Abstract
Background
Animal studies suggested that vitamin D might decrease insulin resistance. Estrogen increased insulin sensitivity and glucose tolerance in rodents. However, sex-specific ...association of vitamin D with insulin resistance in humans remains unclear.
Objectives
To investigate the sex-dependency of the association of insulin resistance and 25-hydroxyvitamin D 25(OH)D in a large Caucasian population.
Methods
Cross-sectional study from out-patients’ blood samples with measurements of 25(OH)D and homeostatic model assessment of insulin resistance (HOMA-IR) drawn at exactly the same day (n = 1887). This cohort was divided into 3 groups: (1) group with vitamin D deficiency (n = 1190), (2) group with vitamin D sufficiency (n = 686), and (3) vitamin D excess groups (n = 11); the vitamin D excess group was excluded from further analysis due to the small size.
Results
Analysis of the entire study population showed that serum 25(OH)D was inversely associated with HOMA-IR Spearman correlation coefficient (rs) = −0.19, P < 0.0001. When considering the vitamin D status, this association was only seen in the vitamin D deficiency group but not in the vitamin D sufficient group. The correlation was sex-dependent: HOMA-IR was inversely correlated with vitamin D in women with vitamin D deficiency (rs = −0.26, P < 0.0001) but not in men with vitamin D deficiency (rs = 0.01, P = 0.714). After multivariate linear regression analysis considering confounding factors, this relationship was again only seen in women.
Conclusion
Vitamin D was inversely and independently associated with insulin resistance only in women with vitamin D deficiency. Based on our data, we suggest that in particular vitamin D deficient women might benefit from vitamin D substitution by improving insulin resistance. This, however, needs to be proven in adequately designed double-blind placebo-controlled clinical studies.
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.
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?
A comprehensive literature search was performed in PubMed Central.
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.
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".
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).
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.
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.
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.
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.
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.
Background and introduction
It is a well-known fact that titanium particles deriving from dental titanium implants (DTI) dissolve into the surrounding bone. Although titanium (TI) is regarded as a ...compatible implant material, increasing concern is coming up that the dissolved titanium particles induce inflammatory reactions around the implant. Specifically, the inflammatory cytokine tumor necrosis factor-alpha (TNF-α) is expressed in the adjacent bone. The transition from TNF-α-induced local inflammation following insertion of DTI surgery to a chronic stage of “silent inflammation” could be a neglected cause of unexplained medical conditions.
Material and methods
The signaling pathways involved in the induction of cytokine release were analyzed by multiplex analysis. We examined samples of jawbone (JB) for seven cytokines in two groups: specimens from 14 patients were analyzed in areas of DTI for particle-mediated release of cytokines. Each of the adjacent to DTI tissue samples showed clinically fatty degenerated and osteonecrotic medullary changes in the JB (FDOJ). Specimens from 19 patients were of healthy JB. In five cases, we measured the concentration of dissolved Ti particles by spectrometry
.
Results
All DTI-FDOJ samples showed RANTES/CCL5 (R/C) as the only extremely overexpressed cytokine. DTI-FDOJ cohort showed a 30-fold mean overexpression of R/C as compared with a control cohort of 19 healthy JB samples. Concentration of dissolved Ti particles in DTI-FDOJ was 30-fold higher than an estimated maximum of 1.000 μg/kg.
Discussion
As R/C is discussed in the literature as a possible contributor to inflammatory diseases, the here-presented research examines the question of whether common DTI may provoke the development of chronic inflammation in the jawbone in an impaired state of healing. Such changes in areas of the JB may lead to hyperactivated signaling pathways of TNF-α induced R/C overexpression, and result in unrecognized sources of silent inflammation. This may contribute to disease patterns like rheumatic arthritis, multiple sclerosis, and other systemic-inflammatory diseases, which is widely discussed in scientific papers.
Conclusion
From a systemic perspective, we recommend that more attention be paid to the cytokine cross-talk that is provoked by dissolved Ti particles from DTI in medicine and dentistry. This may contribute to further development of personalized strategies in preventive medicine.
Lyme disease (LD) is caused by Borrelia burgdorferi and displays different stages, including localized, early disseminated, and persistent infection, all of which are associated with profound ...inflammatory reactions in the host. Induction of proinflammatory cytokines by B. burgdorferi is mainly mediated by outer surface proteins interacting with TLR-2/TLR-1 heterodimers. In this study, we show that TNF-alpha induction by Borrelia lysate was impaired in heterozygous TLR-2 knockout mice, while reactivity to lipoteichoic acid, another TLR-2 ligand signaling via TLR-2/TLR-6 heterodimers, was unaffected. Blood from individuals heterozygous for the TLR-2 polymorphism Arg753Gln was tested for cytokine release upon stimulation with Borrelia lysate, and induction of TNF-alpha and IFN-gamma was significantly lower as compared with individuals not exhibiting this variation. Overexpression of TLR-2 carrying the Arg753Gln polymorphism in HEK 293 cells led to a significantly stronger impairment of activation by TLR-2/TLR-1 ligands as compared with TLR-2/TLR-6 ligands. To study whether heterozygosity for the Arg753Gln variant of TLR-2 influenced susceptibility for LD, we analyzed 155 patients for this polymorphism. The Arg753Gln variant occurs at a significantly lower frequency in LD patients as compared with matched controls (5.8 vs 13.5%, odds ratio 0.393, 95% confidence interval 0.17-0.89, p = 0.033), with an even more pronounced difference when late stage disease was observed (2.3 vs 12.5%, odds ratio 0.163, 95% confidence interval 0.04-0.76, p = 0.018). These data suggest that Arg753Gln may protect from the development of late stage LD due to a reduced signaling via TLR-2/TLR-1.
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.
Background. Local anesthetics (LAs) have potent anti-inflammatory properties. Inflammatory down-regulation is crucial in diseases with overactive immune reactions, such as acute respiratory distress ...syndrome (ARDS) and chronic inflammation. We investigated the influence of four LAs, procaine, lidocaine, mepivacaine, and bupivacaine, on the reduction of tumor necrosis factor-alpha (TNF-α) secretion in lipopolysaccharide (LPS)-activated human leucocytes. Methods. Blood samples of 28 individuals were stimulated with LPS. The reduction of TNF-α production by each of the four LAs added (0.5 mg/mL) was measured and correlated with biometric variables. A response was defined as reduction to <85% of initial levels. Results. All four LAs down-regulated the TNF-α secretion in 44−61%: Bupivacaine (44.4%), lidocaine (61.5%), mepivacaine (44.4%), and procaine (50% of the individuals, “responders”). The TNF-α secretion was reduced to 67.4, 68.0, 63.6, and 67.1% of the initial values in responders. The effects in both patients and healthy persons were the same. Interindividual responses to LAs were not correlated with the duration or type of complaints, basal TNF-α serum level, sex, BMI, or age of responders. Conclusions. Four clinically relevant LAs (amid-LA and ester-LA) attenuate the inflammatory response provoked by LPS. They are potential candidates for drug repositioning in treating overactive immune reactions and chronic inflammation.
Background
Fatty degenerative osteonecrosis in the medullary spaces of the jawbone (FDOJ) may be identified as a lesser known source of RANTES/CCL5 (R/C) overexpression. The chemokine R/C also ...interferes with bone metabolism leading to osteolysis in areas affected by FDOJ. Many dental surgeries require functioning repair mechanisms and these may be disrupted by R/C overexpression.
Objective
To clarify the way in which R/C expression from adipocytes in FDOJ causes a disturbance in osteogenesis and impacts on medullary stem cells by investigating the detection of R/C expression with immunochemical staining.
Materials and methods
We examined the tissue samples of 449 patients with FDOJ to assess the level of the chemokine R/C using bead-based Luminex® analysis. In six clinical case studies of FDOJ, we compared bone density, histological findings, R/C expression, and immunohistochemical staining.
Results
R/C is overexpressed by up to 30-fold in the 449 FDOJ cases when compared with healthy jawbone samples. The comparison of the six clinical cases consistently shows greatly reduced bone density, (i.e., osteolysis), but varies in terms of the level of agreement across the other three parameters.
Discussion
R/C from FDOJ sources may be implicated in several immune responses and considered a key pathogenetic pathway for increased adipogenesis rather than desirable osteogenesis. Adipocytes pathogenetically act via R/C expression in local FDOJ and systemically on the immune system.
Conclusion
R/C may be regarded as an important trigger for possible pathological developments in the fate of hematopoietic stem cells. FDOJ is not a rigidly uniform process but reflects changing stages of development. The absence of correlating findings should not be interpreted as a misdiagnosis. It seems appropriate to direct further research in the field of “maxillo–mandibular osteoimmunology” focusing on R/C overexpression in FDOJ areas. This may contribute to the development of personalized strategies in preventive medicine.
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.
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.
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.
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.
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.
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.
It was shown that hypertension delays SARS CoV-2 viral clearance and exacerbates airway hyperinflammation in the respiratory tract. However, it is unknown whether hypertension determines the ...long-term cellular and humoral response to SARS Cov2. Health care workers (HCWs) after an outbreak of SARS Cov-2 infections were analyzed. Infected HCWs were not vaccinated before blood collection. 5-14 months (median 7 months) after detection of SARS CoV-2 infection, blood was taken to analyze humoral response (S1 IgG and SARS CoV-2 neutralizing antibodies) and cellular (T cell responses to SARS-CoV-2 with Lymphocyte Transformation Test). To identify clinical factors that determine the immune response, a multivariate regression analysis was done considering age, BMI, sex, diabetes, hypertension, smoking, COPD, asthma and time between PCR positivity and blood collection as confounding factors. Infected hypertensive HCWs more often needed to be hospitalized than non-hypertensive HCWs, but were less likely to develop anosmia and myalgia. The long-term humoral and cellular immune response was significantly strengthened in hypertensive versus normotensive infected HCWs. Multivariate regression analysis revealed that hypertension was independently associated with the humoral response to SARS CoV-2 infection. Multivariate regression analysis using same confounding factors for the humoral response showed a clear trend for an association with the cellular response to SARS CoV-2 infection as well. In conclusion, SARS CoV-2 infection strengthened immune response to SARS CoV-2 infection in hypertensive HCWs independent of other risk factors.
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