Osteoimmune Interaction and TH-1/TH-2 Ratio in Jawbone Marrow Defects: An Underestimated Association - Original Research.

Introduction: Osteoimmunology recognizes the relationship between bone cells and immune cells. Chronic osteoimmune dysregulation is present in bone marrow defects of the jaw (BMDJ) as fatty-degenerative osteonecrosis (FDOJ). In comparison to samples from healthy jaw bone, the cytokine analysis of samples of BMDJ/FDOJ from 128 patients showed downregulated TNF-α and IL-6 expression and the singular overexpression of the chemokine RANTES/CCL5. Aim and Objectives: This paper raises the question of whether the osteoimmune defects due to incomplete wound healing in BMDJ/FDOJ in 128 patients are related to dysregulation of the Th1/Th2 ratio and regulatory T cell (T-reg) expression in a control group of 197 BMDJ/FDOJ patients, each presenting with BMDJ/FJOD and one of seven different immune disorders. Material and Methods: In the control group, serum concentrations of the cytokines IFN-y and IL-4 were determined after stimulated cytokine release and displayed as Th1/Th2 ratios. Results: Data show a shift in Th2 in more than 80% (n = 167) of the control cohort of 197 chronically ill patients with concomitant BMDJ/FDOJ. In these 167 subjects, the Th1/Th2 ratio was <6.1 demonstrating impaired immune regulation. Forty-seven subjects or 30% showed not only a shift in Th2 but also excessive T-reg overactivation with levels of >1.900 pg/mL, indicating strongly downregulated immune activity. Discussion: BMDJ/FDOJ is characterized by a lack of Th1 cytokines and an excessive expression of RANTES/CCL5 and IL-1ra and, thus, the inversion of an acute inflammatory cytokine pattern. In contrast, abdominal fat contains a very high proportion of regulatory Th1 cells and produces an inflammatory immune response through the high overexpression of TNF-α and IL-6. The lack of Th1 activation in BMDJ/FDOJ areas inhibits normal wound healing and supports the persistence of BMDJ/FDOJ. Conclusion: The Th1/Th2 ratio requires greater consideration, especially with respect to wound healing following dental surgical interventions, such as jaw surgery, implantation and augmentation, to avoid the emergence of the osteoimmune situation that is characteristic of BMDJ/FDOJ.

Is preexisting inflamed jaw marrow a "hidden" co-morbidity affecting outcomes of COVID-19 infections? - Clinical comparative study.

Introduction: Exceedingly high levels of the chemokine CCL5/RANTES have been found in fatty degenerated osteonecrotic alveolar bone cavities (FDOJ) and aseptic ischemic osteolysis of the jaw (AIOJ) from toothless regions. Because CCL5/RANTES seems to have a prominent role in creating the COVID-19 "cytokine storm", some researchers have used the monoclonal antibody Leronlimab to block the CCR5 on inflammatory cells.Objective: Is preexisting FDOJ/AIOJ jaw marrow pathology a "hidden" co-morbidity affecting some COVID-19 infections? To what extent does the chronic CCL5/RANTES expression from preexisting FDOJ/AIOJ areas contribute to the progression of the acute cytokine storm in COVID-19 patients?Methods: Authors report on reducing the COVID-19 "cytokine storm" by treating infected patients through targeting the chemokine receptor 5 (CCR5) with Leronlimab and interrupting the activation of CCR5 by high CCL5/RANTES signaling, thus dysregulating the inflammatory phase of the viremia. Surgical removal of FDOJ/AIOJ lesions with high CCL5/RANTES from patients with inflammatory diseases may be classified as a co-morbid disease.Results: Both multiplex analysis of 249 FDOJ/AIOJ bone tissue samples as well as serum levels of CCL5/RANTES displayed exceedingly high levels in both specimens.Discussion: By the results the authors hypothesize that chronic CCL5/RANTES induction from FDOJ/AIOJ areas may sensitize CCR5 throughout the immune system, thus, enabling it to amplify its response when confronted with the virus. As conventional intraoral radiography does little to assess the quality of the alveolar bone, ultrasonography units are available to help dentists locate the FDOJ/AIOJ lesions in an office setting.Conclusion: The authors propose a new approach to containment of the COVID-19 cytokine storm by a prophylactic focus for future viral-related pandemics, which may be early surgical clean-up of CCL5/RANTES expression sources in the FDOJ/AIOJ areas, thus diminishing a possible pre-sensitization of CCR5. A more complete dental examination includes trans-alveolar ultrasono-graphy (TAU) for hidden FDOJ/AIOJ lesions.

Comparison of Cytokine RANTES/CCL5 Inflammation in Apical Periodontitis and in Jawbone Cavitations - Retrospective Clinical Study.

Background: Apical periodontitis (AP) is one of the most common endodontic diseases associated with osteo destructive cytokine production. The literature also reports cytokine studies in fatty degenerative osteonecrotic bone marrow defects (BMDJ/FDOJ) independent of AP. Objective: We compare the RANTES/CCL5 (R/C) chemokine production between AP and BMDJ/FDOJ. For both pathologies, the R/C expression was also compared to radiographic diagnosis in 2D-OPG, 3D-CBCT/DVT. Material and Methods: Postoperative samples were collected and divided in three different groups: HB (healthy jawbone) (n=19), APs (n=19), and BMDJ/FDOJ (n=7). The R/C expression was evaluated using multiplex analysis. In addition, two clinical cases from AP and BMDJ/FDOJ groups were randomly selected and radiographic diagnosis in 2D-OPG and 3D-CBCT/DVT was compared to TAU measurements and R/C expression in AP and in BMDJ/FDOJ. Results: BMDJ/FDOJ showed the highest R/C expression (2498.71 pg/mL), followed by AP (841.85 pg/mL) and HB (149.85 pg/mL) (AP vs BMDJ/FDOJ = p=0.01; AP vs HB = p=<0.01; BMDJ/FDOJ vs HB = p=<0.01). In both clinical cases, the radiographic findings depict the AP areas in OPG and CBCT/DVT, in contrast to the BMDJ/FDOJ areas. Conversely, the systemic immunological R/C expressions are threefold and fivefold excessive in both cases. Discussion: AP is recognized as a pathology requiring treatment, while the pathogenesis of BMDJ/FDOJ is controversially discussed in the literature, despite stronger potential systemic immunological effects (breast cancer (case 1) and multiple sclerosis (case 2)). The inadequate radiographic representation of reduced bone density in BMDJ/FDOJ areas could be a reason for this contradiction. Conclusion: The data presented provide the first quantitative analysis of R/C expression in AP and BMDJ/FDOJ. BMDJ/FDOJ showed high R/C expression than AP, besides the diagnostic through radiographs being extremely poor. To cover this imprecision, a radiation-free TAU device is available.

Osseointegration and osteoimmunology in implantology: assessment of the immune sustainability of dental implants using advanced sonographic diagnostics: research and case reports.

OBJECTIVE: Bone marrow defects of the jaw (BMDJ) surrounding dental implants, in combination with impaired bone-to-implant contact (BIC), are difficult to detect in X-rays. This study evaluated BMDJ surrounding titanium (Ti-Impl) and ceramic (Cer-Impl) dental implants and incomplete BIC using a new trans-alveolar ultrasonography device (TAU) with numerical scaling for BIC. METHODS: The titanium stimulation test (Ti-Stim) was used to detect immune overactivation in response to titanium. Bone density surrounding implants was measured using TAU. We also validated osteoimmune dysregulation. RESULTS: TAU values showed reduced BIC and decreased osseointegration for Ti-Impl. Moreover, TAU values in the Cer-Impl group were more than twice those in the Ti-Impl cohort. The multiplex analysis of C-C motif chemokine 5 (CCL5, also known as RANTES) expression revealed a 20-fold increase in BMDJ surrounding Ti-Impl. Higher levels of CCL5 inflammation were present in the positive Ti-Stim group. CONCLUSIONS: Our data indicate that Cer-Impl have an osteoimmune advantage over Ti-Impl. The key determinant for osteoimmune sustainability appears to be the absence of inflammation at the implant site. We therefore recommend the use of TAU to assess the implant site prior to implantation.

Linking Dentistry and Chronic Inflammatory Autoimmune Diseases - Can Oral and Jawbone Stressors Affect Systemic Symptoms of Atopic Dermatitis? A Case Report.

Background: This case report demonstrates the value of ultrasound measurements, and immunological and toxicological diagnostics in addition to current x-ray imaging procedures to diagnose hidden oral and maxillofacial infections. Using a clear scheme shows the procedure of the authors' steps. The positive impact on the patient's dermatological clinical picture is shown. Functional regeneration using metal-free ceramic implants and autologous bone augmentation is demonstrated. After a healing period, a postoperative control took place. Question: Are chronic inflammatory and chronic toxic stressors from the oral region affecting the patient's state of health and dermatological symptoms? Patients and Methods: A 52 year old female suffering from neurodermatitis, who had been therapy-resistant for several years, was rehabilitated by oral surgery and prosthetics. Radiological examinations with orthopantomogram (OPG) and three-dimensional imaging (DVT/CBCT) were inconclusive for possible jawbone inflammatory sites. Immunological, toxicological diagnostics and trans-alveolar bone densitometry with ultrasound (TAU), were able to show immunological and toxicological stressors and areas of reduced bone density. Bone densitometry with ultrasound raised the suspicion of silent inflammations in the jawbone with potentially increased cytokine levels. Results: For the patient incompatible materials, teeth with increased toxin exposure and surrounding softened, fatty, ischaemic bone was removed. Histologies and cytokine profiles were obtained. The resulting defects were functionally regenerated using ceramic implants and autologous augmentation. The cytokine profiles showed significantly elevated RANTES/CCL5, confirming the need for surgical intervention. The patient's atopic dermatitis improved significantly in this case. Summary: Individualized immunological and toxicological diagnostics and trans-alveolar bone density bone densitometry with ultrasound (TAU) identified immunological and toxicological stressors as well as reduced bone density with increased cytokine levels. A therapy-resistant neurodermatitis improved significantly after treatment. Conclusion: This case report illustrates the need for patient-specific and individualized examinations that link dentistry more closely with other medical conditions in order to clarify possible interactions.

RANTES/CCL5 Signaling from Jawbone Cavitations to Epistemology of Multiple Sclerosis - Research and Case Studies.

BACKGROUND: The role played by signaling pathways in the cell-cell communication associated with multiple sclerosis (MS) progression has become a critical area in research. Chemokine RANTES (regulated upon activation, normal T-cell expressed and secreted), also named chemokine C-C motif ligand 5 (CCL5; R/C), is a protein that has been investigated in neuroinflammatory research due to its link to MS development. OBJECTIVE: Research on bone marrow defects in the jawbone (BMDJ), which morphologically presents as fatty-degenerative osteonecrosis of the jawbone (FDOJ), presents overexpression of R/C signaling in affected areas. Here, we try to elucidate the potential link between jawbone-derived R/C and MS. METHODS: Seventeen BMDJ/FDOJ samples extracted from 17 MS patients, as well as samples from 19 healthy controls, were analyzed for R/C expression using bead-based Luminex® analysis. The serum R/C levels from 10 MS patients were examined. Further, bone density, histology, and R/C expression were analyzed in two clinical case studies. RESULTS: High R/C overexpression was found in all BMDJ/FDOJ samples obtained from the MS group. Serum R/C levels were also upregulated in the MS group. R/C serum levels in the MS cohort were higher than in the healthy controls. In contrast, the histology of BMDJ/FDOJ samples showed no inflammatory cells. DISCUSSION: R/C-induced "silent inflammation" in MS is widely discussed in the scientific literature, along with R/C triggering of inflammation in the central nervous system, which might be key in the development of MS. CONCLUSION: The authors suspect that BMDJ/FDOJ may serve as a trigger of MS progression via R/C overexpression. As such, the dental and medical communities should be made aware of BMDJ/FDOJ in cases of MS.

Undetected Jawbone Marrow Defects as Inflammatory and Degenerative Signaling Pathways: Chemokine RANTES/CCL5 as a Possible Link Between the Jawbone and Systemic Interactions?

BACKGROUND: Cytokines, especially chemokines, are of increasing interest in immunology. This study characterizes the little-known phenomenon of "bone marrow defects of the jawbone" (BMDJ) with known overexpression of the chemokine RANTES/CCL5 (R/C). PURPOSE: Our investigation clarifies why BMDJ and the intensity of local R/C overexpression are challenging to detect, as examined in patients with seven different systemic immunological diseases. Specifically, we investigate whether R/C overexpression is specific to certain disease groups or if it represents a type of signal disruption found in all systemic immunological diseases. PATIENTS AND METHODS: In a total of 301 patients, BMDJ was surgically repaired during clinical practice to reduce "silent inflammation" associated with the presence of jaw-related pathologies. In each case of BMDJ, bone density was measured preoperatively (in Hounsfield units [HU]), while R/C expression was measured postoperatively. Each of the 301 patients suffered from allergies, atypical facial and trigeminal pain, or were diagnosed with neurodegenerative diseases, tumors, rheumatism, chronic fatigue syndrome, or parasympathetic disorders. RESULTS: In all BMDJ cases, strongly negative HU values indicated decreased bone density or osteolysis. Consistently, all cases of BMDJ showed elevated R/C expression. These findings were consistently observed in every disease group. DISCUSSION: BMDJ was confirmed in all patients, as verified by the HU measurements and laboratory results related to R/C expression. The hypothesis that a specific subset of the seven disease groups could be distinguished either based on the increased presence of BMDJ and by the overexpression of R/C could not be confirmed. A brief literature review confirms the importance of R/C in the etiology of each of the seven disease groups. CONCLUSION: In this research, the crucial role played by BMDJ and the chemokine R/C in inflammatory and immune diseases is discussed for seven groups of patients. Each specific immune disease can be influenced or propelled by BMDJ-derived R/C inflammatory signaling pathways.

Chronic Fatigue Syndrome and Bone Marrow Defects of the Jaw - A Case Report on Additional Dental X-Ray Diagnostics with Ultrasound.

PURPOSE: This paper aims to demonstrate the additional benefit of ultrasound in the diagnosis of chronic osteolysis and osteonecrosis (bone marrow defects) of the jaw shown in a clinical case report. PATIENTS AND METHODS: A case of chronic fatigue syndrome (CFS) in a young man presenting the typical, ambiguous symptoms, which were accompanied by headaches and tinnitus. X-ray techniques, namely panoramic radiographs (OPG) and cone beam computed tomography (DVT/CBCT), failed to produce any remarkable findings of bone marrow defects (BMDJ) in the jawbone. However, the measurement of bone density using trans-alveolar ultrasound (TAU) indicated a possible bone marrow defect in the lower left jawbone. RESULTS: Surgery was undertaken at the conspicuous area. Additional to softened, ischemic, fatty tissue, a black area was revealed, which was surprisingly subsequently identified as aspergillosis by histopathological analysis. In addition, the excessive local RANTES/CCL5 expression found in the affected area confirmed the necessity for surgical debridement and additional findings of TAU. CONCLUSION: In contrast to radiography, complementary TAU imaging of the BMDJ revealed chronic inflammatory signaling RANTES/CCL5 pathways and fungal colonization. This case report supports the need for additional diagnostic techniques beyond radiographic modalities, which can help to elucidate the diagnostic composition and knowledge of the bone manifestations of systemic diseases.

Effects of Estrogen Receptor and Wnt Signaling Activation on Mechanically Induced Bone Formation in a Mouse Model of Postmenopausal Bone Loss.

In the adult skeleton, bone remodeling is required to replace damaged bone and functionally adapt bone mass and structure according to the mechanical requirements. It is regulated by multiple endocrine and paracrine factors, including hormones and growth factors, which interact in a coordinated manner. Because the response of bone to mechanical signals is dependent on functional estrogen receptor (ER) and Wnt/ß-catenin signaling and is impaired in postmenopausal osteoporosis by estrogen deficiency, it is of paramount importance to elucidate the underlying mechanisms as a basis for the development of new strategies in the treatment of osteoporosis. The present study aimed to investigate the effectiveness of the activation of the ligand-dependent ER and the Wnt/ß-catenin signal transduction pathways on mechanically induced bone formation using ovariectomized mice as a model of postmenopausal bone loss. We demonstrated that both pathways interact in the regulation of bone mass adaption in response to mechanical loading and that the activation of Wnt/ß-catenin signaling considerably increased mechanically induced bone formation, whereas the effects of estrogen treatment strictly depended on the estrogen status in the mice.

Gender differences in knee morphology and the prospects for implant design in total knee replacement.

BACKGROUND: Morphological differences between female and male knees have been reported in the literature, which led to the development of so-called gender-specific implants. However, detailed morphological descriptions covering the entire joint are rare and little is known regarding whether gender differences are real sexual dimorphisms or can be explained by overall differences in size. METHODS: We comprehensively analysed knee morphology using 33 features of the femur and 21 features of the tibia to quantify knee shape. The landmark recognition and feature extraction based on three-dimensional surface data were fully automatically applied to 412 pathological (248 female and 164 male) knees undergoing total knee arthroplasty. Subsequently, an exploratory statistical analysis was performed and linear correlation analysis was used to investigate normalization factors and gender-specific differences. RESULTS: Statistically significant differences between genders were observed. These were pronounced for distance measurements and negligible for angular (relative) measurements. Female knees were significantly narrower at the same depth compared to male knees. The correlation analysis showed that linear correlations were higher for distance measurements defined in the same direction. After normalizing the distance features according to overall dimensions in the direction of their definition, gender-specific differences disappeared or were smaller than the related confidence intervals. CONCLUSIONS: Implants should not be linearly scaled according to one dimension. Instead, features in medial/lateral and anterior/posterior directions should be normalized separately (non-isotropic scaling). However, large inter-individual variations of the features remain after normalization, suggesting that patient-specific design solutions are required for an improved implant design, regardless of gender.

Patient-specific musculoskeletal modeling of the hip joint for preoperative planning of total hip arthroplasty: A validation study based on in vivo measurements.

Validation of musculoskeletal models for application in preoperative planning is still a challenging task. Ideally, the simulation results of a patient-specific musculoskeletal model are compared to corresponding in vivo measurements. Currently, the only possibility to measure in vivo joint forces is to implant an instrumented prosthesis in patients undergoing a total joint replacement. In this study, a musculoskeletal model of the AnyBody Modeling System was adapted patient-specifically and validated against the in vivo hip joint force measurements of ten subjects performing one-leg stance and level walking. The impact of four model parameters was evaluated; hip joint width, muscle strength, muscle recruitment, and type of muscle model. The smallest difference between simulated and in vivo hip joint force was achieved by using the hip joint width measured in computed tomography images, a muscle strength of 90 N/cm2, a third order polynomial muscle recruitment, and a simple muscle model. This parameter combination reached mean deviations between simulation and in vivo measurement during the peak force phase of 12% ± 14% in magnitude and 11° ± 5° in orientation for one-leg stance and 8% ± 6% in magnitude and 10° ± 5° in orientation for level walking.

Development of a biomechanical model of the wrist joint for patient-specific model guided surgical therapy planning: Part 1.

An enhanced musculoskeletal biomechanical model of the wrist joint is presented in this article. The developed computational model features the two forearm bones radius and ulna, the eight wrist bones, the five metacarpal bones, and a soft tissue apparatus. Validation of the model was based on information taken from the literature as well as own experimental passive in vitro motion analysis of eight cadaver specimens. The computational model is based on the multi-body simulation software AnyBody. A comprehensive ligamentous apparatus was implemented allowing the investigation of ligament function. The model can easily patient specific personalized on the basis of image information. The model enables simulation of individual wrist motion and predicts trends correctly in the case of changing kinematics. Therefore, patient-specific multi-body simulation models are potentially valuable tools for surgeons in pre- and intraoperative planning of implant placement and orientation.

A biomechanical model of the wrist joint for patient-specific model guided surgical therapy: Part 2.

An enhanced musculoskeletal biomechanical model of the wrist joint is presented in this article. The computational model is based on the multi-body simulation software AnyBody. Multi body dynamic musculoskeletal models capable of predicting muscle forces and joint contact pressures simultaneously would be valuable for studying clinical issues related to wrist joint degeneration and restoration. In this study, the simulation model of the wrist joint was used for investigating deeper the biomechanical function of the wrist joint. In representative physiological scenarios, the joint behavior and muscle forces were computed. Furthermore, the load transmission of the proximal wrist joint was investigated. The model was able to calculate the parameters of interest that are not easily obtainable experimentally, such as muscle forces and proximal wrist joint forces. In the case of muscle force investigation, the computational model was able to accurately predict the computational outcome for flexion and extension motion. In the case of force distribution of the proximal wrist joint, the model was able to predict accurately the computational outcome for an axial load of 140 N. The presented model and approach of using a multi-body simulation model are anticipated to have value as a predictive clinical tool including effect of injuries or anatomical variations and initial outcome of surgical procedures for patient-specific planning and custom implant design. Therefore, patient-specific multi-body simulation models are potentially valuable tools for surgeons in pre- and intraoperative planning of implant placement and orientation.

Action-based multifield video visualization.

One challenge in video processing is to detect actions and events, known or unknown, in video streams dynamically. This paper proposes a visualization solution, where a video stream is depicted as a series of snapshots at a relatively sparse interval, and detected actions are highlighted with continuous abstract illustrations. The combined imagery and illustrative visualization conveys multi-field information in a manner similar to electrocardiograms (ECG) and seismographs. We thus name this type of video visualization as VideoPerpetuoGram (VPG). In this paper, we describe a system that handles the aw and processed information of the video stream in a multi-field visualization pipeline. As examples, we consider the needs for highlighting several types of processed information, including detected actions in video streams, and estimated relationship between recognized objects. We examine the effective means for depicting multi-field information in VPG, and support our choice of visual mappings through a survey. Our GPU implementation facilitates the VPG-specific viewing specification through a sheared object space, as well as volume bricking and combinational rendering of volume data and glyphs.