Progressive Destruction Research Articles

Electrospinning Fibers Modified with Near Infrared Light‐Excited Copper Nanoparticles for Antibacterial and Bone Regeneration

AbstractBone infection is an inflammatory bone disease caused by infectious microorganisms, which can lead to progressive bone destruction and loss. It is still an urgent and unmet clinical need to develop a rapid and effective sterilized method to reduce bone infection. In this study, near‐infrared (NIR) light‐responsive polydopamine (PDA) adherent Copper nanoparticles (Cu‐NPs) are constructed using electrospun poly lactic acid (PLLA) fibers as a substrate (PLLA@PDA/Cu). Dopamine (DA) is self‐polymerized to synthesize the PDA on the fiber surface, which can reduce Cu2+ to form Cu‐NPs. Results show that the addition of PDA and Cu2+ significantly improves the hydrophilicity and bioactivity of the prepared PLLA@PDA/Cu composite fibers, demonstrating superior physiological stability. Due to the unique photothermal properties of Cu‐NPs, PLLA@PDA/Cu is able to generate a large amount of reactive oxygen species under 808 nm NIR laser irradiation, with a photothermal conversion efficiency of 23.7%. The antimicrobial effect of Cu‐NPs is synergistic with their photothermal effect, which potentiated the antibacterial rate of composite fibers . The results of cell experiments show that this composite fiber demonstrates satisfactory osteogenic and angiogenic properties. In conclusion, a photothermal antibacterial PLLA@PDA/Cu composite fiber with great potential in healing infectious bone defects is successfully engineered.

Regulatory T cells targeting a pathogenic MHC class II: Insulin peptide epitope postpone spontaneous autoimmune diabetes.

In spontaneous type 1 diabetes (T1D) non-obese diabetic (NOD) mice, the insulin B chain peptide 9-23 (B:9-23) can bind to the MHC class II molecule (IAg7) in register 3 (R3), creating a bimolecular IAg7/InsulinB:9-23 register 3 conformational epitope (InsB:R3). Previously, we showed that the InsB:R3-specific chimeric antigen receptor (CAR), constructed using an InsB:R3-monoclonal antibody, could guide CAR-expressing CD8 T cells to migrate to the islets and pancreatic lymph nodes. Regulatory T cells (Tregs) specific for an islet antigen can broadly suppress various pathogenic immune cells in the islets and effectively halt the progression of islet destruction. Therefore, we hypothesized that InsB:R3 specific Tregs would suppress autoimmune reactivity in islets and efficiently protect against T1D. To test our hypothesis, we produced InsB:R3-Tregs and tested their disease-protective effects in spontaneous T1D NOD.CD28-/- mice. InsB:R3-CAR expressing Tregs secrete IL-10 dominated cytokines upon engagement with InsB:R3 antigens. A single infusion of InsB:R3 Tregs delayed the onset of T1D in 95% of treated mice, with 35% maintaining euglycemia for two healthy lifespans, readily home to the relevant target whereas control Tregs did not. Our data demonstrate that Tregs specific for MHC class II: Insulin peptide epitope (MHCII/Insulin) protect mice against T1D more efficiently than polyclonal Tregs lacking islet antigen specificity, suggesting that the MHC II/insulin-specific Treg approach is a promising immune therapy for safely preventing T1D.

Combination Treatment of Locoregionally Aggressive Granulomatosis with Polyangiitis and Cranial Base Infiltration.

To present a personalized approach in three cases of treatment-resistant, locoregionally aggressive forms of cANCA-positive granulomatosis with polyangiitis (GPA) and skull base involvement. Three patients with GPA and skull base involvement were described alongside a critical review of the current literature. All presented patients suffered from GPA with an inflammatory tumor at the skull base, alongside cerebellopontine angle involvement, cranial nerve palsies, cerebellar disorders, concomitant hearing loss, and severe otalgia. Symptoms were associated with progressive granulomatous destruction of the temporal bone, laryngopharynx, and central nervous system infiltration. Treatment with cyclophosphamide and high doses of glucocorticoid steroids were ineffective but subsequent therapy with rituximab was successful in the presented cases. The literature review showed that the course of the disease with skull base involvement is associated with poorer clinical and radiological responses to standard pharmacotherapies. Granulomatous inflammation localized in the skull base is associated with a more aggressive disease progression and is less likely to respond to pharmacotherapy. Standard induction therapy with cyclophosphamide and glucocorticoid steroids may be ineffective. A better response may be achieved by using rituximab and concomitant local treatment with glucocorticoid steroid injections.

Notopterol alleviates the progression of osteoarthritis: An in vitro and in vivo study

Osteoarthritis (OA) is a prevalent degenerative joint disorder caused by the progressive destruction of cartilage and inflammation in the articular cavity. Studies have proved that the inhibition of articular cartilage destruction and generation of inflammatory factors can be effective strategies for treating OA. Notopterol (NOT) is a quality control index of Notopterygium incisum Ting ex H. T. Chang (N. incisum) with anti-inflammatory, antioxidant, and analgesic activities. Moreover, NOT has been used for many years to treat joint diseases. A study using human C28/I2 cells suggested that NOT down-regulated the hypersecretion of inflammatory mediators and alleviated the degradation of the extracellular matrix (ECM). In addition, NOT decreased the overproduction of reactive oxygen species (ROS) and chondrocyte apoptosis through the nuclear factor erythroid-2–related factor 2 (Nrf2) signaling pathway. NOT exerted a chondroprotective effect by partly inhibiting the Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathways and regulating the nuclear factor Nrf2/heme oxygenase-1(HO-1) signaling pathway. In vivo, NOT improved the destruction of articular cartilage in a rat OA model, which may be related to the inhibition of tumor necrosis factor α (TNF-α), interleukin (IL)-1β, IL-6, and IL-12 expressions in synovial fluid. In summary, these results showed that NOT alleviated the progression of OA and is expected to become a new therapy for treating OA clinically.

Multiple refractory intracellular pathogen infections in a human immunodeficiency virus-negative patient with anti-interferon-γ autoantibodies: a case report

BackgroundThe clinical presentation of adult-onset immunodeficiency with anti-interferon (IFN)-γ autoantibodies with intracellular pathogens can be highly variable, which can lead to misdiagnosis during the early stage of disease.Case presentationWe report a complex case of a 54-year-old Chinese male who was human immunodeficiency virus-negative. He had a presence of anti-IFN-γ autoantibodies and suffered from various intracellular pathogenic infections. The patient was admitted to our hospital for the first time in July 2016 with severe pneumonia, and he experienced multiple pneumonia infections between 2017 and 2019. In March 2019, the patient was hospitalized due to pulmonary lesions and multiple-bone destruction. During hospitalization, the patient was confirmed to have disseminated Talaromyces marneffei infection and was successfully treated with antifungal therapy for 1 year. In June 2021, Mycobacterium kansasii infection was detected by positive culture and progressive bone destruction. A high concentration of anti-IFN-γ antibodies was observed in the patient’s serum. In addition, Listeria monocytogenes was isolated by blood culture, and the presence of L. monocytogenes in cerebrospinal fluid was confirmed by next-generation sequencing. Following anti-non-tuberculous mycobacteria (NTM) therapy and anti-bacterial therapy, the patient’s symptoms, pulmonary lesions, and bone destruction gradually improved.ConclusionsAlthough the clinical presentation of adult-onset immunodeficiency with anti-IFN-γ autoantibodies can be highly variable, the diagnosis should be considered if patients suffer from unexplained repeated bacterial or opportunistic infections.Conventional and advanced molecular testing should be used, as needed, for microbiological diagnoses among this special immunodeficient population.

The potential role of synovial cells in the progression and treatment of osteoarthritis.

Osteoarthritis (OA), the commonest arthritis, is characterized by the progressive destruction of cartilage, leading to disability. The Current early clinical treatment strategy for OA often centers on anti-inflammatory or analgesia medication, weight loss, improved muscular function and articular cartilage repair. Although these treatments can relieve symptoms, OA tends to be progressive, and most patients require arthroplasty at the terminal stages of OA. Recent studies have shown a close correlation between joint pain, inflammation, cartilage destruction and synovial cells. Consequently, understanding the potential mechanisms associated with the action of synovial cells in OA could be beneficial for the clinical management of OA. Therefore, this review comprehensively describes the biological functions of synovial cells, the synovium, together with the pathological changes of synovial cells in OA, and the interaction between the cartilage and synovium, which is lacking in the present literature. Additionally, therapeutic approaches based on synovial cells for OA treatment are further discussed from a clinical perspective, highlighting a new direction in the treatment of OA.

Amelioration of Osteoarthritis via Tetrahedral Framework Nucleic Acids Delivering Microrna‐124 for Cartilage Regeneration

AbstractMicroRNAs (miRNAs) regulate several physiological and pathological processes involved in various diseases, including osteoarthritis (OA). OA is the most common global musculoskeletal disorder, characterized by the irreversible progressive destruction of articular cartilage. Supplementation with exogenous miRNAs may represent a promising therapeutic OA treatment, with miRNA‐124 (miR‐124) being a prime candidate for its anti‐inflammatory ability; however, an effective drug delivery system is urgently required to enhance miR‐124 stability and capacity to enter chondrocytes. To this end, tetrahedral framework nucleic acids’ (tFNAs) self‐assembled 3D DNA nanostructures possess superior inherent biocompatibility, versatile functionality, unsurpassed editability, and strong cellular internalization ability. In this study, tFNAs carrying one or three miR‐124 (T‐miR1 or T‐miR3) are successfully synthesized. T‐miR3 is largely absorbed via induced inflammatory chondrocytes by IL‐1β. With reactive oxygen species’ scavenging ability and inflammation‐suppressive miR‐124 release behavior, T‐miR3 efficiently protects chondrocytes against IL‐1β injury in vitro. Additionally, T‐miR3 effectively prevents OA progression by inhibiting chondrocyte apoptosis, smoothing cartilage surfaces, suppressing extracellular matrix degradation, and increasing synovial thickness, effectively protecting in vivo articular cartilage, and illustrating the therapeutic ability of T‐miR3 in OA treatment. This study provides experimental evidence and novel therapeutic strategies for OA treatment in the clinical setting.

Güncel Tanı ve Tedavi Yaklaşımlarıyla MRONJ

ABSTRACT
 Osteonecrosis of the jaw bones is a persistent and rare pathology that develops with progressive bone destruction and bone necrosis as a result of impaired blood supply in the mandible and maxilla. The key point to the prevention and treatment of MRONJ is screening high-risk patients (eg, AAOMS stage 0) predisposed to the disease to detect it at an early stage to effectively prevent the risk of progression and occurrence. Although no exposed bone is seen in clinical examination, osteonecrosis can be diagnosed early by radiographic examination. Therefore, advanced imaging techniques such as MR, SPECT/PET and VELscope are important in the early diagnosis of MRONJ. There is no defined gold standard treatment in the literature and the treatment of MRONJ is often very difficult. Treatment strategies are mainly focused on minimizing the progression or formation of bone necrosis, eliminating pain, controlling infection and optimizing the patient's quality of life. The AAOMS recommends stage-based treatment planning in MRONJ patients. In addition to the treatment methods recommended by the AAOMS, there are research showing that some adjuvant treatments have a positive effect on recovery in MRONJ patients. For example, the use of platelet-rich plasma/fibrin in addition to surgical treatment increasing the success of surgery is one of them. Alternative treatment options are low-level laser therapy, surgical debridement with laser, surgical debridement under the guidance of fluorescent staining method, use of platelet concentrates, ozone and hyperbaric oxygen therapy, pentoxifylline, alpha-tocopherol, photo-bio modulation, use of parathormone or stem cell transplantation into the lesion. In this review, we aimed to update the knowledge, attitudes and behaviors of dentists about MRONJ and to shape the approach to MRONJ with the guidance of current literature.

Wedelolactone Promotes the Chondrogenic Differentiation of Mesenchymal Stem Cells by Suppressing EZH2.

Osteoarthritis (OA) is a degenerative disease that leads to the progressive destruction of articular cartilage. Current clinical therapeutic strategies are moderately effective at relieving OA-associated pain but cannot induce chondrocyte differentiation or achieve cartilage regeneration. We investigated the ability of wedelolactone, a biologically active natural product that occurs in Eclipta alba (false daisy), to promote chondrogenic differentiation. Real-time reverse transcription-polymerase chain reaction, immunohistochemical staining, and immunofluorescence staining assays were used to evaluate the effects of wedelolactone on the chondrogenic differentiation of mesenchymal stem cells (MSCs). RNA sequencing, microRNA (miRNA) sequencing, and isobaric tags for relative and absolute quantitation analyses were performed to explore the mechanism by which wedelolactone promotes the chondrogenic differentiation of MSCs. We found that wedelolactone facilitates the chondrogenic differentiation of human induced pluripotent stem cell-derived MSCs and rat bone-marrow MSCs. Moreover, the forkhead box O (FOXO) signaling pathway was upregulated by wedelolactone during chondrogenic differentiation, and a FOXO1 inhibitor attenuated the effect of wedelolactone on chondrocyte differentiation. We determined that wedelolactone reduces enhancer of zeste homolog 2 (EZH2)-mediated histone H3 lysine 27 trimethylation of the promoter region of FOXO1 to upregulate its transcription. Additionally, we found that wedelolactone represses miR-1271-5p expression, and that miR-1271-5p post-transcriptionally suppresses the expression of FOXO1 that is dependent on the binding of miR-1271-5p to the FOXO1 3'-untranscribed region. These results indicate that wedelolactone suppresses the activity of EZH2 to facilitate the chondrogenic differentiation of MSCs by activating the FOXO1 signaling pathway. Wedelolactone may therefore improve cartilage regeneration in diseases characterized by inflammatory tissue destruction, such as OA.

Bearing Capacity Analysis of the Weak Basement, Progressive Destruction Analysis, and Evaluation of the Dump on an Inclined Strip Section Using the Upper-Limit Method: A Case Study in an Anonymous Open-Cast Coal Mine

Due to terrain and transportation constraints, some open cast mines have to choose a weak basement as their tailings dumping grounds. Therefore, ensuring the bearing capacity and slope stability of dumping grounds on the weak basement is of great significance for the production capacity and economic benefits of open cast mining. To ensure the safety of surrounding facilities and the normal production of open cast mines, the bearing capacity of the dumping ground of a certain open cast mine was calculated using the oblique strip method and verified by numerical simulation. On this basis, the potential failure mode of the dumping ground base was analyzed, and the ultimate bearing capacity of the dumping ground under current conditions was calculated. The results are as follows: (1) The ultimate bearing capacity of the current dumping ground base is 3781 kPa, and the failure mode of the base is overall shear sliding along the base of the dumping ground. (2) When the slope foot increases from 12° to 18°, the stability coefficient and critical bearing capacity coefficient of the slope base decrease by about 21% and 46%, respectively. The slope angle has a greater impact on the bearing capacity of the base, and the height of the slope body has a relatively small impact, with almost no width effect. (3) Compared with the classic Terzaghi method and Prandtl method, the ultimate bearing capacity of the dumping ground base determined using the oblique strip method proposed in this paper is closer to the numerical simulation results, with an error of no more than 5%, a consistent critical sliding surface, and results that are relatively consistent with the engineering practice monitoring of the surface uplift part. The calculation results of the bearing capacity of the weak basement of open cast mine dumping grounds using the oblique strip method are reliable.

Identification of novel TACE inhibitors using DNN based- virtual screening, molecular dynamics and biological evaluation

Rheumatoid Arthritis (RA) is a well-known autoimmune inflammatory disease, distressing roughly 1% of the adult population throughout the globe. Many studies have suggested that overexpression of TNF-α, a pro-inflammatory cytokine, is responsible for the progression of RA. Furthermore, inhibition of the shedding rate of TNF-α is regulated by the TACE (TNF-α converting enzyme) protein and, hence is considered as an important therapeutic target for the prevention of progressive synovial joint destruction in rheumatoid arthritis. In the present study, we have proposed a deep neural network (DNN)-based workflow for the virtual screening of compounds towards the identification of potential inhibitors against the TACE proteins. Subsequently, a set of compounds were shortlisted, based on the molecular docking and subjected to the biological evaluation to validate the inhibitory activities of the screened compounds, determine the practical applicability of the DNN-based model, and strengthen the hypothesis. Out of seven, three compounds (BTB10246, BTB10247, and BTB10245) showed significant inhibition at 10 µM and 0.1 µM concentration. These three compounds also showed a stable and significant interaction potential against the TACE protein as compared with the re-docked complex system and can serve as a novel scaffold for further design of new molecules with improved inhibitory activities against TACE. Communicated by Ramaswamy H. Sarma

1332-P: Comparison of Clinical Characteristics of People Living with Latent Autoimmune Diabetes of the Adult (LADA) and Type 1 Diabetes (T1D) in the Canadian BETTER Registry

Introduction: LADA is known for a slow progression of autoimmune destruction of beta-cells with cases that span a spectrum between classic T1D and T2D phenotypes. To date, lacking a good understanding of LADA has prohibited the release of specific clinical practice guidelines and subsequently an optimal management. Methodology: Cross-sectional analysis of online clinical questionnaires in the Canadian BETTER registry; participants can specify having received a diagnosis of LADA or T1D. Data was analyzed for the first 1464 participants; 131 (9%) reported LADA and 1333 (91%) T1D. Results: At registration; LADA vs T1D were 49 ± 13 y.o. vs 42 ± 15 y.o; 61% vs. 62% females; diabetes duration 10 ± 9 vs. 24 ± 15 years. LADA vs. T1D were older at diagnosis (39 ± 12 vs. 18 ± 12 years old; p<0.001), only half started insulin in first year of diagnosis (52 vs. 97%; p<0.001), more often reported a family history of T1D (46 vs. 32%; p=0.001). For comparable glycemic control (HbA1c < 8.6 mmol/l, <7%, 38 vs. 32%), fewer cases with LADA reported at least an episode in last month of level II hypoglycemia <54 mg/dL (3.0mmol/L) 63% vs. 77%; p= 0.004, severe hypoglycemia rates were 8% vs. 12%, p=0.15. Diabetes related hospitalizations were 10% in LADA vs. 6%, p=0.11, insulin pumps and glucagon were less used in LADA. In a matched analysis for diabetes duration and gender (1:1), glycemic control was still statistically comparable in LADA vs. T1D (HbA1c <7%: 38 vs 35%, p=0.12) as well as rates of nephropathy (6% vs. 11%, p=0.22), neuropathy (12% vs. 7%, p=0.23) and retinopathy (6% vs. 9%, p=0.07) yet with more cardiovascular disease (5% vs. 2%; p=0.02) and less coeliac disease (3 vs. 5%; p=0.001). Data analysis of 3000 participants is ongoing in early 2023. Conclusion: Reported differences may impact LADA management. This study sets the stage for building a prospective Canadian cohort of LADA to undergo deep phenotyping, genotyping and interventional trials. Disclosure M.Issa: None. A.Brazeau: Other Relationship; Dexcom, Inc., Diabète québec, Ordre des diététistes nutritionnistes du Québec, Research Support; Canadian Institutes of Health Research, Fonds de recherche du Québec en Santé. S.Haag: Other Relationship; Omnipod. A.Roy-fleming: None. V.Messier: None. N.Taleb: Consultant; Viatris Inc.

1452-P: Type 1 Diabetes Subphenotypes—A Cluster Analysis

Adult-onset type 1 diabetes (T1D) is a chronic disease with progressive beta-cell destruction. However, individuals with adult-onset T1D are metabolically dissimilar. We aimed to identify metabolically distinct groups in a comprehensively phenotyped cohort of individuals with recent-onset T1D. Participants with T1D (n=550) were split by presence of glutamic-acid decarboxylase antibody (GADA) into a GADA- (n=95) and GADA+ groups (n=455). GADA+ was clustered using partitioning around medoids based on fasting C-peptide, glucose, triglycerides and HDL resulting in 2 distinguished GADA+ clusters. All 3 clusters were compared at baseline (first year of diabetes diagnosis) and after five years of follow-up using ANOVA, chi-squared test and logistic regression adjusted for age and sex. The larger GADA+ cluster (n=285) with younger age, lower BMI and lower C-peptide was termed “classic T1D”. The other GADA+ cluster (n=170) combined features of type 1 and type 2 diabetes and was named “mixed T1D”. Patients of the “mixed T1D” cluster did not gain weight over 5 years (p=0.29), which was not the case for “classic T1D” cluster (p<0.001, increased BMI with an effect size 0.07) and GADA-cluster (p=0.01, effect size 0.04) participants. The “classic T1D” cluster had the highest insulin sensitivity at baseline (p<0.001) that sharply decreased during five years of follow-up. At five years, there was no difference in insulin sensitivity across the 3 clusters (p=0.78). There were no differences in HbA1c levels across clusters neither at baseline (p=0.48) nor after 5 years (p=0.64). Classic T1D participants reported a higher incidence of hypoglycemia (OR 4.92, 95% CI 1.9-13.5, p=0.001). The incidence of both distal peripheral sensory (OR 2.89, 95%CI1.05-8.29, p= 0.041) and cardiac autonomic neuropathy (OR 9.61, 95%CI 2.35-49.8, p= 0.003), was higher in “mixed T1D”. Based on rapidly available laboratory variables, individuals with recent-onset adult type 1 diabetes can be stratified into clusters with different clinical course and complication risk Disclosure K.Prystupa: Other Relationship; Berlin-Chemie AG. S.M.Meyhöfer: Speaker's Bureau; Novo Nordisk, AstraZeneca, Lilly, Amgen Inc., Boehringer-Ingelheim, Novartis. O.P.Zaharia: None. N.Saatmann: None. M.Huttasch: None. K.Strassburger: None. V.Burkart: None. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. A.Fritsche: Advisory Panel; Novo Nordisk, Lilly, Sanofi, Boehringer-Ingelheim, Speaker's Bureau; AstraZeneca, SYNLAB Holding Deutschland GmbH. G.J.Bönhof: None. A.Strom: None. M.Heni: Advisory Panel; Boehringer-Ingelheim, Sanofi, Research Support; Boehringer Ingelheim Inc., Speaker's Bureau; Lilly, Bayer Inc., Sanofi, Boehringer-Ingelheim, Novo Nordisk, Amryt Pharma Plc. J.Seissler: None. J.Szendroedi: None. A.F.Pfeiffer: Advisory Panel; Abbott Diabetes, Speaker's Bureau; Novo Nordisk, Sanofi-Aventis Deutschland GmbH. M.W.Stumvoll: None.

855-P: Evolution of KT-A112, an AAV-Mediated Gene Therapy for the Treatment of Type 1 Diabetes

Type 1 Diabetes (T1D) is a chronic, life-threatening autoimmune disorder characterized by profound insulin deficiency that results from progressive destruction of insulin-producing pancreatic β-cells. For over a century, exogenous insulin delivery was the only option to help T1D patients manage persistent hyperglycemia and reduce the risk of severe microvascular and macrovascular complications. Recent exploratory treatments use complex cell-based therapies requiring long-term immunosuppression. This abstract describes a unique AAV-mediated gene therapy approach to drive skeletal muscle expression of human glucokinase (GcK) and human insulin (INS). One-time IM administration to the quadriceps, gastrocnemius and tibialis anterior muscles of STZ-induced diabetic mice resulted in dose-related increases of pharmacologically active INS at fasting levels (~1 ng/mL) and human C-peptide that decreased fed and fasted blood glucose, lowered HbA1c by >5% at the highest dose, and reduced AUCGlu upon oral glucose challenge. Elevated triglycerides seen in control STZ-treated animals were normalized. No hypoglycemia or other adverse effects were observed through 8 weeks. No immunosuppression was required. Next steps in evaluation of KT-A112 involve a rolling dose-escalation study in STZ-treated NHPs. Disclosure C.Smith: Consultant; Horizon Therapeutics plc, Employee; Kriya Therapeutics. F.Bosch: None. M.Rhodes: None. W.W.Harrington: Consultant; Kriya Therapeutics. M.Stone: None. U.Karadge: None. J.Liu: None. W.J.Quinn: Employee; Kriya Therapeutics. A.Bassiri: None. J.Mallory: Employee; Kriya Therapeutics. V.Jimenez: None.

Correlation between serum α-Klotho levels and different stages of periodontitis

BackgroundPeriodontitis is an inflammatory disease characterized by inflammation and progressive destruction of periodontal tissues including alveolar bone. α-klotho protein is a multifunctional protein related to age-related diseases, inflammatory diseases, and bone metabolism-related diseases. However, large-sample epidemiological research evidence on the correlation between α-Klotho and the aggravation of periodontitis stages is still lacking.MethodsCross-sectional study data of participants aged between 40 and 79 years in the National Health and Nutrition Examination Survey 2013‒2014 were selected and analyzed. The stages of periodontitis of the participants were determined according to the 2018 World Workshop Classification of Periodontal and Peri-implant Diseases. The serum α-Klotho levels in people with periodontitis in different stages were evaluated. Then the correlation between serum α-Klotho levels and different stages of periodontitis was analyzed by multiple linear regression (stepwise regression method).ResultsA total of 2378 participants were included in the study. The serum α-Klotho levels in people with stage I/II, III and IV periodontitis were 896.16 ± 304.84, 871.08 ± 266.42 and 840.52 ± 286.24 pg/mL, respectively. The levels of α-Klotho in people with stage IV periodontitis were significantly lower than those in people with stage I/II and III periodontitis. Linear regression analysis results showed that compared to stage I/II periodontitis, serum α-Klotho levels were significantly negatively correlated with stage III (B ± SE = -37.28 ± 16.00, 95% CI: -68.66 ~ -25.91, P = 0.020) and stage IV (B ± SE = -69.37 ± 16.11, 95% CI: -100.97 ~ -37.77, P < 0.001) periodontitis.ConclusionThe serum α-Klotho levels were negatively correlated with the severity of periodontitis. With the aggravation of periodontitis stages, the serum α-Klotho levels gradually decreased.

THE PROBLEM OF FORECASTING THE ROD STRUCTURES SURVIVABILITY

Purpose. Methods of metal structures calculation which would take into account sudden changes of the design scheme and its elements destruction as a result, are not perfect enough and are often fragmentary. The research of survivability of multi-element bar structures affected by negative factors will improve the efficiency of the such structures calculation with the prospect of further expanding the possibilities of forecasting the survivability of metal structures depending on its operation conditions. As a research object three-dimensional metal bar structures are considered, which are characterized by a high degree of production significance and responsibility during the operation. Methodology. The considered normative documents do not have a single approach regarding the identification of the problem and technique of generating possible solutions, but they combine all the listed standards. Approaches and methods for assessing the degree of a structure damage or serviceability are somewhat different: in some documents the area of damaged floor structures is limited; in others, the state of structures that have not gone out of work is assessed; as well as the economic forecast of a new building construction or restoring an old one. If we group the normative documents’ provisions of the different countries, we can single out two established approaches on "progressive destruction" protection. According to the first approach, it is necessary to use indirect protection measures, according to the second one, it is necessary to use the ability of key (bearing) elements to perceive damaging effects, the ability of structure to redistribute loads in case of some elements’ failures. Results. To increase the stability of building structures to progressive destruction, metal ones particularly, it is necessary to consider the possibility of local destruction already at the stage of building design. Its increase is facilitated by a decrease in the number of hinged joints, in some cases the use of integral structural elements, the use of building materials affected by plastic deformation, as well as the identification of building structure elements which under normal operating conditions do not perform bearing functions, but perform them in the case of the local destruction appearance. Scientific novelty. The analyses of the regulatory base and the researchers’ works in a number of countries including Ukraine regarding the progressive destruction is performed. The necessity to improve the concept of designing construction objects is justified. The basis of this concept should consist of both theoretical research and experimental confirmation of the accepted assumptions. Practical value. The necessity of forming a unified approach for determining the problem of survivability and durability of structures, redistribution of loads on undamaged structural elements is substantiated. Directions for the development of measures and design solutions regarding the prevention of the progressive destruction of multi-element bar structures are proposed.

Cartilage-Related Collagens in Osteoarthritis and Rheumatoid Arthritis: From Pathogenesis to Therapeutics.

Collagens serve essential mechanical functions throughout the body, particularly in the connective tissues. In articular cartilage, collagens provide most of the biomechanical properties of the extracellular matrix essential for its function. Collagen plays a very important role in maintaining the mechanical properties of articular cartilage and the stability of the ECM. Noteworthily, many pathogenic factors in the course of osteoarthritis and rheumatoid arthritis, such as mechanical injury, inflammation, and senescence, are involved in the irreversible degradation of collagen, leading to the progressive destruction of cartilage. The degradation of collagen can generate new biochemical markers with the ability to monitor disease progression and facilitate drug development. In addition, collagen can also be used as a biomaterial with excellent properties such as low immunogenicity, biodegradability, biocompatibility, and hydrophilicity. This review not only provides a systematic description of collagen and analyzes the structural characteristics of articular cartilage and the mechanisms of cartilage damage in disease states but also provides a detailed characterization of the biomarkers of collagen production and the role of collagen in cartilage repair, providing ideas and techniques for clinical diagnosis and treatment.

Association of elevated IL-6 with poor glycemic control in periodontitis patients

Background: Interleukin-6 (IL-6) is a proinflammatory cytokine expressed in numerous chronic inflammatory diseases whose ability to alter the pathophysiology and progression of periodontitis is well documented. Further its role in diabetes mellitus by creating an insulin resistance responsible for poor glycemic control is also being evaluated. The aim was to compare the levels of IL-6 in gingival crevicular fluid in periodontitis patients with and without diabetes and to analyze these levels in patients with poor glycemic control (HBA1c), in order to assess its role in the progression of periodontal destruction. Methods: 60 chronic periodontitis patients confirmed with CPITN index of age group 30-70 years were enrolled for the study. GCF samples from 30 patients with diabetes confirmed using HBA1c reports and 30 without diabetes using Cimasoni method were collected and stored at -70degreescelsiusand subjected to ELISA for IL-6 using krishgen human IL-6 ELISA kit as per manufacturer's instruction. Descriptive and inferential statistics were used using SPSS software. Results: While the diabetic group readings ranged from 4.4 Pg/µl to 7.0 Pg/µl with a mean of 5.8pg/µl, the non- diabetic group ranged from 1.5 Pg/µl to 4.8 Pg/µl with a mean value of3.24 pg/µl. There was a prominent increase in the IL-6 levels in diabetic when compared to non- diabetic which was statistically significant with p value &lt; 0.001. Further, among the diabetic groups, patients with poor HBA1c with reading more than 7.7% showed a significant increase in IL-6 levels when compared to below 6.8%. Conclusions: The IL-6 levels in GCF were increased in chronic periodontitis patients with diabetes and more so in patients with poor glycemic control when compared to non-diabetic group. Therefore, periodontitis along with diabetes can play a major role in the inflammatory response within the periodontium.

Identification of the relationship between biomarkers of autophagy, apoptosis and inflammation in the acute period of atherothrombotic ischemic stroke

The postischemic inflammatory response plays a significant role in the pathogenesis of acute ischemic stroke (IS). It has been established that acute IS is accompanied by aseptic inflammation, which induces the activation of costimulatory molecules in the process of innate immunity response to brain tissue damage. The constantly progressive destruction of neuronal antigens contributes to an increase in the volume of the ischemic lesion. Evidence continues to accumulate indicating an important role of NLRP3-mediated inflammation in the pathogenesis of IS. It has been shown that autophagy is involved in the inflammatory cascade in acute IS. Many of the anti-inflammatory mechanisms mediated by autophagy in acute IS involve the key autophagic proteins Beclin-1, LC3, and p62. Experimental studies have shown that autophagy suppresses the activation of NLRP3 inflammation. Data on cross interactions between apoptosis and autophagy in the pathogenesis of IS are still controversial. The aim of the study was to evaluate the relationship between biomarkers of autophagy, inflammation, and apoptosis in the dynamics of the acute period of atherothrombotic IS. The article presents the results of a dynamic study of the serum concentration of the key autophagy biomarkers Beclin-1, LC3 and p62, apoptosis indicators Bcl-2 and p53, pro-inflammatory cytokines IL-1β, TNFα, IL-8, IL-18 which are involved in postischemic neuroinflammation. A statistically significant increase in the studied parameters was established in comparison with the control group. The maximum increase in the studied biomarkers is noted on the 1st day after the development of ischemia in patients with a severe course of the disease. The relationship between autophagy activity, apoptosis biomarkers, and some indicators of the systemic inflammatory response in patients with moderate and severe atherothrombotic stroke was revealed. The results obtained confirm the literature data on the involvement of autophagy in the regulation of the postischemic inflammatory response.

Treatment of TMJ Osteoarthritis

Osteoarthritis (OA) is common disease that can lead to severe pain and dysfunction in any joint, including the temporomandibular joint (TMJ). The treatment strategy for TMJ OA aims at reducing pain, preventing the progression of condylar bone destruction, and restoring joint function. Conservative therapy including nonste-roidal anti-inflammatory drugs, occlusal splint, and physical therapy, and arthrocentesis are the most common treatments for TMJ OA. These therapies are effective in most cases in relieving the signs and symptoms.