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Johann Lechner,1 Volker von Baehr,2 Florian Notter,1 Fabian Schick1 1Clinic for Integrative Dentistry, Munich, Germany; 2Department of Immunology and Allergology, Institute for Medical Diagnostics, Berlin, GermanyCorrespondence: Johann Lechner, Gruenwalder Str. 10A, Munich, 81547, Germany, Tel +49 89 697 0129, Fax +49 89 692 5830, Email drlechner@aol.comIntroduction: 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. Keywords: osteoimmunology, T-cells, Th1/Th2 shift, jawbone, osteoclastogenesis, RANTES/CCL5

Joana Vasconcelos e Cruz,1,2 Florian Notter,3 Fabian Schick,3 Johann Lechner4 1Dental Materials, Egas Moniz School of Health & Science, Caparica, Portugal; 2Dental Materials, Centro de Investigação Interdisciplinar Egas Moniz (CiiEM), Caparica, Portugal; 3Dental Surgeon, Clinic for Integrative Dentistry, Munich, Germany; 4Head, Clinic for Integrative Dentistry, Munich, GermanyCorrespondence: Johann Lechner, Gruenwalder Str. 10A, Munich, 81547, Germany, Tel +49 89 697 0129, Fax +49 89 692 5830, Email drlechner@aol.comBackground: 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. Keywords: bone marrow, RANTES/CCL5, apical periodontitis, osteonecrosis, dental radiography, ultrasonography

Joé Diederich,1 Hendrik Schwagten,2 Georges Biltgen,3 Johann Lechner,4 Kurt E Müller5 1Center for General, Clinical Environmental and Functional Medicine, Colmar-Berg, Luxembourg; 2Private Practice, Center for Biological Dentistry, Luxembourg-City, Luxembourg; 3Private Practice, Center for Biological Dentistry, Diekirch, Luxembourg; 4Private Practice, Centre for Integrative Dentistry, Munich, Germany; 5Dermatology, Clinical Environmental Medicine, Functional Medicine, Preventive Medicine, Dresden International University, Kempten, GermanyCorrespondence: Joé Diederich, 4b, Avenue G. Smith, Colmar-Berg, L-7740, Luxembourg, Tel +352 268866-1, Fax +352 268866-66, Email diederichjoe@gmail.comPurpose: The presence of bone marrow defects of the jawbone (BMDJ) is associated with increased levels of inflammatory cytokines such as RANTES/CCL5. The purpose of this study was to analyze if BMDJ therapy under real-world conditions reduces RANTES/CCL5 serum levels in BMDJ patients.Patients and Methods: During this retrospective study, 113 BMDJ patients received either no treatment (n = 57), BMDJ surgery (n = 25), tooth extraction (n = 20), or root canal treatment (n = 11). Serum concentrations of RANTES/CCL5, C-reactive protein (CRP), and Tumor Necrosis Factor-α (TNF-α) were assessed before and after treatment (interventional group) and at the beginning and end of the study period (control group). Statistical analyses of the results were performed by the two-sample t-test and Bonferroni post hoc test with ANOVA for multiple comparisons.Results: BMDJ were detected in all patients with 4.42 ± 2.75 BMDJ findings per patient. RANTES/CCL5 levels were significantly reduced by any treatment when compared to no treatment (p < 0.001; effect size d = 0.90). This effect was most pronounced in the BMDJ surgery group (p < 0.001; effect size d = 1.30). In contrast, RANTES/CCL5 serum concentrations further increased in untreated patients. Mean duration between pre- and post-treatment RANTES/CCL5 measurements was 22.86 ± 19.36 weeks, with no correlation with RANTES/CCL5 levels in any interventional group or in the total sample (p = 0.104).Conclusion: BMDJ surgery, tooth extraction, and root canal treatment significantly reduce RANTES/CCL5 serum concentrations in BMDJ patients, with surgery being most beneficial. Further research is required to establish regular RANTES/CCL5 assessments as part of an improved diagnosis, monitoring, and evaluation of therapy success in BMDJ patients.Keywords: bone marrow defect of the jawbone, osteolysis, osteonecrosis of the jaw, RANTES, dental

Joé Diederich,1 Hendrik Schwagten,2 Georges Biltgen,3 Johann Lechner,4 Kurt E Müller5 1Center for General, Clinical Environmental and Functional Medicine, Colmar-Berg, Luxembourg; 2Private Practice, Center for Biological Dentistry, Luxembourg-City, Luxembourg; 3Private Practice, Center for Biological Dentistry, Diekirch, Luxembourg; 4Private Practice, Centre for Integrative Dentistry, Munich, Germany; 5Dermatology, Clinical Environmental Medicine, Functional Medicine, Preventive Medicine, Dresden International University, Kempten, GermanyCorrespondence: Joé Diederich, 4b, Avenue G. Smith, Colmar-Berg, L-7740, Luxembourg, Tel +352 268866-1, Fax +352 268866-66, Email diederichjoe@gmail.com

Fabian Schick, Johann Lechner, Florian Notter Clinic for Integrative Dentistry, Munich, GermanyCorrespondence: Fabian Schick, Clinic for Integrative Dentistry, Gruenwalder Str. 10A, Munich, 81547, Germany, Tel +49 89 697 00 55, Email drfabischick@outlook.deBackground: 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.Graphical Abstract: Keywords: atopic dermatitis, CCL5/RANTES, osteoimmunology, ceramic implants, autologous augmentation, silent inflammation, FDOJ, trans alveolar ultrasonography

Johann Lechner, Fabian Schick Clinic for Integrative Dentistry, Munich, GermanyCorrespondence: Johann LechnerClinic for Integrative Dentistry, Gruenwalder Street 10A, Munich, 81547, GermanyTel +49 89 697 0129Fax +49 89 692 5830Email drlechner@aol.comPurpose: 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.Keywords: chronic fatigue syndrome, radiographic diagnostics, bone marrow defect, osteonecrosis, RANTES/CCL5, trans-alveolar ultrasonography

Johann Lechner,1 Tilman Schulz,2 Beatrice Lejeune,3 Volker von Baehr4 1Clinic Integrative Dentistry Munich, Munich, Germany; 2Klinikum Bayreuth, Bayreuth, Germany; 3Labo’Life France, Nantes, France; 4Institute for Medical Diagnostics, Berlin, GermanyCorrespondence: Johann LechnerClinic Integrative Dentistry Munich, Praxisklinik Gruenwalder Str. 10A, Munich, 81547, GermanyTel +49 89 6970129Fax +49 89 6925830Email drlechner@aol.comBackground: The role of signaling pathways as part of the cell-cell communication within cancer progression becomes a crucial area. Chemokine RANTES (regulated upon activation, normal T-cell expressed and secreted), also known as the chemokine C-C motif ligand 5 (CCL5) (R/C), is a protein on which cancer research focus due to its link with aggressive cancer development.Objective: Research on fatty-degenerative osteonecrosis in jawbone (FDOJ) shows striking overexpression of R/C in these areas. Here we try to elucidate a potential link between jawbone-derived R/C and breast cancer (BC) and compare these findings by immunohistochemical staining.Methods: Thirty-nine FDOJ samples extracted from 39 BC patients and samples from 19 healthy control were analyzed for R/C expression using bead-based Luminex® analysis. R/C levels from 5 BC patients were measured in serum before and after FDOJ surgery. Bone density, histology, R/C expression, and immunohistochemistry were analysed in 4 clinical case studies. The R/C staining of two FDOJ BC patients is compared with the immunohistochemical staining of BC cell preparations.Results: A high overexpression of R/C was seen in all FDOJ samples. R/C levels in serum were statistically downregulated after FDOJ surgery (p=0.0241).Discussion: R/C induced “silent inflammation” in BC is widely discussed in scientific papers along with R/C triggering of different signaling pathways, which might be a key point in the development of BC.Conclusion: Hypothesis that FDOJ may serve as a trigger of BC progression through R/C overexpression was set by the authors, who thus inspire clinicians to make aware of FDOJ throughout the dental and medical community in BC cases.Keywords: chemokine RANTES/CCL5, osteonecrosis of the jawbone, breast cancer, bead-based Luminex® analysis, hyperactivated signaling pathways

Johann Lechner,1 Marlene Schmidt,2 Volker von Baehr,3 Fabian Schick4 1Head of the Clinic for Integrative Dentistry, Munich, Germany; 2Data Scientist at STEYR Motorenwerke, Steyr, Austria; 3Head of the Department of Immunology and Allergology, Institute for Medical Diagnostics, Berlin, Germany; 4Dental Surgeon, Clinic for Integrative Dentistry, Munich, GermanyCorrespondence: Johann Lechner Tel +49-89-6970129Fax +49-89-6925830Email drlechner@aol.comBackground: 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.Keywords: bone marrow defects, jawbone, RANTES/CCL5 inflammatory signaling pathways, silent inflammation, systemic immune diseases

Johann Lechner,1 Volker von Baehr,2 Bernd Zimmermann3 1Clinic for Integrative Dentistry, Munich, Germany; 2Department of Immunology and Allergology, Institute for Medical Diagnostics, Berlin, Germany; 3QINNO, Wessling, GermanyCorrespondence: Johann LechnerClinic for Integrative Dentistry, Gruenwalder Str. 10A, Munich 81547, GermanyTel +49-89-6970129Fax +49-89-6925830Email drlechner@aol.comIntroduction: Bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) is a complication of intravenous (IV) BP therapy. BP therapy locally affects the dentoalveolar area, while systemic effects are associated with parenteral/IV BP use. Despite numerous publications, the pathogenesis of BRONJ is not fully understood, as only some patients receiving IV BPs develop BRONJ.Purpose: Can impaired bone remodeling (found in aseptic-ischemic osteonecrosis of the jaw [AIOJ], bone marrow defects [BMD], or fatty-degenerative osteonecrosis of the jaw [FDOJ]) represent a risk factor for BRONJ formation?Patients and Methods: A literature search clarified the relationship between AIOJ, BMD, FDOJ, and BRONJ, in which common characteristics related to signal cascades, pathohistology, and diagnostics are explored and compared. A case description examining non-exposed BRONJ is presented.Discussion: Non-exposed BRONJ variants may represent one stage in undetected BMD development, and progression to BRONJ results from BPs.Conclusion: Unresolved wound healing at extraction sites, where wisdom teeth have been removed for example, may contribute to the pathogenesis of BRONJ. With IV BP administration, persisting AIOJ/BMD/FDOJ areas may be behind BRONJ development. Therapeutic recommendations include IV BP administration following AIOJ/BMD/FDOJ diagnosis and surgical removal of ischemic areas. BPs should not be regarded as the only cause of osteonecrosis.Keywords: bisphosphonates, bone marrow defects, osteonecrosis of the jaw, RANTES/CCL5, ultrasound sonography

Johann Lechner,1 Wolfgang Mayer2 1Immunology, Clinic Integrative Dentistry, Munich, Germany; 2Laboratory, Lab4more, Munich, GermanyCorrespondence: Johann LechnerImmunology, Clinic Integrative Dentistry, Munich, GermanyTel +4989-697 00 55Fax +49 89-692 58 30Email drlechner@aol.comBackground: Mitochondriopathy has recently been linked to several immune system diseases. Historically, there have been many conversations regarding the possible toxic effects of root-filled teeth (RFT), although discussions about the possible decreases in adenosine triphosphate (ATP) activity on the mitochondrial membrane, as caused by dental toxins, are rare. In fact, only a few methods currently exist to assess toxin release in teeth.Objective: An experimental clinical study design is used to investigate the extent to which RFT release toxins in a solution created specifically following extraction (Tox-sol). Our laboratory is investigating the extent to which these Tox-sols reduce ATP activity in patients.Patients and Methods: RFTs were identified and extracted to assess their local toxin release using a semi-quantitative volatile sulfur compound indicator (VSCI). These RFTs are placed in an aqueous solution at room temperature for 24 hours and subsequently removed. The resulting solution (Tox-sol) is diluted to 1:100; peripheral blood mononuclear cells (PBMCs) obtained from patients were added to the solution in the laboratory. The remaining ATP activity was measured on the mitochondrial membrane and was compared with the baseline ATP activity of each patient.Results: The total population (n=30) showed a ∼ 10% reduction in ATP activity following 24 hours of exposure to the Tox-sol. Three groups emerged with greatly reduced (n=16), neutral (n=10), and increased (n=4) ATP activity. In four different disease groups (rheumatism, neurological disorders, allergies, and tumors), a non-disease specific inhibition of ATP activity was observed.Discussion: The study design was limited, as patients were exposed to the Tox-sol and PBMC fraction for only 24 hours. The actual exposure time in a patient’s mouth can continue for years and the actual levels can increase over time. Disease-specific effects of Tox-sol were not found.Conclusion: Within the short exposure time of 24 hours, and at a dilution of 1:100, the Tox-sol caused a median decrease in ATP activity of ∼ 15% in 50% of test subjects. A practical VSCI reliably showed the effects of toxic sulfur compounds on the RFT. The toxic degradation products of biogenic amines from RFT can thus serve as possible contributing factors in the development of mitochondriopathies.Keywords: mitochondrial membrane, endodontically treated teeth, hydrogen sulfide, thioether, ATP activity

Johann Lechner,1 Bernd Zimmermann,2 Marlene Schmidt,3 Volker von Baehr4 1Department of Clinical Research, Clinic Integrative Dentistry, Munich, Germany; 2Medical Devices, QINNO, Wessling, Germany; 3Department of Statistics, STEYR Motorenwerke, Steyr, Austria; 4Department of Immunology and Allergology, Institute for Medical Diagnostics Berlin, GermanyCorrespondence: Johann Lechner Tel +49-89-6970129Fax +49-89-6925830Email drlechner@aol.comIntroduction: The presently used impulse echo ultrasound examination is not suitable to provide relevant and reliable information about the jawbone, because ultrasound (US) almost completely reflects from the hard cortical jawbone. At the same time, “focal osteoporotic bone marrow defects” (BoneMarrowDefects = BMD) in jawbone are the subject of scientific presentations and discussions.Purpose: Can a newly developed trans-alveolar ultrasonic sonography (TAU-n) device locate and ascertain BMD?Patients and Methods: TAU-n consists of a two-part handpiece with an extraoral ultrasound transmitter and an intraoral ultrasound receiver. The TAU-n computer display shows the different jawbone densities with corresponding colour coding. The changes in jawbone density are also displayed numerically. The validation of TAU-n readings: A usual orthopantomogram (2D-OPG) on its own is not suitable for unequivocally determining jawbone density and has to be excluded from this validation. For validation, a 3D-digital volume tomogram/cone beam computer tomogram (DVT/CBCT) with the capacity to measure Hounsfield units (HU) and a TAU-n are used to determine the presence of preoperative BMD in 82 patient cases. Postoperatively, histology samples and multiplex analysis of RANTES/CCL5 (R/C) expression derived from surgically cleaned BMD areas are evaluated.Results: In all 82 bone samples, DVT-HU, TAU-n values and R/C expressions show the presence of BMD with chronic inflammatory character. However, five histology samples showed no evidence of BMD. All four evaluation criteria (DVT-HU, TAU-n, R/C, histology) confirm the presence of BMD in each of the 82 samples.Conclusion: The TAU-n method almost completely matches the diagnostic reliability of the other methods. The newly developed TAU-n scanner is a reliable and radiation-free option to detect BMD.Keywords: trans-alveolar ultrasonography, cone beam computed tomography, RANTES/CCL5, Hounsfield units, cavitational osteonecrosis of jawbone

Johann Lechner,1 Tatjana Rudi,2 Volker von Baehr3 1Clinic for Integrative Dentistry, Munich 81547, Germany; 2Institute for Epidemiological Studies, Berlin 10709, Germany; 3Department of Immunology and Allergology, Institute for Medical Diagnostics in MVZ GbR, Berlin 12247, Germany Background: The immune and bone systems are closely linked via cytokine cross-talk. This interdisciplinary field of research is referred to as osteoimmunology and pertains to inflammatory and osteoarticular diseases that feature the primary expression of tumor necrosis factor-alpha (TNF-α) and IL-6.Objective: Are there bone resorptive processes wherein chronic inflammatory conditions are not linked to TNF-α and IL-6 expression, but rather to the expression of other cytokines?Materials and methods: A comprehensive literature search was performed in PubMed Central.Discussion: Although all diseases with cytokines involved in bone resorption (TNF-α and IL-6) are at the forefront of destructive inflammatory processes, there is one exception in the literature: fatty oxide osteoporosis/osteolysis in the jawbone (FDOJ), which is associated with significant bone softening. However, it should be noted that TNF-α and IL-6 fall below the levels found in a healthy jawbone in this condition. Another conspicuous finding is that there is a nearly 35-fold overexpression of the chemokine RANTES/CCL5 (R/C) in all FDOJ cases studied thus far in the literature. Conclusion: FDOJ appears to represent a unique cytokine and inflammatory pattern from osteolysis in the body. R/C can be defined as the dominant carrier of a “maxillomandibular osteoimmunology”. Keywords: bone resorption, chemokine RANTES, CCL5, tumor necrosis factor-alpha, maxillomandibular osteoimmunology, maxillomandibular

Johann Lechner,1 Jürgen Aschoff,2 Tatjana Rudi3 1Clinic for Integrative Dentistry, Munich, Germany; 2Center for Integrative Healing, Wuppertal, Germany; 3Statistics at Institute for Epidemiological Studies, Berlin, Germany Background: Recent research on vitamin D indicates that our current understanding of the factors leading to chronic inflammation should be revised. One of the key mechanisms by which microbial immunosuppression occurs is the suppression of one of the most common endogenous cell nucleus receptors: the vitamin D receptor (VDR). Autoimmune diseases may be correlated with VDR deactivation (VDR-deac) which occurs when the receptor is no longer able to transcribe antimicrobial agents. Excess 1,25-dihydroxyvitamin D (1,25D) is not converted to 25-hydroxyvitamin D (25D); thus, high 1,25D levels may be accompanied by low 25D values. Patients and methods: Since 1,25D promotes osteoclast activity and may thereby cause osteoporosis, fatty-degenerative osteolysis of the jaw (FDOJ), as described by our team, may also be associated with VDR-deac. In 43 patients, vitamin D conversion, immune system function and the quality of bone resorption and formation in the jawbone were related factors that may enhance chronic inflammatory processes. Here, we examine the relationship between immunology and bone metabolism among 43 FDOJ patients and those with immune system diseases (ISDs). Results: We provide a link between FDOJ, RANTES/CCL5 overexpression and VDR-deac. Conclusion: The clinical data demonstrate the interaction between VDR-deac and proinflammatory RANTES/CCL5 overexpression in FDOJ patients. Keywords: vitamin D receptor; chemokine RANTES/CCL5, osteopathy of the jawbone, immune system diseases, osteoimmunology

Johann Lechner,1 Sabine Schuett,2 Volker von Baehr2 1Clinic for Integrative Dentistry, Munich, 2Department of Immunology and Allergology, Institute for Medical Diagnostics in MVZ GbR, Berlin, Germany Abstract: Of the definitions listed in the International Statistical Classification of Diseases and Related Health Problems, tenth revision (ICD-10), two disease descriptions can be found together: "idiopathic aseptic bone necrosis" and "avascular bone necrosis." The relevant literature on both the conditions abbreviates both as "aseptic ischemic osteonecrosis in the jawbone" (AIOJ). To shed light on the clinical details of this condition, osteolytic jawbone samples of 24 patients with different systemic immunological diseases were examined using four steps: presurgical dental X-ray, postsurgical histology, polymerase chain reaction DNA analysis (PCR DNA) of bacteria, and RANTES/CCL5 (R/C) expression. These four steps showed that neither X-ray nor histology delivered unambiguous results with respect to inflammatory processes; furthermore, the PCR results did not show evidence of any microbial load within the jaw samples. However, there is a striking, coherent overexpression of chemokine R/C in the AIOJ samples. This study proved the aseptic existence of "silent inflammation" within the jawbone. The ICD-10 (AIOJ) definition, which is hard to interpret, can now be substantiated with clinical evidence, while the cytokine expressions described in this report can explain the systemic immunological effects observed within the group of examined patients. Keywords: jawbone, osteonecrosis, RANTES, CCL5, silent inflammation, aseptic inflammation, PCR, ICD-10

Johann Lechner,1 Volker von Baehr2 1Clinic for Integrative Dentistry, Munich, Germany; 2Compartment of Immunology and Allergology, Institute for Medical Diagnostics, Berlin, Germany Abstract: Persistent microorganisms in endodontically treated teeth produce volatile sulfur compounds (VSC) such as methyl mercaptan, hydrogen sulfide, and thioether. In this retrospective study, we evaluated the ex vivo immune response of peripheral blood mononuclear cells to sulfur compounds in 354 patients with systemic diseases. These systemic findings are correlated with semiquantitative values of a VSC indicator applied directly on endodontically treated teeth. Data elucidate the role of VSC in patients with immunologic diseases and the role of a semiquantitative chairside test, like the VSC indicator presented here, in correlation to IFNg and IL-10 sensitization in peripheral blood mononuclear cells. The association between ex vivo-stimulated cytokines and endodontically derived sulfur components is supported by the fact that the number of interferon gamma- and/or interleukin-10-positive sensitized patients declined significantly 3–8 months after extraction of the corresponding teeth. Keywords: mercaptan, hydrogen sulfide, thioether, interferon gamma, interleukin 10

Johann Lechner Clinic for Integrative Dentistry, Munich, Germany Introduction: There is a need to clarify the extent to which the most common diagnostic tool in dentistry – two-dimensional panoramic tomography (2D-OPG) – is suitable for identifying fatty degenerative osteolysis of jawbone (FDOJ). Materials and methods: To obtain a qualitative assessment of edentulous jawbone sections, the results from 2D-OPG with a defined X-ray density (XrDn), expression of the cytokine RANTES (regulated on activation, normal T-cell expressed and secreted), and a transalveolar ultrasound system for measuring jawbone density were compared. Results: The difference in the XrDn of healthy jawbone and FDOJ are minimal, whereas RANTES is up to 25-fold higher in FDOJ. In contrast to 2D-OPG, transalveolar ultrasound showed coincidental findings in FDOJ areas. Discussion: Comparisons of the data revealed a discrepancy between the XrDn of 2D-OPGs and the medullary osteopathies in the jawbone like FDOJ. Conclusion: The data suggest that there is a critical attitude toward the use of 2D-OPG as a sole imaging diagnostic tool for assessing chronic inflammatory processes in the jawbone. Specifically, 2D-OPG is objectively not suitable for depicting FDOJ. Keywords: osteonecrotic jawbone, silent inflammation, RANTES, bone density measurement

Johann Lechner,1 Volker von Baehr2 1Clinic for Integrative Dentistry, Munich, Germany; 2Compartment of Immunology and Allergology on Institute for Medical Diagnostics in MVZ GbR, Berlin, Germany Background: Jawbone cavitations (JC) are hollow dead spaces in jawbones with dying or dead bone marrow. These areas are defined as fatty degenerative osteonecrosis of the jawbone or neuralgia-inducing cavitational osteonecrosis and may produce facial pain. These afflictions have been linked to the immune system and chronic illnesses. Surgical debridement of JC is reported to lead to an improvement in immunological complaints, such as rheumatic, allergic, and other inflammatory diseases (ID). Little is known about the underlying cause/effect relationship. Objectives: JC bone samples were analyzed to assess the expression and quantification of immune modulators that can play a role in the pathogenesis of IDs. The study supports a potential mechanism where JC is a mediating link in IDs. Materials and methods: Samples of fatty softened bone taken from JCs were extracted from 31 patients. The specimens were analyzed by bead-based multiplex technology and tested for seven immune messengers. Results: Regulated upon activation, normal T-cell expressed, and secreted (RANTES) and fibroblast growth factor (FGF)-2 were found at high levels in the JCs tested. Other cytokines could not be detected at excessive levels. Discussion: The study confirms that JC is able to produce inflammatory messengers, primarily RANTES, and, secondarily, FGF-2. Both are implicated in many serious illnesses. The excessive levels of RANTES/FGF-2 in JC patients with amyotrophic lateral sclerosis, multiple sclerosis, rheumatoid arthritis, and breast cancer are compared to levels published in medical journals. Levels detected in JCs are higher than in the serum and cerebrospinal fluid of amyotrophic lateral sclerosis and multiple sclerosis patients and four-fold higher than in breast cancer tissue. Conclusion: This study suggests that JC might serve as a fundamental cause of IDs, through RANTES/FGF-2 production. Thus, JC and implicated immune messengers represent an integrative aspect of IDs and serve as a possible cause. Removing JCs may be a key to reversing IDs. There is a need to raise awareness about JC throughout medicine and dentistry. Keywords: RANTES/CCL5, fibroblast growth factor, FGF-2, bead-based Luminex analysis, osteolytic degenerated jaw bone, NICO, systemic signaling pathways

Researchers from the National Water Research Institute, Ontario, Canada revealed that the Agassiz Ice Cap in Greenland showed high levels of lead during spring despite the implementation of the use of unleaded gasoline since the 1970s.