Necroptotic TNFα-Syndecan 4-TNFα Vicious Cycle as a Therapeutic Target for Preventing Temporomandibular Joint Osteoarthritis

Temporomandibular joint osteoarthritis (TMJOA) is a chronic degenerative disease for which the underlying mechanism still remains unclear. Compared with apoptosis and autophagy, necroptosis causes greater harm to tissue homeostasis by releasing damage-associated molecular patterns (DAMPs). However, the role of necroptosis and downstream key DAMPs in TMJOA is unknown. Here, rodent models of TMJOA were established by the unilateral anterior crossbite (UAC). Transmission electron microscopy (TEM) and immunohistochemistry of receptor interacting protein kinase 3 (RIPK3)/phosphorylation of mixed lineage kinase domain-like protein (pMLKL) were conducted to evaluate the occurrence of necroptosis in vivo. The therapeutic effects of blocking necroptosis were achieved by intra-articularly injecting RIPK3 or MLKL inhibitors and using RIPK3 or MLKL knockout mice. In vitro necroptosis of condylar chondrocyte was induced by combination of tumor necrosis factor alpha (TNFα), second mitochondria-derived activator of caspases (SMAC) mimetics and carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]- fluoromethylketone (z-VAD-fmk). The possible DAMPs released by necroptotic chondrocytes were screened by quantitative proteomics and blocked by specific antibody. Translucent cytosol, swollen organelles, and ruptured cell membranes, features of necroptosis, were frequently manifested in chondrocytes at the early stage of condylar cartilage degeneration in TMJOA, which was accompanied by upregulation of RIPK3/pMLKL. Inhibiting or knocking out RIPK3/MLKL significantly prevented cartilage degeneration. DAMPs released by necroptotic condylar chondrocytes, such as syndecan 4 (SDC4) and heat shock protein 90 (HSP90), were verified. Furthermore, blocking the function of SDC4 significantly attenuated the expression of TNFα in cartilage and synovium, and accordingly increased cartilage thickness and reduced synovial inflammation. Thus, the necroptotic vicious cycle of TNFα-SDC4-TNFα contributes to cartilage degeneration and synovitis, and can serve as a potential therapeutic target for treating TMJOA. © 2022 American Society for Bone and Mineral Research (ASBMR).     

Changes in Bone Marrow Adipose Tissue in Transgender and Gender Non-Conforming Youth Undergoing Pubertal Suppression: A Pilot Study

Pubertal suppression with gonadotropin-releasing hormone (GnRH) agonists in transgender and gender non-conforming (TGNC) youth may affect acquisition of peak bone mass. Bone marrow adipose tissue (BMAT) has an inverse relationship with bone mineral density (BMD). To evaluate the effect of pubertal suppression on BMAT, in this pilot study we prospectively studied TGNC youth undergoing pubertal suppression and cisgender control participants with similar pubertal status over a 12-month period. BMD was measured by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. Magnetic Resonance T1 relaxometry (T1-R) and spectroscopy (MRS) were performed to quantify BMAT at the distal femur. We compared the change in BMD, T1-R values, and MRS lipid indices between the two groups. Six TGNC (two assigned female and four assigned male at birth) and three female control participants (mean age 10.9 and 11.7 years, respectively) were enrolled. The mean lumbar spine BMD Z-score declined by 0.29 in the TGNC group, but increased by 0.48 in controls (between-group difference 0.77, 95% CI: 0.05, 1.45). Similar findings were observed with the change in trabecular volumetric BMD at the 3% tibia site (-4.1% in TGNC, +3.2% in controls, between-group difference 7.3%, 95% CI: 0.5%-14%). Distal femur T1 values declined (indicative of increased BMAT) by 7.9% in the TGNC group, but increased by 2.1% in controls (between-group difference 10%, 95% CI: -12.7%, 32.6%). Marrow lipid fraction by MRS increased by 8.4% in the TGNC group, but declined by 0.1% in controls (between-group difference 8.5%, 95% CI: -50.2%, 33.0%). In conclusion, we observed lower bone mass acquisition and greater increases in BMAT indices by MRI and MRS in TGNC youth after 12 months of GnRH agonists compared with control participants. Early changes in BMAT may underlie an alteration in bone mass acquisition with pubertal suppression, including alterations in mesenchymal stem cells within marrow.     

Everyday footwear: An overview of what we know and what we should know on ill-fitting footwear and associated pain and pathology

Footwear has been used to protect feet for millennia with socially exclusive population adopting stylish and fashionable shoes with expensive materials. In terms of historic timeline, only more recently footwear has been worn by all classes in the western world as an integral part of their apparel. Traditionally, footwear has been constructed from natural materials, mainly leather, but has recently benefitted from the flexibility that technology has provided with a plethora materials and new design innovations. Although it has expanded the availability for a variety of consumers, the choice and fit continue to be problematic with many individuals wearing shoes that are ill-fitting. Provision of specific footwear advice for problem feet is poorly evidenced and is heavily practitioner dependant limiting its efficacy. There is limited understanding as to the changes that can occur from regularly wearing footwear that is unsuitable in shape, style and construction which is referred to as ill-fitting. Current research on the effect that everyday footwear has on foot function and pain focuses mainly on women’s shoes, particularly high heels. Defining what is a good fitting shoe, that does not damage the foot or mechanics of walking, may need to be individualised, but best fit is based on loose historical parameters rather than research evidence. The aim of this overview is to highlight aspects of current research, establishing what is known about the effect’s shoes have on the feet as well as exploring the mythology around footwear fit and advice that is often historical in nature.     

Celastrol inhibits microglial pyroptosis and attenuates inflammatory reaction in acute spinal cord injury rats

Pyroptosis pathway is closely related to inflammation. However, Celastrol effect on pyroptosis pathway after spinal cord injury (SCI) are poorly understood. We studied the anti-inflammatory and neuroprotective effects of Celastrol on acute spinal cord injury in rats, and its anti-inflammatory effects on lipopolysaccharide (LPS)/ATP-induced microgliosis. Our results show that Celastrol can improve the recovery of hindlimb motor function after SCI in Sprague-Dawley (SD) rats, and reduce the cavity area of spinal cord injury along with the neuronal loss. Celastrol simultaneously reduced the activation of microglia (especially M1 microglia) in the spinal cord, inhibited the pyroptosis-related proteins (NLRP3 ASC Caspase-1 GSDMD), reduced the release of TNF-α IL-1β and IL-18 inflammatory factors, and increased the release of IL10 cytokines. In vitro studies showed that Celastrol reduced the toxicity resulting from the administration of LPS with ATP to BV-2 cells, inhibited the pyroptosis-related proteins (NLRP3 Caspase-1 GSDMD), and inhibited the release of corresponding inflammatory factors. Finally, Celastrol can inhibit the expression of NFκB/p-p65 in vitro and in vivo. Our results show that Celastrol can attenuate the inflammatory response of the spinal cord after SCI, which is associated with inhibition of microglial activation and pyroptosis pathway. Further study to explore the use of Celastrol to treat SCI is warranted.     

Infusions of Large Synthetic HDL Containing Trimeric apoA-I Stabilize Atherosclerotic Plaques in Hypercholesterolemic Rabbits

BackgroundAmong strategies to reduce the remaining risk of cardiovascular disease, interest has focused on using infusions of synthetic high-density lipoprotein (sHDL).MethodsNew Zealand rabbits underwent a perivascular injury at both carotids and were randomly allocated into 2 protocols: (1) a single-dose study, where rabbits were treated with a single infusion of sHDL containing a trimeric form of human apoA-I (TN-sHDL, 200 mg/kg) or with Placebo; (2) a multiple-dose study, where 4 groups of rabbits were treated 5 times with Placebo or TN-sHDL at different doses (8, 40, 100 mg/kg). Plaque changes were analysed in vivo by intravascular ultrasound. Blood was drawn from rabbits for biochemical analyses and cholesterol efflux capacity evaluation.ResultsIn both protocols, atheroma volume in the Placebo groups increased between the first and the second intravascular ultrasound evaluation. A stabilization or a slight regression was instead observed vs baseline in the TN-sHDL-treated groups (P < 0.005 vs Placebo after infusion). TN-sHDL treatment caused a sharp rise of plasma-free cholesterol levels and a significant increase of total cholesterol efflux capacity. Histologic analysis of carotid plaques showed a reduced macrophage accumulation in TN-sHDL-treated rabbits compared with Placebo (P < 0.05).ConclusionsOur results demonstrate that acute and subacute treatments with TN-sHDL are effective in stabilizing atherosclerotic plaques in a rabbit model. This effect appears to be related to a reduced intraplaque accumulation of inflammatory cells. Besides recent failures in proving its efficacy, sHDL treatment remains a fascinating therapeutic option for the reduction of cardiovascular risk.     

Effect of Dexmedetomidine infusion during hip fracture surgery on hemodynamic parameters and blood loss: A triple-blinded Randomized Clinical Trial

Introduction In this study, we aim to assess the intra-operative effect of dexmedetomidine administration on the hemodynamic parameters and bleeding volume during hip fracture surgery.Patients and methods we designed and implemented a triple-blinded randomized clinical trial to objectively compare the effects of 0.5 µg/kg/h infusion of dexmedetomidine with placebo (equal amount of normal saline) during hip fracture surgery. All included cases were between 30 and 70 years old and underwent surgery for fixation of a proximal femur fracture from September 26, 2020 until February 15, 2021. They were all ASA class I or II with preoperative hemoglobin levels of 10 mg/dL or higher. Surgical blood loss and hemodynamic parameters were documented.Results 76 patients were enrolled. There were no significant differences in baseline patient characteristics. The bleeding rate was 620 ± 190.0 mL for the normal saline group and 476 ± 177.98 mL in the dexmedetomidine group (P = 0.04). No significant effect on hemodynamic parameters was observed.Conclusion Based on the current study, intravenous infusion of dexmedetomidine during hip fracture surgery under general anesthesia reduced the amount of intraoperative bleeding without causing any significant hemodynamic disturbances.Registration number IRCT20191222045857N1 (Iranian Registry of Clinical Trials)     

Influenza vaccination and the endurance against air pollution among elderly with acute coronary syndrome

ObjectiveAir pollution, weather condition and influenza are known risk factors of acute coronary syndrome (ACS) among elderly people. The influenza vaccine (IV) has been shown to reduce major cardiovascular events. The purpose of this study was to compare resistance to air pollution and weather factors causing ACS between vaccinated and less-vaccinated elderly people.MethodsA case–crossover design was applied to 1835 elderly ACS patients who were obtained from the 1-million sample of Taiwan National Health Insurance Research Data with inclusion criteria: (1) the first diagnosis of ACS was in cold season and at age 68 or more, (2) had received the free IV program at least once during the period 3 years before the ACS. They were stratified into two groups: 707 had received flu vaccinations for all the 3 years and the remaining 1128 had not. The measurements of air pollutants, temperature, and humidity corresponding to each of the 3 days prior to the ACS diagnosis date were retrieved from the data banks of the Taiwan Environmental Protection Administration and Central Weather Bureau.FindingsIncreases in air pollution concentrations of CO, NO₂, PM₁₀ or PM_2.5 and decreases in temperature significantly influenced the risk of ACS for the non-continuously vaccinated elderly population; however, less significant effects were observed for the continuously vaccinated population.ConclusionConsecutive influenza vaccination may potentially offer resistance against the detrimental effects of air pollution and changes in temperature in frail elderly adults with ACS. Future studies are needed to directly assess the interaction effect between the vaccination and environmental factors on ACS.