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Aims

In this investigation, we administered oxidative stress to nucleus pulposus cells (NPCs), recognized DNA-damage-inducible transcript 4 (DDIT4) as a component in intervertebral disc degeneration (IVDD), and devised a hydrogel capable of conveying small interfering RNA (siRNA) to IVDD.

Methods

An in vitro model for oxidative stress-induced injury in NPCs was developed to elucidate the mechanisms underlying the upregulation of DDIT4 expression, activation of the reactive oxygen species (ROS)-thioredoxin-interacting protein (TXNIP)-NLRP3 signalling pathway, and nucleus pulposus pyroptosis. Furthermore, the mechanism of action of small interfering DDIT4 (siDDIT4) on NPCs in vitro was validated. A triplex hydrogel named siDDIT4@G5-P-HA was created by adsorbing siDDIT4 onto fifth-generation polyamidoamine (PAMAM) dendrimer using van der Waals interactions, and then coating it with hyaluronic acid (HA). In addition, we established a rat puncture IVDD model to decipher the hydrogel’s mechanism in IVDD.


The Bone & Joint Journal
Vol. 106-B, Issue 4 | Pages 412 - 418
1 Apr 2024
Alqarni AG Nightingale J Norrish A Gladman JRF Ollivere B

Aims

Frailty greatly increases the risk of adverse outcome of trauma in older people. Frailty detection tools appear to be unsuitable for use in traumatically injured older patients. We therefore aimed to develop a method for detecting frailty in older people sustaining trauma using routinely collected clinical data.

Methods

We analyzed prospectively collected registry data from 2,108 patients aged ≥ 65 years who were admitted to a single major trauma centre over five years (1 October 2015 to 31 July 2020). We divided the sample equally into two, creating derivation and validation samples. In the derivation sample, we performed univariate analyses followed by multivariate regression, starting with 27 clinical variables in the registry to predict Clinical Frailty Scale (CFS; range 1 to 9) scores. Bland-Altman analyses were performed in the validation cohort to evaluate any biases between the Nottingham Trauma Frailty Index (NTFI) and the CFS.


Bone & Joint Research
Vol. 13, Issue 2 | Pages 52 - 65
1 Feb 2024
Yao C Sun J Luo W Chen H Chen T Chen C Zhang B Zhang Y

Aims

To investigate the effects of senescent osteocytes on bone homeostasis in the progress of age-related osteoporosis and explore the underlying mechanism.

Methods

In a series of in vitro experiments, we used tert-Butyl hydroperoxide (TBHP) to induce senescence of MLO-Y4 cells successfully, and collected conditioned medium (CM) and senescent MLO-Y4 cell-derived exosomes, which were then applied to MC3T3-E1 cells, separately, to evaluate their effects on osteogenic differentiation. Furthermore, we identified differentially expressed microRNAs (miRNAs) between exosomes from senescent and normal MLO-Y4 cells by high-throughput RNA sequencing. Based on the key miRNAs that were discovered, the underlying mechanism by which senescent osteocytes regulate osteogenic differentiation was explored. Lastly, in the in vivo experiments, the effects of senescent MLO-Y4 cell-derived exosomes on age-related bone loss were evaluated in male SAMP6 mice, which excluded the effects of oestrogen, and the underlying mechanism was confirmed.


Bone & Joint Research
Vol. 12, Issue 9 | Pages 601 - 614
21 Sep 2023
Gu P Pu B Liu T Yue D Xin Q Li H Yang B Ke D Zheng X Zeng Z Zhang Z

Aims

Mendelian randomization (MR) is considered to overcome the bias of observational studies, but there is no current meta-analysis of MR studies on rheumatoid arthritis (RA). The purpose of this study was to summarize the relationship between potential pathogenic factors and RA risk based on existing MR studies.

Methods

PubMed, Web of Science, and Embase were searched for MR studies on influencing factors in relation to RA up to October 2022. Meta-analyses of MR studies assessing correlations between various potential pathogenic factors and RA were conducted. Random-effect and fixed-effect models were used to synthesize the odds ratios of various pathogenic factors and RA. The quality of the study was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomization (STROBE-MR) guidelines.


Orthopaedic Proceedings
Vol. 105-B, Issue SUPP_12 | Pages 32 - 32
23 Jun 2023
Jacobs JJ Agarwal P Leurgans SE Agrawal S Ayton S Bush AI Hall DJ Schneider J Pourzal R
Full Access

Both total joint arthroplasty (TJA) and Alzheimer's Disease (AD) are prevalent in elderly populations. It is the goal of this study to determine if the presence of implant metals originating from TJA correlates with the onset with higher implant metal content in the brain and AD pathology. Tissue samples from four brain regions of 701 (229 with TJA) participants from an ongoing longitudinal cohort study (Rush Memory and Aging Project) was analyzed including the inferior-temporal-cortex (ITC), which is associated with early onset of AD. Implant metal (Co, Cr, Mo, Ti, Al) content was determined by ICP-MS. Comparisons were conducted between the no-TJA-group and a TJA group. Due to the higher likelihood of Co release the TJA group was further differentiated in a THA (N=146) and a TKA/TSA (N=83) group. Diffuse and neuritic amyloid plaques and phosphorylated tau were assessed and summarized as standard measures of AD pathology. We used separate linear regression models adjusted for age, sex, education, and APOɛ4-status for the associations of all metals (log-transformed) with global AD pathology, amyloid plaques, and phosphorylated tau. The THA group had higher cobalt content across all brain regions (p=0.003) and within the ITC (p=0.051) compared to the no-TJA group, whereas the TKA/TSA group did not. Across all tissue samples, Co was associated with higher amyloid load (β=0.35, p=0.027), phosphorylated tau (β=0.47, p=0.011), and global AD pathology (β=0.19, 0.0004) in the ITC. The presence of TJA itself was not associated with AD pathology. We showed that only Co content was higher within the ITC in persons with THA. We found among all tested metals that Co was consistently associated with AD pathology. Although we found an association of cobalt with AD pathology, the cross-sectional nature of this study does not allow the determination of cause and effect


Orthopaedic Proceedings
Vol. 105-B, Issue SUPP_7 | Pages 76 - 76
4 Apr 2023
LU X BAI S LIN Y YAN L LI L WANG M JIANG Z WANG H YANG B YANG Z WANG Y FENG L JIANG X PONOMAREV E LEE W LIN S KO H LI G
Full Access

Based on Ilizarov's law of tension-stress principle, distraction histogenesis technique has been widely applied in orthopaedic surgery for decades. Derived from this technique, cranial bone transport technique was mainly used for treating cranial deformities and calvarial defects. Recent studies reported that there are dense short vascular connections between skull marrow and meninges for immune cells trafficking, highlighting complex and tight association between skull and brain. Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia without effective therapy. Meningeal lymphatics have been recognized as an important mediator in neurological diseases. The augmentation of meningeal lymphatic drainage might be a promising therapeutic target for AD. Our proof-of-concept study has indicated that cranial bone transport can promote ischemic stroke recovery via modulating meningeal lymphatic drainage function, providing a rationale for treating AD using cranial bone maneuver (CBM). This study aims to investigate the effects of CBM on AD and to further explore the potential mechanisms. Transgenic 5xFAD mice model was used in this study. After osteotomy, a bone flap was used to perform CBM without damaging the dura. Open filed test, novel object recognition test and Barn's maze test were used to evaluate neurological functions of 5xFAD mice after CBM treatment. Congo red and immunofluorescence staining were used to evaluate amyloid depositions and Aβ plaques in different brain regions. Lymphangiogenesis and the level of VEGF-C were examined after CBM treatment. OVA-A647 was intra-cisterna-magna injected to evaluate meningeal lymphatic drainage function after CBM treatment. CBM significantly improved memory functions and reduced amyloid depositions and Aβ plaques in the hippocampus of 5xFAD mice. A significant increase of meningeal lymphatic vessels in superior sagittal sinus and transverse sinus, and the upregulation of VEGF-C in meninges were observed in 5xFAD mice treated with CBM. Moreover, CBM remarkably enhanced meningeal lymphatic drainage function in 5xFAD mice (n=5-16 mice/group for all studies). CBM may promote meningeal lymphangiogenesis and lymphatic drainage function through VEGF-C-VEGFR3 pathway, and further reduce amyloid depositions and Aβ plaques and alleviate memory deficits in AD


Bone & Joint Research
Vol. 12, Issue 1 | Pages 80 - 90
20 Jan 2023
Xu J Si H Zeng Y Wu Y Zhang S Liu Y Li M Shen B

Aims

Degenerative cervical spondylosis (DCS) is a common musculoskeletal disease that encompasses a wide range of progressive degenerative changes and affects all components of the cervical spine. DCS imposes very large social and economic burdens. However, its genetic basis remains elusive.

Methods

Predicted whole-blood and skeletal muscle gene expression and genome-wide association study (GWAS) data from a DCS database were integrated, and functional summary-based imputation (FUSION) software was used on the integrated data. A transcriptome-wide association study (TWAS) was conducted using FUSION software to assess the association between predicted gene expression and DCS risk. The TWAS-identified genes were verified via comparison with differentially expressed genes (DEGs) in DCS RNA expression profiles in the Gene Expression Omnibus (GEO) (Accession Number: GSE153761). The Functional Mapping and Annotation (FUMA) tool for genome-wide association studies and Meta tools were used for gene functional enrichment and annotation analysis.


Bone & Joint Research
Vol. 10, Issue 11 | Pages 704 - 713
1 Nov 2021
Zhang H Li J Xiang X Zhou B Zhao C Wei Q Sun Y Chen J Lai B Luo Z Li A

Aims

Tert-butylhydroquinone (tBHQ) has been identified as an inhibitor of oxidative stress-induced injury and apoptosis in human neural stem cells. However, the role of tBHQ in osteoarthritis (OA) is unclear. This study was carried out to investigate the role of tBHQ in OA.

Methods

OA animal model was induced by destabilization of the medial meniscus (DMM). Different concentrations of tBHQ (25 and 50 mg/kg) were intraperitoneally injected in ten-week-old female mice. Chondrocytes were isolated from articular cartilage of mice and treated with 5 ng/ml lipopolysaccharide (LPS) or 10 ng/ml interleukin 1 beta (IL-1β) for 24 hours, and then treated with different concentrations of tBHQ (10, 20, and 40 μM) for 12 hours. The expression levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in blood were measured. The expression levels of interleukin 6 (IL-6), IL-1β, and tumour necrosis factor alpha (TNF-α) leptin in plasma were measured using enzyme-linked immunoabsorbent assay (ELISA) kits. The expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) signalling pathway proteins, and macrophage repolarization-related markers, were detected by western blot.


The Bone & Joint Journal
Vol. 103-B, Issue 2 | Pages 299 - 304
1 Feb 2021
Goto E Umeda H Otsubo M Teranishi T

Aims

Various surgical techniques have been described for total hip arthroplasty (THA) in patients with Crowe type III dislocated hips, who have a large acetabular bone defect. The aim of this study was to evaluate the long-term clinical results of patients in whom anatomical reconstruction of the acetabulum was performed using a cemented acetabular component and autologous bone graft from the femoral neck.

Methods

A total of 22 patients with Crowe type III dislocated hips underwent 28 THAs using bone graft from the femoral neck between 1979 and 2000. A Charnley cemented acetabular component was placed at the level of the true acetabulum after preparation with bone grafting. All patients were female with a mean age at the time of surgery of 54 years (35 to 68). A total of 18 patients (21 THAs) were followed for a mean of 27.2 years (20 to 33) after the operation.


The Bone & Joint Journal
Vol. 102-B, Issue 7 | Pages 959 - 964
1 Jul 2020
Malik AT Li M Khan SN Alexander JH Li D Scharschmidt TJ

Aims

Currently, the US Center for Medicaid and Medicare Services (CMS) has been testing bundled payments for revision total joint arthroplasty (TJA) through the Bundled Payment for Care Improvement (BPCI) programme. Under the BPCI, bundled payments for revision TJAs are defined on the basis of diagnosis-related groups (DRGs). However, these DRG-based bundled payment models may not be adequate to account appropriately for the varying case-complexity seen in revision TJAs.

Methods

The 2008-2014 Medicare 5% Standard Analytical Files (SAF5) were used to identify patients undergoing revision TJA under DRG codes 466, 467, or 468. Generalized linear regression models were built to assess the independent marginal cost-impact of patient, procedural, and geographic characteristics on 90-day costs.


The Bone & Joint Journal
Vol. 101-B, Issue 12 | Pages 1520 - 1525
1 Dec 2019
Clark NJ Samuelsen BT Alentorn-Geli E Assenmacher AT Cofield RH Sperling JW Sánchez-Sotelo J

Aims

Reverse shoulder arthroplasty (RSA) reliably improves shoulder pain and function for a variety of indications. However, the safety and efficacy of RSA in elderly patients is largely unknown. The purpose of this study was to report the mortality, morbidity, complications, reoperations, and outcomes of primary RSA in patients aged > 80 years.

Patients and Methods

Between 2004 and 2013, 242 consecutive primary RSAs were performed in patients aged > 80 years (mean 83.3 years (sd 3.1)). Of these, 53 were lost to follow-up before two years and ten had died within two years of surgery, leaving 179 for analysis of survivorship, pain, motion, and strength at a minimum of two years or until revision surgery. All 242 patients were considered for the analysis of 90-day, one-year, and overall mortality, medical complications (90-day and overall), surgical complications, and reoperations. The indications for surgery included rotator cuff arthropathy, osteoarthritis, fracture, the sequela of trauma, avascular necrosis, and rheumatoid arthritis. A retrospective review of the medical records was performed to collect all variables. Survivorship free of revision surgery was calculated at two and five years.


Bone & Joint Research
Vol. 8, Issue 7 | Pages 290 - 303
1 Jul 2019
Li H Yang HH Sun ZG Tang HB Min JK

Objectives

The aim of this study was to provide a comprehensive understanding of alterations in messenger RNAs (mRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) in cartilage affected by osteoarthritis (OA).

Methods

The expression profiles of mRNAs, lncRNAs, and circRNAs in OA cartilage were assessed using whole-transcriptome sequencing. Bioinformatics analyses included prediction and reannotation of novel lncRNAs and circRNAs, their classification, and their placement into subgroups. Gene ontology and pathway analysis were performed to identify differentially expressed genes (DEGs), differentially expressed lncRNAs (DELs), and differentially expressed circRNAs (DECs). We focused on the overlap of DEGs and targets of DELs previously identified in seven high-throughput studies. The top ten DELs were verified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) in articular chondrocytes, both in vitro and in vivo.


Orthopaedic Proceedings
Vol. 100-B, Issue SUPP_9 | Pages 8 - 8
1 May 2018
Zourob E Latimer L Mohamed A Anto J Rajeev A
Full Access

Introduction. Patients with pre-existing dementia are more susceptible to hip fracture due to various risk factors such as age, decreased activity leading to sarcopenia and osteoporosis, Vitamin D deficiency and presence of Apolipoprotein gene. The mortality associated with dementia and fracture neck of femurs was thought to be 2.3 times more than that of patients with intact cognitive function. The aim of this study is to assess the mortality of patients at 28 days, 4 months and one year after undergoing surgery for fracture neck of femurs. Methods. A retrospective study of 184 patients admitted with fracture neck of femur and had dementia for a period from April 2014 to August 2016 were carried out. The patient demographics, AMT score, pre-operative co-morbidities, perioperative mortality and one year mortality were analysed. Results. A total no. of 1007 patients was admitted with fracture neck of femurs during the study period. 184 patients were found to have pre fracture dementia. The mean age was87.088 years (Range 64–101). There was 42 males and 142 females. The average ASA grade was 2–3. 99 patients (53.8%) had Alzheimer's disease, 50 patients (27%) had vascular dementia and 35 patients (19.2%) had other types of dementia.94 patients (51%) had more than one co-morbidity. The average AMT score was 0.66(normal range 0–10). The total number of patients died was 114(62%). The overall mortality at 28 days was 24 %(44 patients=0.0001), 4 months was 46 %(84 patients) and one year was 62 %(114 patients, p=0.0001). In 90(49%) patients who had only dementia and no other co-morbidities(ASA grade 1–2) the mortality at 28 days was 20% (p=0.0051), 4 months was 40% and at one year 61%(p=0.0001). Conclusion. In our study we found that the overall mortality in patients with dementia and fracture neck of femurs is 62% and the perioperative mortality rate was 24%. The peri-operative mortality rate was 20% in patients with pure dementia. The mortally rate in dementia with fracture neck of femurs patients was far more than what is noted in the literature


Bone & Joint Research
Vol. 6, Issue 12 | Pages 640 - 648
1 Dec 2017
Xia B Li Y Zhou J Tian B Feng L

Objectives

Osteoporosis is a chronic disease. The aim of this study was to identify key genes in osteoporosis.

Methods

Microarray data sets GSE56815 and GSE56814, comprising 67 osteoporosis blood samples and 62 control blood samples, were obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified in osteoporosis using Limma package (3.2.1) and Meta-MA packages. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to identify biological functions. Furthermore, the transcriptional regulatory network was established between the top 20 DEGs and transcriptional factors using the UCSC ENCODE Genome Browser. Receiver operating characteristic (ROC) analysis was applied to investigate the diagnostic value of several DEGs.


Bone & Joint 360
Vol. 5, Issue 3 | Pages 38 - 40
1 Jun 2016
Worlock PH


The Bone & Joint Journal
Vol. 97-B, Issue 8 | Pages 1046 - 1049
1 Aug 2015
Abdel MP Cross MB Yasen AT Haddad FS

The aims of this study were to determine the functional impact and financial burden of isolated and recurrent dislocation after total hip arthroplasty (THA). Our secondary goal was to determine whether there was a difference between patients who were treated non-operatively and those who were treated operatively.

We retrospectively reviewed 71 patients who had suffered dislocation of a primary THA. Their mean age was 67 years (41 to 92) and the mean follow-up was 3.8 years (2.1 to 8.2).

Because patients with recurrent dislocation were three times more likely to undergo operative treatment (p < 0.0001), they ultimately had a significantly higher mean Harris Hip Score (HHS) (p = 0.0001), lower mean Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores (p = 0.001) and a higher mean SF-12 score (p < 0.0001) than patients with a single dislocation. Likewise, those who underwent operative treatment had a higher mean HHS (p < 0.0001), lower mean WOMAC score (p < 0.0001) and a higher mean SF-12 score (p < 0.0001) than those who were treated non-operatively.

Recurrent dislocation and operative treatment increased costs by 300% (£11 456; p < 0.0001) and 40% (£5217; p < 0.0001), respectively.

The operative treatment of recurrent dislocation results in significantly better function than non-operative management. Moreover, the increase in costs for operative treatment is modest compared with that of non-operative measures.

Cite this article: Bone Joint J 2015; 97-B:1046–9.


Bone & Joint Research
Vol. 4, Issue 5 | Pages 84 - 92
1 May 2015
Hamamura K Nishimura A Iino T Takigawa S Sudo A Yokota H

Objectives

Salubrinal is a synthetic agent that elevates phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) and alleviates stress to the endoplasmic reticulum. Previously, we reported that in chondrocytes, Salubrinal attenuates expression and activity of matrix metalloproteinase 13 (MMP13) through downregulating nuclear factor kappa B (NFκB) signalling. We herein examine whether Salubrinal prevents the degradation of articular cartilage in a mouse model of osteoarthritis (OA).

Methods

OA was surgically induced in the left knee of female mice. Animal groups included age-matched sham control, OA placebo, and OA treated with Salubrinal or Guanabenz. Three weeks after the induction of OA, immunoblotting was performed for NFκB p65 and p-NFκB p65. At three and six weeks, the femora and tibiae were isolated and the sagittal sections were stained with Safranin O.


The Bone & Joint Journal
Vol. 97-B, Issue 5 | Pages 654 - 661
1 May 2015
Jämsen E Peltola M Puolakka T Eskelinen A Lehto MUK

We compared the length of hospitalisation, rate of infection, dislocation of the hip and revision, and mortality following primary hip and knee arthroplasty for osteoarthritis in patients with Alzheimers disease (n = 1064) and a matched control group (n = 3192). The data were collected from nationwide Finnish health registers. Patients with Alzheimers disease had a longer peri-operative hospitalisation (median 13 days vs eight days, p < 0.001) and an increased risk for hip revision with a hazard ratio (HR) of 1.76 (95% confidence interval (CI) 1.03 to 3.00). Dislocation was the leading indication for revision. There was no difference in the rates of infection, dislocation of the hip, knee revision and short-term mortality. In long-term follow-up, patients with Alzheimer’s disease had a higher mortality (HR 1.43; 95% CI 1.22 to 1.70), and only one third survived ten years post-operatively. Increased age and comorbidity were associated with longer peri-operative hospitalisation in patients with Alzheimers disease. Cite this article: Bone Joint J 2015;97-B:654–61


Bone & Joint Research
Vol. 1, Issue 1 | Pages 8 - 12
1 Jan 2012
Shigemura T Kishida S Eguchi Y Ohtori S Nakamura J Kojima M Masuda Y Takahashi K

Objectives

The purpose of this study was to assess N-acetyl aspartate changes in the thalamus in patients with osteoarthritis of the hip using proton magnetic resonance spectroscopy.

Methods

Nine patients with osteoarthritis of the hip (symptomatic group, nine women; mean age 61.4 years (48 to 78)) and nine healthy volunteers (control group, six men, three women; mean age 30.0 years (26 to 38)) underwent proton magnetic resonance spectroscopy to assess the changes of N-acetyl aspartate in the thalamus.


The Journal of Bone & Joint Surgery British Volume
Vol. 93-B, Issue 10 | Pages 1411 - 1415
1 Oct 2011
Wainwright C Theis J Garneti N Melloh M

We compared revision and mortality rates of 4668 patients undergoing primary total hip and knee replacement between 1989 and 2007 at a University Hospital in New Zealand. The mean age at the time of surgery was 69 years (16 to 100). A total of 1175 patients (25%) had died at follow-up at a mean of ten years post-operatively. The mean age of those who died within ten years of surgery was 74.4 years (29 to 97) at time of surgery. No change in comorbidity score or age of the patients receiving joint replacement was noted during the study period. No association of revision or death could be proven with higher comorbidity scoring, grade of surgeon, or patient gender.

We found that patients younger than 50 years at the time of surgery have a greater chance of requiring a revision than of dying, those around 58 years of age have a 50:50 chance of needing a revision, and in those older than 62 years the prosthesis will normally outlast the patient. Patients over 77 years old have a greater than 90% chance of dying than requiring a revision whereas those around 47 years are on average twice as likely to require a revision than die. This information can be used to rationalise the need for long-term surveillance and during the informed consent process.