glaucoma in European and East Asian populations: A bidirectional two-sample mendelian randomization study.

BACKGROUND: Previous studies have indicated a heightened susceptibility to cataract and glaucoma among rheumatoid arthritis (RA) patients, while it remains uncertain whether RA is causally associated with cataract and glaucoma. A two-sample mendelian randomization (MR) analysis was used to investigate the causal associations between RA, cataract and glaucoma in European and East Asian populations. METHODS: In the European population, genome-wide association study (GWAS) summary statistics for cataract (372,386 individuals) and glaucoma (377,277 individuals) were obtained from the FinnGen consortium (R9), while RA summary data were derived from a meta-analysis of GWAS encompassing 97173 samples. In the East Asian population, summary data for cataract (212453 individuals), glaucoma (212453 individuals), and RA (22515 individuals) were sourced from the IEU Open GWAS project. Inverse-variance weighted (IVW, random-effects) method served as the primary analysis, complemented by MR‒Egger regression, weighted median, weighted mode and simple mode methods. Additionally, various sensitivity tests, including Cochran's Q test, MR‒Egger intercept, MR pleiotropy Residual Sum and Outlier test and leave-one-out test were performed to detect the heterogeneity, horizontal pleiotropy and stability of the analysis results. RESULTS: Following stringent screening, the number of selected instrumental variables ranged from 8 to 56. The IVW results revealed that RA had an increased risk of cataract (OR = 1.041, 95% CI = 1.019-1.064; P = 2.08×10-4) and glaucoma (OR = 1.029, 95% CI = 1.003-1.057; P = 2.94×10-2) in European populations, and RA displayed a positive association with cataract (OR = 1.021, 95% CI = 1.004-1.039; P = 1.64×10-2) in East Asian populations. Other methods also supported those results by IVW, and sensitivity tests showed that our analysis results were credible and stable. CONCLUSIONS: This study revealed a positive causality between RA and the increased risk of cataract and glaucoma, which provides guidance for the early prevention of cataracts and glaucoma in patients with RA and furnishes evidence for the impact of RA-induced inflammation on ophthalmic diseases.

Causal associations between circulating inflammatory cytokines and blinding eye diseases: a bidirectional Mendelian randomization analysis.

Background: Previous studies have explored the associations between circulating inflammatory cytokines and blinding eye diseases, including glaucoma, cataract and macular degeneration. However, the causality of these associations remains controversial. This study employs a bidirectional Mendelian randomization (MR) study to investigate the causal relationships between 41 circulating inflammatory cytokines and these blinding eye diseases. Methods: Summary data for glaucoma, cataract, macular degeneration and 41 circulating inflammatory cytokines were publicly available. The inverse variance weighted (IVW) method was employed as the main analysis method. Additionally, various sensitivity tests, including MR-Egger regression, weighted median, weight mode, Cochran's Q test, MR pleiotropy Residual Sum and Outlier test, and leave-one-out test, were conducted to evaluate sensitivity and stability of results. Results: The IVW analysis identified six circulating inflammatory cytokines causally associated with the risk of blinding eye diseases: Monokine induced by interferon-gamma (MIG) for glaucoma, interleukin-1 receptor antagonist (IL-1ra), IL-6, IL-10, and platelet derived growth factor BB (PDGFbb) for cataract, and MIG and hepatocyte growth factor (HGF) for macular degeneration. However, it is noteworthy that none of these associations remained significant after Bonferroni correction (p < 0.0004). Reverse MR analyses indicated that cataract may lead to a decrease in vascular endothelial growth factor (VEGF) levels (OR: 3.326 × 10-04, 95% CI: 5.198 × 10-07 - 2.129 × 10-01, p = 0.0151). Conclusion: This study highlights the potential roles of specific inflammatory cytokines in the development of glaucoma, cataract and macular degeneration. Moreover, it suggests that VEGF is likely to be involved in cataract development downstream. These findings offer insights for early prevention and novel therapeutic strategies for these blinding eye diseases.

PUD@HA/PEEK Scaffold Induces Subchondral Bone Regeneration to Repair Osteochondral Defect in Rabbits.

Osteochondral defects (OCDs) pose a significant challenge in clinical practice, and recent advancements in their repair indicate that satisfying subchondral bone repair may be critical for this. Herein, a series of hydroxyapatite/poly(ether ether ketone) (HA/PEEK) scaffolds were fabricated with varying mass percentages (0, 20, 30, and 40%) to induce subchondral bone regeneration. Subsequently, an optimal scaffold with 40% HA/PEEK was selected to establish osteochondral scaffolds with poly(ether urethane) urea-Danshensu (PUD) for repairing the OCD. The material characteristics of HA/PEEK and PUD were investigated using scanning electron microscopy, tensile, swelling, and fatigue tests, and cytological experiments. The effects of serial HA/PEEK scaffolds on subchondral bone repair were then assessed by using microcomputed tomography, hard tissue slicing, and histological staining. Furthermore, the optimal 40% HA/PEEK scaffold was used to develop osteochondral scaffolds with PUD to observe the effect on the OCD repair. HA/PEEK materials exhibited an even HA distribution in PEEK. However, when composited with HA, PEEK exhibited inferior mechanical strength. 40%HA/PEEK scaffolds showed an optimum effect on in vivo subchondral bone repair. Cartilage regeneration on 40%HA/PEEK scaffolds was pronounced. After PUD was introduced onto the HA/PEEK, the PUD@40%HA/PEEK scaffold produced the expected effect on the repair of the OCD in rabbits. Therefore, achieving satisfactory subchondral bone repair can benefit surficial cartilage repair. The PUD@40%HA/PEEK scaffold could induce subchondral bone regeneration to repair the OCD in rabbits and could provide a novel approach for the repair of the OCD in clinical practice.

Large-scale causal analysis of gut microbiota and six common complications of diabetes: a mendelian randomization study.

BACKGROUND: This study aimed to reveal the association between the gut microbiota (GM) and six diabetic complications: diabetic hypoglycemia; ketoacidosis; nephropathy; neuropathy; retinopathy; and Charcot's foot. METHODS: GM data were obtained from the MiBioGen consortium and Dutch Microbiome Project while data on the six diabetic complications were obtained from the FinnGen consortium. Two-sample Mendelian randomization (TSMR) was performed to explore the association between GM and the common diabetic complications. Inverse MR analysis was conducted to examine the effect of diabetic complications on the identified GM. Sensitivity tests were conducted to validate the stability of the results. Finally, multivariate MR (MVMR) was performed to determine whether GM had a direct influence on the diabetic complications. RESULTS: After multiple corrections, the inverse variance weighted (IVW) results predicted 61 suggestive markers between GM and six diabetic complications. In particular, the IVW results revealed that the Bacteroidia class and Bacteroidales order were positively associated with diabetic hypoglycemia while the Verrucomicrobiae class and Verrucomicrobiales order were positively associated with diabetic nephropathy. Based on the replication analysis, these results were identified to be stable. MVMR showed that the results remained stable after accounting for traditional risk factors. CONCLUSION: Extensive causal associations were found between GM and diabetic complications, which may provide new insights into the mechanisms of microbiome-mediated complications of diabetes.

Decellularized extracellular matrix scaffold seeded with adipose-derived stem cells promotes neurorestoration and functional recovery after spinal cord injury through Wnt/ß-catenin signaling pathway regulation.

Spinal cord injury (SCI) causes tissue destruction and neuronal apoptosis, which impede neural function recovery. Therefore, promoting neuronal regeneration and neural pathway reconstruction is crucial. In this study, a novel and facile decellularized extracellular matrix (dECM) scaffold seeded with adipose-derived stem cells (ADSCs) (dECM scaffolds/ADSCs) was reported. The dECM scaffold maintained the original three-dimensional network structure of spinal cord tissue and contained various small pores.In vitrostudies demonstrated that dECM scaffolds exhibited excellent biocompatibility, facilitated efficient adhesion and proliferation of ADSCs, and promoted the secretion of neurotrophin-3 and neuronal differentiation in the microenvironment after SCI.In vivostudies further showed that dECM scaffolds/ADSCs could alleviate inflammatory and apoptotic reactions, providing a favorable microenvironment for promoting endogenous nerve regeneration rather than glial scars formation, ultimately achieving recovery of hind limb function in rats. Notably, ICG-001 effectively reversed the therapeutic effect of dECM scaffolds/ADSCs, proving that dECM scaffolds/ADSCs promoted functional recovery after SCI by regulating the Wnt/ß-catenin signaling pathway. Overall, dECM scaffolds/ADSCs can simulate the physiological characteristics of the spinal cord and exert neurorestorative potential, providing a new therapeutic strategy for SCI.

Transcriptome-wide association study identifies new susceptibility genes and pathways for spondyloarthritis.

BACKGROUND: Spondyloarthritis (SpA) is a group of multifactorial bone diseases influenced by genetic factors, the environment and lifestyle. However, current studies have found a limited number of SpA-related genes, and the genetic and pathogenic mechanisms of SpA are still unclear. METHODS: A tissue-specific transcriptome-wide association study (TWAS) of SpA was performed using GWAS (including 3966 SpA patients and 448,298 controls) summary data and gene expression weights of whole blood and skeletal muscle. The SpA-associated genes identified by TWAS were further compared with the differentially expressed genes (DEGs) identified in the SpA gene expression profile acquired from the Gene Expression Omnibus database (GEO, GSE58667). Finally, functional enrichment and annotation analyses of the identified genes were performed. RESULTS: The TWAS detected 499 suggestive genes associated with SpA in whole blood and skeletal muscle, such as CTNNAL1 (PSM = 3.04 × 10-2, PWB = 9.58 × 10-3). The gene expression profile of SpA identified 20 candidate genes that overlapped in the TWAS data, such as MCM4 (PTWAS = 1.32 × 10-2, PDEG = 2.75 × 10-2) and KIAA1109 (PTWAS = 3.71 × 10-2, PDEG = 4.67 × 10-2). Enrichment analysis of the genes identified by TWAS identified 93 significant GO terms and 33 KEGG pathways, such as mitochondrion organization (GO: 0007005) and axon guidance (hsa04360). CONCLUSION: We identified multiple candidate genes that were genetically related to SpA. Our study may provide novel clues regarding the genetic mechanism, diagnosis, and treatment of SpA.

Polyphosphazene nanodrugs for targeting delivery and inflammation responsive release of curcumin to treat acute lung injury by effectively inhibiting cytokine storms.

An excessive inflammatory response induced by cytokine storms is the primary reason for the deterioration of patients with acute lung injury (ALI). Though natural polyphenols such as curcumin (CUR) have anti-inflammation activity for ALI treatment, they often have limited efficacy due to their poor solubility in water and oxidising tendency. This study investigates a highly cross-linked polyphosphazene nano-drug (PHCH) developed by copolymerisation of CUR and acid-sensitive units (4-hydroxy-benzoic acid (4-hydroxy-benzylidene)-hydrazide, D-HBD) with hexachlorotripolyphosphonitrile (HCCP) for improved treatment of ALI. PHCH can prolong the blood circulation time and targeted delivery into lung inflammation sites by enhancing CUR's water dispersion and anti-oxidant properties. PHCH also demonstrates the inflammation-responsive release of CUR in an inflammation environment due to the acid-responsive degradation of hydrazine bonds and triphosphonitrile rings in PHCH. Therefore, PHCH has a substantial anti-inflammation activity for ALI treatment by synergistically improving CUR's water-solubility, bioavailability and biocompatibility. As expected, PHCH attenuates the cytokine storm syndrome and alleviates inflammation in the infected cells and tissues by down-regulating several critical inflammatory cytokines (TNF-α, IL-1ß, and IL-8). PHCH also decreases the expression of p-p65 and C-Caspase-1, inhibiting NLRP3 inflammasomes and suppressing NF-κB signalling pathways. The administrated mice experiments confirmed that PHCH accumulation was enhanced in lung tissue and showed the efficient scavenging ability of reactive oxygen species (ROS), effectively blocking the cytokine storm and alleviating inflammatory damage in ALI. This smart polyphosphazene nano-drug with targeting delivery property and inflammation-responsive release of curcumin has excellent potential for the clinical treatment of various inflammatory diseases, including ALI.

Curcumin-Containing polyphosphazene nanodrug for Anti-Inflammation and nerve regeneration to improve functional recovery after spinal cord injury.

The microenvironment of excessive inflammation and the activation of apoptotic signals are primary barriers to neurological recovery following spinal cord injury (SCI). Thus, long-lasting anti-inflammation has become an effective strategy to navigate SCI. Herein, a curcumin (CUR)-containing nanosystem (FCTHPC) with high drug loading efficiency was reported via assembling hydrophobic CUR into cross-linked polyphosphazene (PPZ), and simultaneous loading and coordinating with porous bimetallic polymers for greatly enhanced the water-solubility and biocompatibility of CUR. The nanosystem is noncytotoxic when directing its biological activities. By inhibiting the expression of pro-inflammatory factors (IL-1ß, TNF-α and IL-6) and apoptotic proteins (C-caspase-3 and Bax/Bcl-2), which may be accomplished by activating the Wnt/ß-catenin pathway, the versatile FCTHPC can significantly alleviate the damage to tissues and cells caused by inflammation and apoptosis in the early stage of SCI. In addition, the long-term in vivo studies had demonstrated that FCTHPC could effectively inhibit the formation of glial scars, and simultaneously promote nerve regeneration and myelination, leading to significant recovery of spinal cord function. This study emphasises the promise of the biocompatible CUR-based nanosystem and provides a fresh approach to effectively treat SCI.

Corrigendum: Causal associations between common musculoskeletal disorders and dementia: a Mendelian randomization study.

[This corrects the article DOI: 10.3389/fnagi.2023.1253791.].

Causal associations between common musculoskeletal disorders and dementia: a Mendelian randomization study.

Introduction: Dementia and musculoskeletal disorders (MSDs) are major public health problems. We aimed to investigate the genetic causality of common MSDs and dementia. Methods: Two-sample Mendelian randomization (MR) was used in this study. MR analysis based on gene-wide association study (GWAS) data on osteoarthritis (OA), dementia with Lewy bodies, and other MSDs and dementia types were obtained from the Genetics of Osteoarthritis consortium, IEU-open GWAS project, GWAS catalog, and FinnGen consortium. Rigorously selected single-nucleotide polymorphisms were regarded as instrumental variables for further MR analysis. Inverse-variance weighted, MR-Egger regression, weight median, simple mode, and weight mode methods were used to obtain the MR estimates. Cochran's Q test, MR-Egger and MR-Pleiotropy Residual Sum and Outlier analysis, and the leave-one-out test were applied for sensitivity testing. Results: The inverse-variance weighted method showed that hip OA was genetically associated with a lower risk of dementia, unspecified dementia, dementia in Alzheimer's disease, and vascular dementia. Kneehip OA was inversely associated with unspecified dementia and vascular dementia. Rheumatoid arthritis, juvenile idiopathic arthritis and seronegative rheumatoid arthritis were inversely associated with frontotemporal dementia, and rheumatoid arthritis was inversely associated with unspecified dementia. Simultaneously, ankylosing spondylitis was an independent risk factor for dementia, dementia with Lewy bodies, and dementia in Alzheimer's disease. Sensitivity tests showed that heterogeneity and horizontal pleiotropy did not exist in these associations. The leave-one-out test showed that these associations were stable. Conclusion: We found that some MSDs were associated with the risk of dementia and provide evidence for the early detection of dementia in patients with MSDs and for the impact of inflammation on the central nervous system.