Lef1 ablation alleviates cartilage mineralization following posttraumatic osteoarthritis induction.

Cartilage mineralization is a tightly controlled process, imperative for skeletal growth and fracture repair. However, in osteoarthritis (OA), cartilage mineralization may impact the joint range of motion, inflict pain, and increase chances for joint effusion. Here we attempt to understand the link between inflammation and cartilage mineralization by targeting Sirtuin 1 (SIRT1) and lymphoid enhancer binding factor 1 (LEF1), both reported to have contrasting effects on cartilage. We find that inflammatory-dependent cleavage of SIRT1 or its cartilage-specific genetic ablation, directly enhanced LEF1 expression accompanied by a catabolic response. Applying a posttraumatic OA (PTOA) model to cartilage-specific Sirt1 nulls displayed severe OA, which was accompanied by synovitis, meniscal mineralization, and osteophyte formation of the lateral joint compartment. Alternatively, cartilage-specific Lef1 nulls presented reduced lateral mineralization, OA severity, and local pain. Differential gene expression analysis revealed that Lef1 ablation reduced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Toll-like receptor (Tlr) pathways, while enhancing SRY-Box transcription factor 9 (Sox9) and cartilaginous extracellular matrix genes. The results support a link between inflammation and Lef1-dependent cartilage mineralization, mediated by the inactivation of Sirt1. By ablating Lef1 in a PTOA model, the structural and pain-related phenotypes of OA were reduced, in part, by preventing cartilage mineralization of the lateral joint compartment, partially manifested by meniscal tissue mineralization. Overall, these data provide a molecular axis to link between inflammation and cartilage in a PTOA model.

Cushioned Footwear Effect on Pain and Gait Characteristics of Individuals with Knee Osteoarthritis: A Double-Blinded 3 Month Intervention Study.

One of the recommendations for individuals with knee osteoarthritis (OA) is the use of specific footwear, such as sturdy or cushioned shoes. However, the long-term use effects of using cushioned shoes on the pain and spatiotemporal gait parameters in individuals with knee OA are yet to be reported. We therefore aimed to compare the efficacy of cushioned sport footwear versus sham shoes on motor functions, pain and gait characteristics of individuals with knee OA who used the shoes for 3 months. In a double-blinded study, we provided 26 individuals with knee OA with cushioned sport shoes and 12 individuals with knee OA with similar sport shoes without cushioning for 3 months. The gait analysis, the timed up and go (TUG) test and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) were conducted and the pain levels were measured at the baseline, 1 month, and 3 months after the baseline. We found that the cushioned shoes reduce the amount of pain (based on WOMAC) in the affected knee and increase functionality in the research group, but not in the control group. Gait velocity and cadence were increased in both groups. Gait spatiotemporal parameters and their symmetry were unaffected during the intervention. We conclude that the use of cushioned shoes should be recommended to individuals with knee OA for alleviating pain.

The impact of femoral bone quality on cementless total hip pre-operative templating.

INTRODUCTION: Accurate templating is an integral part of pre-operative planning for total hip arthroplasty (THA). Templating of cementless implant accuracy has been average. The aim of this study was to assess the impact of Dorr femoral classification on the accuracy of pre-operative digital templating. PATIENTS AND METHODS: This was a retrospective study of cementless THA pre-operative planning using one implant design. A total of 210 primary THA were reviewed. A total of 102 cementless THAs matched the exclusion and inclusion criteria, using one implant combination, were analyzed by an orthopaedic resident and a fellowship trained arthroplasty surgeon. Each x-ray was evaluated and assigned a femoral Dorr classification. Accuracy of templating was determined by comparing the templated size with the actual implant size both for the femoral and acetabular components. RESULT: Out of the 102 cases, exact templating size was achieved in 35.3% for the acetabulum, 25.5% for the femur, and only in 9.8% for both components. Reasonable templating, ± one of the actual size, was achieved in 78.4% for the acetabulum, 74.5% for the femur, and 60.8% for both components. Use of Dorr femoral type classification did not result in better templating accuracy. CONCLUSION: Pre-operative hip cementless templating using digital x-rays with double marker method do not improve accuracy compared to other methods available for templating. Accounting for bone quality using the Dorr femoral classification did not improve accuracy.

New-Onset Perioperative Atrial Fibrillation Is Associated with Increased All-Cause Mortality in Elderly Patients Undergoing Total Knee and Hip Replacements.

INTRODUCTION: Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are common surgeries performed in elderly patients with osteoarthritis. Limited data address the clinical significance of perioperative atrial fibrillation (AF) in these patients. This study aimed to determine whether preexisting or new-onset AF is associated with increased 1-year all-cause mortality rates in the elderly population. METHODS: 280 patients over the age of 60 undergoing THA or TKA with perioperative AF and 280 control-matched patients were retrospectively identified, and their files reviewed. The primary end point was 1-year all-cause mortality from the date of the surgery. RESULTS: Of the 280 patients with perioperative AF, 37 had new-onset AF with a 1-year all-cause mortality rate of 10.8%. This mortality was significantly higher in patients with new-onset AF compared to patients without AF or patients with previous AF (10.8% vs. 1.1% and 2.5%, respectively; p = 0.005). On multivariate analysis, this difference remained significant after adjustment for risk factors associated with all-cause mortality. CONCLUSIONS: One-year all-cause mortality in elderly patients undergoing TKA or THA is significantly increased in the patients that develop new postoperative AF. These patients warrant increased clinical surveillance following surgery.

Serum NT/CT SIRT1 ratio reflects early osteoarthritis and chondrosenescence.

OBJECTIVE: Previous work has established that the deacetylase sirtuin-1 (SIRT1) is cleaved by cathepsin B in chondrocytes subjected to proinflammatory stress, yielding a stable but inactive N-terminal (NT) polypeptide (75SIRT1) and a C-terminal (CT) fragment. The present work examined if chondrocyte-derived NT-SIRT1 is detected in serum and may serve as an investigative and exploratory biomarker of osteoarthritis (OA). METHODS: We developed a novel ELISA assay to measure the ratio of NT to CT of SIRT1 in the serum of human individuals and mice subjected to post-traumatic OA (PTOA) or age-dependent OA (ADOA). We additionally monitored NT/CT SIRT1 in mice subject to ADOA/PTOA followed by senolytic clearance. Human chondrosenescent and non-senescent chondrocytes were exposed to cytokines and analysed for apoptosis and NT/CT SIRT1 ratio in conditioned medium. RESULTS: Wild-type mice with PTOA or ADOA of moderate severity exhibited increased serum NT/CT SIRT1 ratio. In contrast, this ratio remained low in cartilage-specific Sirt1 knockout mice despite similar or increased PTOA and ADOA severity. Local clearance of senescent chondrocytes from old mice with post-traumatic injury resulted in a lower NT/CT ratio and reduced OA severity. While primary chondrocytes exhibited NT/CT ratio increased in conditioned media after prolonged cytokine stimulation, this increase was not evident in cytokine-stimulated chondrosenescent cells. Finally, serum NT/CT ratio was elevated in humans with early-stage OA. CONCLUSIONS: Increased levels of serum NT/CT SIRT1 ratio correlated with moderate OA in both mice and humans, stemming at least in part from non-senescent chondrocyte apoptosis, possibly a result of prolonged inflammatory insult.

Total Knee Arthroplasty for Valgus Deformity via a Lateral Approach: Clinical Results, Comparison to Medial Approach, and Review of Recent Literature.

BACKGROUND: Total knee arthroplasty (TKA) for valgus deformity is a challenge. The standard medial parapatellar approach may not be universally useful for this. We have adopted the lateral approach to valgus knees. Here we describe our experience with this approach, present early results, and compare them to the medial approach. METHODS: Our institutional registry was queried for all patients with valgus deformity who underwent a TKA via a lateral approach between 2013 and 2016. The registry was also queried for patients with valgus deformity who underwent a TKA through a medial approach in previous years and this data was compared to the study group. RESULTS: Seventy-nine valgus knees in 72 patients were operated through a lateral approach. Deformity was corrected by 10.8°, from 16.2° to 5.4° (P < .001). Patellar tilt improved from -2.3° to 0.3° (P = .037). Seven implants (9%) were constrained. Mean operating time was 87 minutes (range 53-137). Twenty-five knees in 23 patients were operated via the medial approach. Deformity was corrected by 7.3°, from 13.2° to 5.9° (P < .001). Mean operating time was 137 minutes (range 90-230). Constrained implants were used in 16% of cases. The lateral approach allowed better correction of valgus deformity (10.8 vs 7.3, P = .03) and shorter operative times (87 vs 137 minutes, P < .001). CONCLUSION: A lateral approach TKA for valgus deformity improves knee alignment and patellar tilt. Compared to the medial approach, it allows better correction of the deformity, shorter operating times, and perhaps less use of constrained implants.

Ablation of the mammalian lectin galectin-8 induces bone defects in mice.

Mice overexpressing galectin-8 [gal-8 transgenic (Tg)], a secreted mammalian lectin, exhibit enhanced bone turnover and reduced bone mass, similar to cases of postmenopausal osteoporosis. Here, we show that gal-8 knockout (KO) mice have increased bone mass accrual at a young age but exhibit accelerated bone loss during adulthood. These phenotypes can be attributed to a gal-8-mediated increase in receptor activator of NF-κB ligand (RANKL) expression that promotes osteoclastogenesis, combined with direct inhibition of osteoblast differentiation, evident by reduced bone morphogenetic protein (BMP) signaling, reduced phosphorylation of receptor regulated mothers against decapentaplegic homolog (R-SMAD) and reduced expression of osteoblast differentiation markers osterix, osteocalcin, runt-related transcription factor 2 (RUNX2), dentin matrix acidic phosphoprotein-1 (DMP1), and alkaline phosphatase. At the same time, gal-8 promotes expression of estrogen receptor α (ESR1). Accordingly, the rate of bone loss is accelerated in ovariectomized, estrogen-deficient gal-8 Tg mice, whereas gal-8 KO mice, having low levels of ESR1, are refractory to ovariectomy. Finally, gal-8 mRNA positively correlates with the mRNA levels of osteoclastogenic markers RANKL, tartrate-resistant acid phosphatase, and cathepsin K in human femurs. Collectively, these findings identify gal-8 as a new physiologic player in the regulation of bone mass.-Vinik, Y., Shatz-Azoulay, H., Hiram-Bab, S., Kandel, L., Gabet, Y., Rivkin, G., Zick, Y. Ablation of the mammalian lectin galectin-8 induces bone defects in mice.

Informal (Hallway) medical consultation in orthopedics-is it as common as it seems?

INTRODUCTION: Informal (hallway) medical consultation is an integral part of the physician's work. As musculoskeletal complaints are very common, orthopedic surgeons stand in the frontline of this practice. Many of these consultations are poorly, if at all, documented, thus imposing a potential medical danger to the patient and a medicolegal danger to the surgeon. We conducted this first study to examine whether this practice is common among the orthopedic surgeons in university hospital. METHODS: In this prospective study, a 2-month record of informal consultations was kept. Six orthopedic surgeons-two joint reconstruction surgeons, one spine surgeon, two arthroscopy and sports medicine surgeons, and a shoulder surgeon participated. They recorded the details of the consulter, whether the consultation was for himself or somebody else, the major complaint, and whether it was a second opinion. All patients were advised to go to the formal orthopedic consultation and no advice or treatment was given. At the end of 2 months, each surgeon was asked to evaluate the percentage of cases he had failed to report. RESULTS: During the 2-month period, 158 people asked for informal (hallway) consultations. 11 of them (7%) were physicians, 114 (72%) were other hospital personnel, 26 (17%) were unrelated to hospital, and 6 (4%) were treated patients' relatives. 93 (59%) of consultations were about the consulter himself and the rest were about a relative or a friend. 41 (26%) were requests for a second opinion. The estimated percentage of not reported cases was 10-40%; when the number of consultations was corrected for these figures, it reached 208 consultations in 2 months. DISCUSSION: In this prospective study, six participating surgeons recorded 158 informal consultation requests in 2 months. If a correction is performed, it averages 0.6 consultations a day for a surgeon (or, if only workdays are counted-0.8 consultations a day). Orthopedic surgeons should be aware of this frequent habit and send these patients to a formal consultation.

Long Term Results of Liner Polyethylene Cementation Technique in Revision for Peri-acetabular Osteolysis.

Patients with peri-acetabular osteolysis around a well fixed cementless acetabular component may be treated with liner exchange. When the locking mechanism is unreliable or unavailable, cementing the liner into the fixed acetabular component is a feasible option. The purpose of this study was to evaluate the clinical and radiographic long term results of this technique. Forty hip revisions with liner cementation in 37 patients were performed. The minimum follow up was 10 years. Modified Harris Hip Score and recent x rays were reviewed. Four hips were re-revised. Two patients were diagnosed with exacerbation of osteolysis but refused revision. Dislocation rate was relatively high (16%). Liner cementation technique in revision hip surgery is useful in patients with a well fixed metal backed acetabular component.

75-kd sirtuin 1 blocks tumor necrosis factor α-mediated apoptosis in human osteoarthritic chondrocytes.

OBJECTIVE: Sirtuin 1 (SirT1) has been implicated in the regulation of human cartilage homeostasis and chondrocyte survival. Exposing human osteoarthritic (OA) chondrocytes to tumor necrosis factor α (TNFα) generates a stable and enzymatically inactive 75-kd form of SirT1 (75SirT1) via cathepsin B-mediated cleavage. Because 75SirT1 is resistant to further degradation, we hypothesized that it has a distinct role in OA, and the present study was undertaken to identify this role. METHODS: The presence of cathepsin B and 75SirT in OA and normal human chondrocytes was analyzed. Confocal imaging of SirT1 was used to monitor its subcellular trafficking following TNFα stimulation. Coimmunofluorescence staining for cathepsin B, mitochondrial cytochrome oxidase subunit IV, and lysosome-associated membrane protein 1 together with SirT1 was performed. Human chondrocytes were tested for apoptosis by fluorescence-activated cell sorter analysis and immunoblotting for caspases 3 and 8. Human chondrocyte mitochondrial extracts were obtained and analyzed for 75SirT1-cytochrome c association. RESULTS: Confocal imaging and immunoblot analyses following TNFα challenge of human chondrocytes demonstrated that 75SirT1 was exported to the cytoplasm and colocalized with the mitochondrial membrane. Consistent with this, immunoprecipitation and immunoblot analyses revealed that 75SirT1 is enriched in mitochondrial extracts and associates with cytochrome c following TNFα stimulation. Preventing nuclear export of 75SirT1 or reducing levels of full-length SirT1 and 75SirT1 augmented chondrocyte apoptosis in the presence of TNFα. Levels of cathepsin B and 75SirT1 were elevated in OA versus normal chondrocytes. Additional analyses showed that human chondrocytes exposed to OA-derived synovial fluid generated the 75SirT1 fragment. CONCLUSION: These data suggest that 75SirT1 promotes chondrocyte survival following exposure to proinflammatory cytokines.

Total knee arthroplasty using a computerized assisted stereotaxic navigation system with bluetooth communication in obese patients - A randomized controlled study.

Correct mechanical alignment (180° hip-knee-angle (HKA)) may be difficult to obtain on a consistent basis in obese patients. This is a randomized controlled study comparing the post-operative coronal alignment in obese patients between two surgical total knee arthroplasty (TKA) techniques - conventional and computer assisted navigation. The primary outcome was the post-operative HKA. A total of 60 patients were assigned to undergo conventional total knee arthroplasty (30 patients) or computerized assisted stereotaxic navigation system with Bluetooth communication surgery (30 patients). One patient from the study group was excluded due to malfunction of the navigation system. Good quality x-rays were available in 57 patients. There was no difference between the groups. Post-operative HKA was 2.8° and 2.9° in the study and control groups, respectively (p = 0.87). In obese patients undergoing TKA, computerized navigation had no impact on post-op HKA. Clincal Trial Registration Number: HMO 0092-13.

Natural history of changes in knee skin temperature following total knee arthroplasty: a systematic review and meta-analysis.

Patients undergoing total-knee arthroplasty (TKA) have transient increases in anterior knee skin temperature (ST) that subside as recovery progresses-except in cases of systemic or local prosthetic joint infections (PJI). This meta-analysis was designed to quantify the changes in knee ST following TKA in patients with uncomplicated recovery as a prerequisite for assessing the usefulness of thermal imaging for diagnosis of PJI. This meta-analysis (PROSPERO-CRD42021269864) was performed according to PRISMA guidelines. PUBMED and EMBASE were searched for studies reporting knee ST of patients that underwent unilateral TKA with uncomplicated recovery. The primary outcome was the weighted means of the differences in ST between the operated and the non-operated knees (ΔST) for each time point (before TKA, and 1 day; 1,2, and 6 weeks; and 3,6, and 12-months post-TKA). For this analysis, 318 patients were included from 10 studies. The elevation in ST was greatest during the first 2-weeks (ΔST = 2.8 °C) and remained higher than pre-surgery levels at 4-6 weeks. At 3-months, ΔST was 1.4 °C. It decreased to 0.9 °C and 0.6 °C at 6 and 12-months respectively. Establishing the baseline profile of knee ST following TKA provides the necessary first step for evaluating the usefulness of thermography for the diagnosis of post-procedural PJI.

New Versus Old-How Reliable Is the New OTA/AO Classification for Trochanteric Hip Fractures?

OBJECTIVE: To evaluate the intraobserver and interobserver reliability of the 2018 OTA/AO trochanteric hip fracture (THF) classification compared with the 1983 OTA/AO Muller classification system. To further delineate the reliability of classifying stable and unstable THF using the 2 classification systems. DESIGN: Radiographic observational study. SETTING: Multicenter, one Level 1 and one Level 2 trauma centers. PARTICIPANTS/PATIENTS: Seventy-three radiographic series of patients treated operatively for THF were evaluated by 6 orthopaedic surgeons. INTERVENTION: The OTA/AO THF classification system was applied by each surgeon to 73 cases in 2 independent assessments performed 4 weeks apart: once by the old classification followed by the new 2018 OTA/AO classification. Each radiographic series included lateral hip and anteroposterior initial radiographs. Eight random cases were duplicated in each of the surveys to evaluate the intraobserver reliability. MAIN OUTCOME MEASUREMENTS: Intraobserver and interobserver of the group, subgroup and fracture stability classification determined by the interclass coefficient (ICC) and Cohen kappa values. RESULTS: The interobserver reliability for the group classification (31A1/A2/A3) was moderate using the new classification, whereas substantial agreement was shown using the old classification (0.49 and 0.69, respectively). The reliability of the fracture stability classification was higher using the old classification (0.70 vs. 0.52). Subgroup classifications interobserver agreement was fair for both classification systems, although lower reliability was shown in the old classification (0.34 vs. 0.31). CONCLUSIONS: The new OTA/AO classification has a lower interobserver reliability for THF classification when compared with the old one.

Repairing a critical cranial defect using WISP1-pretreated chondrocyte scaffolds.

In cranial flat bone fractures, spontaneous bone repair will occur only when the fracture ends are in close contact. However, in cases wherein bone discontinuity is extensive, surgical interventions are often required. To this end, autologous bone is harvested and surgically integrated into the site of fracture. Here we propose to use cartilage, as an alternative autologous source, to promote cranial fracture repair. The advantage of this approach is the potential reduction in donor site morbidity, likely due to the avascular and aneural nature of cartilage. As a first step we attempted to induce cartilage mineralization in vitro, using micromass primary chondrocyte cultures, incubated with BMP2 and/or WISP1, which were examined histologically following a 3-week culture period. Next, chondrocyte seeded collagen scaffolds were evaluated in vitro for expression profiles and ALP activity. Finally, chondrocyte-seeded collagen scaffolds were implanted in a Lewis rats 8 mm critical calvaria defect model, which was imaged via live CT for 12 weeks until sacrifice. End points were analyzed for microCT, histology, and serum levels of bone related markers. Micromass cultures exhibited an osseous inducing trend following WISP1 administration, which was maintained in chondrocyte seeded scaffolds. Accordingly, in vivo analysis was carried out to assess the impact of WISP1-pretreated chondrocytes (WCS) versus untreated chondrocytes (UCS) in calvaria defect model and compared to untreated control comprised of a defect-associated blood clot (BC) or empty collagen scaffold (CS) implant. Live CT and microCT exhibited higher mineralization volumes in critical defect implanted with UCS, with some structural improvements in WCS. Histological analysis exhibited higher anabolic bone formation in WCS and trabecular bone was detected in WCS and UCS groups. Chondrocytes implanted into critical cranial defect expedite the formation of native-like osseous tissue, especially after WISP1 priming in culture. Ultimately, these data support the use of autologous chondrocytes to repair critical maxillofacial defects.

Chondrocytes supplemented to bone graft-containing scaffolds expedite cranial defect repair.

Critical maxillofacial bone fractures do not heal spontaneously, thus, often there is a need to facilitate repair via surgical intervention. Gold standard approaches, include the use of autologous bone graft, or devices supplemented with osteogenic growth factors and bone substitutes. This research aimed to employ a critical size calvaria defect model, to determine if the addition of chondrocytes to collagen-containing bone graft substitute, may expedite bone repair. As such, using a critical size rat calvaria defect, we implanted a collagen scaffold containing bone graft substitute (i.e., Bone graft scaffold, BG) or BG supplemented with costal chondrocytes (cBG). The rats were subjected to live CT imaging at 1, 6, 9, and 12 weeks following the surgical procedure and sacrificed for microCT imaging of the defect site. Moreover, serum markers and histological evaluation were assessed to determine osseous tissue regeneration and turnover. Live CT and microCT indicated cBG implants displayed expedited bone repair vs, BG alone, already at 6 weeks post defect induction. cBG also displayed a shorter distance between the defect edges and greater mineral apposition distance compared to BG. Summerizing, the data support the addition of chondrocytes to bone substitute, accelerates the formation of new bone within a critical size defect.

HU308 Mitigates Osteoarthritis by Stimulating Sox9-Related Networks of Carbohydrate Metabolism.

Osteoarthritis (OA) is characterized by progressive, irreversible erosion of articular cartilage accompanied by severe pain and immobility. This study aimed to assess the effect and mechanism of action of HU308, a selective cannabinoid receptor type 2 (CB2) agonist, in preventing OA-related joint damage. To test the assumption that HU308 could prevent OA-related joint damage, Cnr2 null mice and wild type (WT) mice were aged to reach 20 months and analyzed for joint structural features. OA was induced in WT mice via a post-traumatic procedure or aging, followed by HU308 local (intra-articular) or systemic (intraperitoneal) administration, respectively. Additional analyses of time and dose courses for HU308 were carried out in human primary chondrocytes, analyzed by RNA sequencing, RT-PCR, chromatin immunoprecipitation, and immunoblotting. Our results showed that Cnr2 null mice exhibited enhanced age-related OA severity and synovitis compared to age-matched WT mice. Systemic administration of HU308 to 16-month-old mice improved pain sensitivity and maintained joint integrity, which was consistent with the intra-articular administration of HU308 in post-traumatic OA mice. When assessing human chondrocytes treated with HU308, we uncovered a dose- and time-related increase in ACAN and COL2A1 expression, which was preceded by increased SOX9 expression due to pCREB transcriptional activity. Finally, transcriptomic analysis of patient-derived human chondrocytes identified patient subpopulations exhibiting HU308-responsive trends as judged by enhanced SOX9 expression, accompanied by enriched gene networks related to carbohydrate metabolism. Collectively, the results showed that HU308 reduced trauma and age-induced OA via CB2-pCREB dependent activation of SOX9, contributing to augmented gene networks related to carbohydrate metabolism. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

The effect of steroid injection into the shoulder on glycemia in patients with type 2 diabetes.

Background: Injections of corticosteroids into or around joints have been reported to increase blood glucose in patients with diabetes due to corticosteroid absorption into the bloodstream. However, the magnitude, duration, and clinical implications of local corticosteroid injections on glycemic control are not clear. The purpose of this study was to evaluate the effects of corticosteroid injection to the shoulder on glycemia in patients with type 2 diabetes mellitus using a continuous glucose monitoring device. Methods: Twenty-five patients with symptomatic shoulder problems and type 2 diabetes mellitus, not treated with insulin, prescribed a corticosteroid injection into the shoulder, were investigated. The patients were connected to a flash glucose monitoring system, which continuously monitored interstitial glucose levels. Data were collected 3 days before injection and for additional 11 days after corticosteroid injection. We analyzed glucose levels in the first 3 days (early postinjection) and on days 4-11 (late postinjection) after the injection and compared them to the preinjection period. The outcome measures included change in the average glucose levels, per patient, between the preinjection and postinjection periods and the differences in the time spent at glucose >180 mg/dL, >250 mg/dL, and >350 mg/dL, per patient, between the preinjection and postinjection periods. Results: The increase in the mean glucose level per patient was statistically significant from 136 mg/dL in the preinjection period to 159 mg/dL in the first 3 days after the injection and returned to normal thereafter. Time at blood glucose >250 mg/dL increased from 4.3% in the preinjection period to 9.5% on the first day after the injection. It then decreased to 7% on day 2, 3.8% on day 3, and 1.4% in the late postinjection period. New onset of glucose levels >350 mg/dL was found in 4 of 25 patients during the early postinjection period. In all 4 patients, the exposure to severe hyperglycemia (>350 mg/dL) was short. None of the patients required intensification of the antidiabetic treatment or insulin injections. Conclusion: Local corticosteroid injection to the shoulder can create a significant, short-term increase in systemic glucose levels in patients with D2DM not treated with insulin. Some of these patients may have periods with glucose above 350 mg %. However, these glycemic changes are short lived and are mostly limited to the 2-3 days after the injection. In addition, none of the patients in our study needed any change in antidiabetic treatment or any medical care after the injection.

A Fenchone Derivative Effectively Abrogates Joint Damage Following Post-Traumatic Osteoarthritis in Lewis Rats.

BACKGROUND: In a previous report, we have identified the cannabinoid receptor 2 (CB2) agonist HU308 to possess a beneficial effect in preventing age and trauma-induced osteoarthritis (OA) in mice. The effects of HU308 were largely related to the capacity of this compound to induce cartilage anabolism which was dependent on the CREB/SOX9 axis, and exhibited pro-survival and pro-proliferative hallmarks of articular cartilage following treatment. Here, we utilized the novel cannabinoid-fenchone CB2 agonists (1B, 1D), which were previously reported to render anti-inflammatory effects in a zymosan model. METHODS: Initially, we assessed the selectivity of CB2 using a Gs-protein receptor cAMP potency assay, which was also validated for antagonistic effects dependent on the Gi-protein receptor cAMP pathway. Based on EC50 values, 1D was selected for a zymosan inflammatory pain model. Next, 1D was administered in two doses intra-articularly (IA), in a post-traumatic medial meniscal tear (MMT, Lewis rats) model, and compared to sham, vehicle, and a positive control consisting of fibroblast growth factor 18 (FGF18) administration. The histopathological assessment was carried out according to the Osteoarthritis Research Society International (OARSI) guidelines for rat models following 28 days post-MMT. RESULTS: The G protein receptor assays confirmed that both 1B and 1D possess CB2 agonistic effects in cell lines and in chondrocytes. Co-administering a CB2 antagonists to 25 mg/kg 1D in a paw inflammatory pain model abolished 1D-related anti-swelling effect and partially abolishing its analgesic effects. Using an MMT model, the high dose (i.e., 24 µg) of 1D administered via IA route, exhibited reduced cartilage damage. Particularly, this dose of 1D exhibited a 30% improvement in cartilage degeneration (zonal/total tibial scores) and lesion depth ratios (44%), comparable to the FGF18 positive control. Synovitis scores remained unaffected and histopathologic evaluation of subchondral bone damage did not suggest that 1D treatment changed the load-bearing ability of the rats. Contrary to the anabolic effect of FGF18, synovial inflammation was observed and was accompanied by increased osteophyte size. CONCLUSION: The structural histopathological analysis supports a disease-modifying effect of IA-administered 1D compound without any deleterious effects on the joint structure.

Muscle activity while ambulating on stairs and slopes: A comparison between individuals scheduled and not scheduled for knee arthroplasty and healthy controls.

OBJECTIVE: To examine muscle activity patterns of the lower limbs while ascending and descending stairs and slope in adults with knee Osteoarthritis (knee-OA), who were scheduled or not scheduled for Total Knee Replacement (TKR) and healthy controls. METHODS: This cross-sectional study included three groups: knee-OA subjects scheduled for TKR (TKR group; N = 15) and not scheduled for TKR (NTKR group; N = 15) and age-matched controls (N = 11). Outcome measures included: joint range of motion (ROM), Timed Up and Go (TUG), joint pain levels, and functional disability (Oxford) score. Also, durations of muscle activity (rectus femoris, semitendinosus, medial gastrocnemius, bilaterally, and soleus, and tibialis anterior of the OA limb) were recorded while the subjects ascended and descended stairs and a level surface. RESULTS: Both knee-OA groups had significantly higher Oxford scores and bilateral knee pain levels compared to the control group. The TKR group had higher TUG score compared to the NTKR group. The activation duration of the Tibialis Anterior of the OA limb while ascending and descending stairs and slope were higher in the TKR group compared to the NTKR group. No differences in muscle activity durations were found when comparing the OA limb to contralateral limb. CONCLUSION: The muscle activity strategies differentiated between individuals scheduled and not scheduled for TKR. The longer duration of muscle activity of Tibialis Anterior muscle in the TKR group compared to the NTKR group suggest that customized prehabilitation program is required for these groups.

Kinematics following gait perturbation in adults with knee osteoarthritis: Scheduled versus not scheduled for knee arthroplasty.

OBJECTIVE: To compare recovery kinematics following trip-simulated perturbation during gait between three groups: adults without knee Osteoarthritis (OA) and adults with OA, scheduled and not scheduled for Total Knee Replacement (TKR). METHODS: People with OA scheduled for TKR (TKR group; N = 19) and not scheduled (NTKR group; N = 17) were age-matched with People without OA (N = 19). Outcome measures included: joint range of motion (ROM), Timed Up and Go (TUG), joint pain levels, Oxford score, Instrumental Activities of Daily Living Questionnaire, and the Activities-specific Balance Confidence Scale. Also, spatiotemporal gait parameters and joint kinematics were recorded during perturbed and unperturbed gait. The perturbed gait data were normalized by unperturbed gait data. RESULTS: There were no differences between the two OA groups in the four questionnaire scores and joint ROM. The TUG score of the TKR group was higher than that of the NTKR group. There were no statistically significant between-group differences in the normalized spatiotemporal parameters. The OA groups showed statistically significant lower anterior pelvic tilt ranges and higher maximal hip adduction of the contralateral limb compared to the Non-OA group. When the contralateral limb was perturbed, the TKR group showed significantly lower pelvic rotation range compared to the NTKR and Non-OA groups. When the OA limb was perturbed, the maximal hip flexion of the injured limb was significantly lower and the maximal knee flexion higher in the OA groups compared with the Non-OA group. CONCLUSION: The recovery strategy from trip-simulated perturbation of individuals with OA differs from that of individuals without OA. This may emphasize the importance of devising a treatment plan that focuses on improving balance and reactions to gait perturbation.