Influence of gender on periodontal outcomes: A retrospective analysis of eight randomized clinical trials.

AIMS: To explore the influence of gender on periodontal treatment outcomes in a dataset of eight RCTs conducted in Brazil, United States, and Germany. METHODS: Clinical parameters were compared between men and women with stages III/IV grades B/C generalized periodontitis at baseline and 1-year post-therapy, including scaling and root planing with or without antibiotics. RESULTS: Data from 1042 patients were analyzed. Men presented a tendency towards higher probing depth (p = .07, effect size = 0.11) and clinical attachment level (CAL) than women at baseline (p = .01, effect size = 0.16). Males also presented statistically significantly lower CAL gain at sites with CAL of 4-6 mm at 1-year post-therapy (p = .001, effect size = 0.20). Among patients with Grade B periodontitis who took antibiotics, a higher frequency of women achieved the endpoint for treatment (i.e., ≤4 sites PD ≥5 mm) at 1 year than men (p < .05, effect size = 0.12). CONCLUSION: Men enrolled in RCTs showed a slightly inferior clinical response to periodontal therapy in a limited number of sub-analyses when compared to women. These small differences did not appear to be clinically relevant. Although gender did not dictate the clinical response to periodontal treatment in this population, our findings suggest that future research should continue to explore this topic.

Tooth Loss and Chronic Pain: A Population-based Analysis of the National Health and Nutrition Examination Survey.

Poor oral health conditions in adults are associated with chronic pain. A nationwide cross-sectional study was conducted to investigate the link between tooth loss and chronic pain. The study involved 8,662 participants from the National Health and Nutrition Examination Survey. Tooth count was categorized into 4 groups, and chronic pain was defined as persistent pain lasting over 3 months despite treatment. Location of the chronic pain, demographics, comorbidities, lifestyle determinants, and dietary intake were retrieved. Univariate and multivariate logistic regression were used to explore cross-sectional associations between tooth count and chronic pain. Compared to participants with more than 20 teeth, those with severe tooth loss presented greater odds of chronic pain (adjusted odds ratio [aOR] = 2.111, 95% confidence intervals (CI) = 1.213-3.676 for patients with 1-8 teeth). Edentulous participants presented with significantly higher odds of chronic pain in the lower extremities (78.4%) and buttocks (49.5%). In the multivariate model, apart from rheumatic arthritis (aOR = 4.004, 95% CI = 2.766-5.798), variables of higher chronic pain included smoking (aOR = 1.518, 95% CI = 1.228-1.878), and hypertension (aOR = 1.463, 95% CI = 1.013-2.112). On the contrary, being Mexican American (aOR = .603, 95% CI = .414-.880) was associated with lower odds of chronic pain. The findings suggested a significant link between chronic pain and tooth loss, independent of ethnicity, lifestyle determinants, and immune-mediated inflammatory diseases including rheumatoid arthritis. PERSPECTIVE: A U.S. nationwide study examined tooth loss and chronic pain. Those with severe tooth loss had increased odds of chronic pain. Edentulous individuals presented higher odds of pain in lower extremities and buttocks. This study highlighted the link between tooth loss and chronic pain, independent of comorbidities and lifestyle factors.

Modulating the sEH/EETs Axis Restrains Specialized Proresolving Mediator Impairment and Regulates T Cell Imbalance in Experimental Periodontitis.

Epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids are short-acting lipids involved in resolution of inflammation. Their short half-life, due to its metabolism by soluble epoxide hydrolase (sEH), limits their effects. Specialized proresolving mediators (SPMs) are endogenous regulatory lipids insufficiently synthesized in uncontrolled and chronic inflammation. Using an experimental periodontitis model, we pharmacologically inhibited sEH, examining its impact on T cell activation and systemic SPM production. In humans, we analyzed sEH in the gingival tissue of periodontitis patients. Mice were treated with sEH inhibitor (sEHi) and/or EETs before ligature placement and treated for 14 d. Bone parameters were assessed by microcomputed tomography and methylene blue staining. Blood plasma metabololipidomics were carried out to quantify SPM levels. We also determined T cell activation by reverse transcription-quantitative PCR and flow cytometry in cervical lymph nodes. Human gingival samples were collected to analyze sEH using ELISA and electrophoresis. Data reveal that pharmacological sEHi abrogated bone resorption and preserved bone architecture. Metabololipidomics revealed that sEHi enhances lipoxin A4, lipoxin B4, resolvin E2, and resolvin D6. An increased percentage of regulatory T cells over Th17 was noted in sEHi-treated mice. Lastly, inflamed human gingival tissues presented higher levels and expression of sEH than did healthy gingivae, being positively correlated with periodontitis severity. Our findings indicate that sEHi preserves bone architecture and stimulates SPM production, associated with regulatory actions on T cells favoring resolution of inflammation. Because sEH is enhanced in human gingivae from patients with periodontitis and connected with disease severity, inhibition may prove to be an attractive target for managing osteolytic inflammatory diseases.

Immunomodulation of periodontitis with SPMs.

Inflammation is a critical component in the pathophysiology of numerous disease processes, with most therapeutic modalities focusing on its inhibition in order to achieve treatment outcomes. The resolution of inflammation is a separate, distinct pathway that entails the reversal of the inflammatory process to a state of homoeostasis rather than selective inhibition of specific components of the inflammatory cascade. The discovery of specialized pro-resolving mediators (SPMs) resulted in a paradigm shift in our understanding of disease etiopathology. Periodontal disease, traditionally considered as one of microbial etiology, is now understood to be an inflammation-driven process associated with dysbiosis of the oral microbiome that may be modulated with SPMs to achieve therapeutic benefit.

A novel lncRNA-mediated epigenetic regulatory mechanism in periodontitis.

Periodontitis is a highly prevalent chronic inflammatory disease with an exaggerated host immune response, resulting in periodontal tissue destruction and potential tooth loss. The long non-coding RNA, LncR-ANRIL, located on human chromosome 9p21, is recognized as a genetic risk factor for various conditions, including atherosclerosis, periodontitis, diabetes, and cancer. LncR-APDC is an ortholog of ANRIL located on mouse genome chr4. This study aims to comprehend the regulatory role of lncR-APDC in periodontitis progression. Our experimental findings, obtained from lncR-APDC gene knockout (KO) mice with induced experimental periodontitis (EP), revealed exacerbated bone loss and disrupted pro-inflammatory cytokine regulation. Downregulation of osteogenic differentiation occurred in bone marrow stem cells harvested from lncR-APDC-KO mice. Furthermore, single-cell RNA sequencing of periodontitis gingival tissue revealed alterations in the proportion and function of immune cells, including T and B cells, macrophages, and neutrophils, due to lncR-APDC silencing. Our findings also unveiled a previously unidentified epithelial cell subset that is distinctively presenting in the lncR-APDC-KO group. This epithelial subset, characterized by the positive expression of Krt8 and Krt18, engages in interactions with immune cells through a variety of ligand-receptor pairs. The expression of Tff2, now recognized for its role in chronic inflammatory conditions, exhibited a notable increase across various tissue and cell types in lncR-APDC deficient mice. Additionally, our investigation revealed the potential for a direct binding interaction between lncR-APDC and Tff2. Intra-gingival administration of AAV9-lncR-APDC was shown to have therapeutic effects in the EP model. In conclusion, our results suggest that lncR-APDC plays a critical role in the progression of periodontal disease and holds therapeutic potential for periodontitis. Furthermore, the presence of the distinctive epithelial subpopulation and significantly elevated Tff2 levels in the lncR-APDC-silenced EP model offer new perspectives on the epigenetic regulation of periodontitis pathogenesis.

Long non-coding RNA APDC plays important regulatory roles in metabolism of bone and adipose tissues.

The long noncoding RNA (lncR) ANRIL in the human genome is an established genetic risk factor for atherosclerosis, periodontitis, diabetes, and cancer. However, the regulatory role of lncR-ANRIL in bone and adipose tissue metabolism remains unclear. To elucidate the function of lncRNA ANRIL in a mouse model, we investigated its ortholog, AK148321 (referred to as lncR-APDC), located on chr4 of the mouse genome, which is hypothesized to have similar biological functions to ANRIL. We initially revealed that lncR-APDC in mouse bone marrow cells (BMSCs) and lncR-ANRIL in human osteoblasts (hFOBs) are both increased during early osteogenesis. Subsequently, we examined the osteogenesis, adipogenesis, osteoclastogenesis function with lncR-APDC deletion/overexpression cell models. In vivo, we compared the phenotypic differences in bone and adipose tissue between APDC-KO and wild-type mice. Our findings demonstrated that lncR-APDC deficiency impaired osteogenesis while promoting adipogenesis and osteoclastogenesis. Conversely, the overexpression of lncR-APDC stimulated osteogenesis, but impaired adipogenesis and osteoclastogenesis. Furthermore, KDM6B was downregulated with lncR-APDC deficiency and upregulated with overexpression. Through binding-site analysis, we identified miR-99a as a potential target of lncR-APDC. The results suggest that lncR-APDC exerts its osteogenic function via miR-99a/KDM6B/Hox pathways. Additionally, osteoclasto-osteogenic imbalance was mediated by lncR-APDC through MAPK/p38 and TLR4/MyD88 activation. These findings highlight the pivotal role of lncR-APDC as a key regulator in bone and fat tissue metabolism. It shows potential therapeutic for addressing imbalances in osteogenesis, adipogenesis, and osteoclastogenesis.

Wintersweet (Chimonanthus praecox) toxicity in 5 sheep.

Two sheep presented with acute tonic-clonic seizures, opisthotonos, absent pupillary light reflexes and abnormal vital signs within 18 hours after observed consumption of leaves from an ornamental shrub later identified as wintersweet (Chimonanthus praecox). Despite symptomatic treatment, both sheep died. Three other sheep that consumed the plant died after displaying similar clinical signs, resulting in 2 deaths the prior evening and 1 recovery the next morning. Gross necropsy and histologic findings were diagnostically inconclusive. Rumen contents tested positive for the alkaloid calycanthine, a centrally-acting convulsant known to be present in wintersweet. Case reports of calycanthine toxicity in ruminants are limited, with no detailed reports published in the United States. Calycanthine has been isolated from the seeds, flowers, and leaves of the plant. Wintersweet is part of the family Calycanthaceae that including 3 species native to North America, all of which pose a neurologic risk to ruminants if consumed.

Complement components C3b and C4b as potential reliable site-specific diagnostic biomarkers for periodontitis.

OBJECTIVE: This study aimed to investigate the correlation between the expression levels of C3b and C4b in human gingival tissue (GT) and gingival crevicular fluid (GCF) and disease severity in human periodontitis and to determine whether C3b and C4b are significant site-specific complementary diagnostic markers for periodontitis. BACKGROUND: A variety of biomarkers that have potential for informing diagnoses of periodontitis have been proposed. The complement components C3b and C4b were found to be positively correlated with disease severity. The therapeutic effect of targeting C3b and C4b on inflammatory bone loss in experimental periodontitis models has been studied. However, studies on the diagnostic potential of the gingival C3b and C4b expression levels for periodontitis are scarce. METHODS: The expression levels of C3b and C4b in the GT and GCF were investigated via immunohistochemistry and enzyme-linked immunosorbent assay, respectively. The correlation between the expression levels of C3b and C4b and disease severity with probing depth as well as the clinical attachment level were determined. To evaluate the diagnostic accuracy of the C3b and C4b expression levels at the periodontitis sites, the receiver operating characteristic (ROC) curve, cut-off point, area under the ROC curve, sensitivity, and specificity were analyzed. RESULTS: The expression levels of C3b and C4b in human GT and GCF were significantly positively correlated with periodontitis severity. The expression levels of combined C3b + C4b in the GT can significantly differentiate the disease status at the tissue level (p < .0001). Similarly, the expression levels of C3b + C4b in GCF can statistically distinguish periodontitis sites from healthy ones (p < .0001). CONCLUSIONS: Locally deposited C3b and C4b were positively correlated with periodontitis severity and recognized as site-specific diagnostic biomarkers for clinicopathological features in periodontitis. The association between the C3b and C4b network and periodontitis may be further understood and provide a basis for the development of novel screening as well as diagnostic and therapeutic strategies for periodontitis.

Resolution of inflammation in oral diseases.

The resolution of inflammation is an essential endogenous process that protects host tissues from an exaggerated chronic inflammatory response. Multiple interactions between host cells and resident oral microbiome regulate the protective functions that lead to inflammation in the oral cavity. Failure of appropriate regulation of inflammation can lead to chronic inflammatory diseases that result from an imbalance between pro-inflammatory and pro-resolution mediators. Thus, failure of the host to resolve inflammation can be considered an essential pathological mechanism for progression from the late stages of acute inflammation to a chronic inflammatory response. Specialized pro-resolving mediators (SPMs), which are essential polyunsaturated fatty acid (PUFA)-derived autacoid mediators, aid in regulating the endogenous inflammation resolving process by stimulating immune cell-mediated clearance of apoptotic polymorphonuclear neutrophils, cellular debris, and microbes, restricting further neutrophil tissue infiltration, and counter-regulating pro-inflammatory cytokine production. The SPM superfamily contains four specialized lipid mediator families: lipoxins, resolvins, protectins, and maresins that can activate resolution pathways. Understanding the crosstalk between resolution signals in the tissue response to injury has therapeutic application potential for preventing, maintaining, and regenerating chronically damaged tissues. Here, we discuss the fundamental concepts of resolution as an active biochemical process, novel concepts demonstrating the role of resolution mediators in tissue regeneration in periodontal and pulpal diseases, and future directions for therapeutic applications with particular emphasis on periodontal therapy.

Dysregulation of CXCL1 Expression and Neutrophil Recruitment in Insulin Resistance and Diabetes-Related Periodontitis in Male Mice.

Insulin resistance and hyperglycemia are risk factors for periodontitis and poor wound healing in diabetes, which have been associated with selective loss of insulin activation of the PI3K/Akt pathway in the gingiva. This study showed that insulin resistance in the mouse gingiva due to selective deletion of smooth muscle and fibroblast insulin receptor (SMIRKO mice) or systemic metabolic changes induced by a high-fat diet (HFD) in HFD-fed mice exacerbated periodontitis-induced alveolar bone loss, preceded by delayed neutrophil and monocyte recruitment and impaired bacterial clearance compared with their respective controls. The immunocytokines, CXCL1, CXCL2, MCP-1, TNFα, IL-1ß, and IL-17A, exhibited delayed maximal expression in the gingiva of male SMIRKO and HFD-fed mice compared with controls. Targeted overexpression of CXCL1 in the gingiva by adenovirus normalized neutrophil and monocyte recruitment and prevented bone loss in both mouse models of insulin resistance. Mechanistically, insulin enhanced bacterial lipopolysaccharide-induced CXCL1 production in mouse and human gingival fibroblasts (GFs), via Akt pathway and NF-κB activation, which were reduced in GFs from SMIRKO and HFD-fed mice. These results provided the first report that insulin signaling can enhance endotoxin-induced CXCL1 expression to modulate neutrophil recruitment, suggesting CXCL1 as a new therapeutic direction for periodontitis or wound healing in diabetes. ARTICLE HIGHLIGHTS: The mechanism for the increased risks for periodontitis in the gingival tissues due to insulin resistance and diabetes is unclear. We investigated how insulin action in gingival fibroblasts modulates the progression of periodontitis in resistance and diabetes. Insulin upregulated the lipopolysaccharide-induced neutrophil chemoattractant, CXCL1, production in gingival fibroblasts via insulin receptors and Akt activation. Enhancing CXCL1 expression in the gingiva normalized diabetes and insulin resistance-induced delays in neutrophils recruitment and periodontitis. Targeting dysregulation of CXCL1 in fibroblasts is potentially therapeutic for periodontitis and may also improve wound healing in insulin resistance and diabetes.

Polyunsaturated Fatty Acids and Their Immunomodulatory Actions in Periodontal Disease.

Polyunsaturated fatty acids (PUFAs) are a diverse set of molecules with remarkable contributions to human physiology. They not only serve as sources of fuel but also cellular structural components as well as substrates that provide bioactive metabolites. A growing body of evidence demonstrates their role in inflammation. Inflammation in the presence of a polymicrobial biofilm contributes to the pathology of periodontitis. The role PUFAs in modulating immuno-inflammatory reactions in periodontitis is only beginning to be uncovered as research continues to unravel their far-reaching immunologic implications.

Oral hygiene, mouthwash usage and cardiovascular mortality during 18.8 years of follow-up.

Aim(s) We tested the following hypotheses: would better oral hygiene self-care (OHS) influence cardiovascular (CVD) mortality? Will using mouthwash in addition to OHS affect CVD mortality? How does mouthwash usage impact the oral microbes?Design and methods Among 354 dentate subjects from the Kuopio Oral Health and Heart study, the association of OHS with CVD mortality was assessed using Cox regression analyses, adjusting for age, sex, smoking, dyslipidemia, diabetes, hypertension and education. Additionally, whether using mouthwash would affect this relationship was evaluated.Results In the multivariable-adjusted models, OHS was associated with a 51% reduction in the risk of CVD mortality (hazard ratio [HR] 0.49 [0.28-0.85]; p = 0.01). Even those who had coronary artery disease at baseline showed a marginally significant benefit (0.50 [0.24-1.06]; p = 0.07). However, mouthwash usage did not change OHS effects (HR = 0.49 [0.27-0.87]; p = 0.01), indicating no additional benefits nor detriments. All tested microbes trended to decrease with mouthwash usage in the short term, but none were statistically significant.Conclusion Good OHS significantly lowered the risk of CVD mortality relative to poor OHS. Mouthwash usage did not show any long-term harm or benefit on CVD mortality beyond the benefits rendered by brushing and flossing.

Chlorhexidine gel topical application ameliorates inflammatory bone loss in experimental periodontitis.

OBJECTIVES: This study aimed to evaluate the impact of chlorhexidine (CHX) gel on inflammation-induced periodontal tissue destruction, osteoclastogenesis, subgingival microbiota, and on the modulation of the RANKL/OPG as well as inflammatory mediators during bone remodeling in vivo. MATERIALS AND METHODS: Ligation- and LPS injection-induced experimental periodontitis were created to investigate the effect of topical application of CHX gel in vivo. Alveolar bone loss, osteoclast number and gingival inflammation was evaluated by micro-CT, histological, immunohistochemistry and biochemical analysis. The composition of the subgingival microbiota was characterized by 16S rRNA gene sequencing. RESULTS: Data shows significant decreases in the alveolar bone destruction in rats from ligation-plus-CHX gel group compared to ligation group. In addition, significant decreases in the number of osteoclasts on bone surface and the protein level of receptor activator of nuclear factor κB ligand (RANKL) in gingival tissue were observed in rats from ligation-plus-CHX gel group. Moreover, data shows significantly decreased inflammatory cell infiltration and decreased expression of cyclooxygenase (COX-2) and inducible NO synthase (iNOS) in gingival tissue from ligation-plus-CHX gel group versus ligation group. Assessment of the subgingival microbiota revealed changes in rats with CHX gel application treatment. CONCLUSION: HX gel presents protective effect on gingival tissue inflammation, osteoclastogenesis, RANKL/OPG expression, inflammatory mediators, and alveolar bone loss in vivo, which may have a translational impact on the adjunctive use in the management of inflammation-induced alveolar bone loss.

Targeting therapeutic agent against C3b/C4b, SB002, on the inflammation-induced bone loss in experimental periodontitis.

AIMS: To use experimental periodontitis models in rats to investigate the correlation between local expression of the complement components C3b and C4b in periodontal tissues and disease severity, and to assess the therapeutic effects of targeting C3b/C4b on inflammatory bone loss. MATERIALS AND METHODS: The gingival expression of C3, C3b, and C4b in animal experimental periodontitis models were analysed immunohistochemically. The therapeutic effects of the C3b/C4b inhibitor (SB002) on ligation-induced experimental periodontitis was examined using biochemical, histological, and immunohistochemical analyses. RESULTS: The gingival expression levels of C3, C3b, and C4b were positively correlated with the severity of periodontitis. Moreover, both single and multiple injections of the C3b/C4b inhibitor had preventive and therapeutic effects on alveolar bone loss in ligation-induced experimental periodontitis with no associated adverse consequences. CONCLUSIONS: The association between C3b/C4b and periodontitis may provide a basis for the development of novel therapeutic strategies for periodontitis and other inflammatory diseases.

Soluble epoxide hydrolase inhibition enhances production of specialized pro-resolving lipid mediator and promotes macrophage plasticity.

BACKGROUND AND PURPOSE: Epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids (EpFA) are lipid mediators that are rapidly inactivated by soluble epoxide hydrolase (sEH). Uncontrolled and chronic inflammatory disorders fail to sufficiently activate endogenous regulatory pathways, including the production of specialized pro-resolving mediators (SPMs). Here, we addressed the relationship between SPMs and the EET/sEH axis and explored the effects of sEH inhibition on resolving macrophage phenotype. EXPERIMENTAL APPROACH: Mice were treated with a sEH inhibitor, EETs, or sEH inhibitor + EETs (combination) before ligature placement to induce experimental periodontitis. Using RT-qPCR, gingival samples were used to examine SPM receptors and osteolytic and inflammatory biomarkers. Maxillary alveolar bone loss was quantified by micro-CT and methylene blue staining. SPM levels were analysed by salivary metabolo-lipidomics. Gingival macrophage phenotype plasticity was determined by RT-qPCR and flow cytometry. Effects of sEH inhibition on macrophage polarization and SPM production were assessed with bone marrow-derived macrophages (BMDMs). KEY RESULTS: Pharmacological inhibition of sEH suppressed bone resorption and the inflammatory cytokine storm in experimental periodontitis. Lipidomic analysis revealed that sEH inhibition augmented levels of LXA4, RvE1, RvE2, and 4-HDoHE, concomitant with up-regulation of LTB4R1, CMKLR1/ChemR23, and ALX/FPR2 SPM receptors. Notably, there is an impact on gingival macrophage plasticity was affected suggesting an inflammation resolving phenotype with sEH inhibition. In BMDMs, sEH inhibition reduced inflammatory macrophage activation, and resolving macrophages were triggered to produce SPMs. CONCLUSION AND IMPLICATIONS: Pharmacological sEH inhibition increased SPM synthesis associated with resolving macrophages, suggesting a potential target to control osteolytic inflammatory disorders.

Resolvin D1 modulates periodontal ligament fibroblast function.

BACKGROUND: The resolution of inflammation is an active process mediated by specialized lipid mediators called lipoxins and resolvins. Periodontal ligament fibroblasts (PDLFs) play a significant role in periodontal regeneration. The purpose of the current study was to determine the impact of resolvin D1 (RvD1) on human PDLF cell wound healing and proliferation, receptor expression (G-protein-coupled receptor 32 [GPR32] and formyl peptide receptor 2 [ALX/FPR2]), and cytokine expression and release. METHODS: PDLFs were stimulated with interleukin-1ß (IL-1ß) (500 pg/ml) with and without RvD1 (100 nM). RvD1 receptor expression was determined by quantitative real-time polymerase chain reaction (qPCR), immunofluorescence microscopy, and fluorescence-activated cell sorting. Wound closure was measured by a scratch assay, and proliferation was determined by bromodeoxyuridine incorporation. Interleukin-6 (IL-6), interleukin-8 (IL-8), monocyte chemoattractant protein-1, cyclooxygenase-2, matrix metalloproteinases-1, -2, and -3 (MMP-1, -2, and -3), tissue inhibitors of metalloproteinases-1 and -2 (TIMP-1 and -2), prostaglandin E2, and osteoprotegerin (OPG) gene expression and production were measured using qPCR and Western blotting, multiplex immunoassay, and enzyme-linked immunosorbent assay. RESULTS: PDLF expressed GPR32 and ALX/FPR2. RvD1 reversed IL-1ß-induced inhibition of wound healing and proliferation of PDLF. IL-1ß also induced the production of proinflammatory cytokines and MMPs. This effect was reversed by RvD1. RvD1 reversed IL-1ß-induced inhibition of TIMP-1, TIMP-2, and OPG. CONCLUSION: The data suggested that RvD1 has a pro-wound healing, proliferative, and anti-inflammatory impact on the PDLF that favors periodontal regeneration.

Bidirectional Relationship Between Osteoarthritis and Periodontitis: A Population-Based Cohort Study Over a 15-year Follow-Up.

Objective: To identify the relationship between osteoarthritis and periodontitis. Methods: 144,788 periodontitis patients and 144,788 propensity score-matched controls without history of periodontitis were enrolled in this cohort study. A Cox proportional hazard model was used to estimate the risk of osteoarthritis. Survival analysis was utilized to assess the time-dependent effect of periodontitis on osteoarthritis. Age and gender were stratified to identify subgroups at risk. A symmetrical case-control analysis was designed to determine the relationship between present periodontitis and history of osteoarthritis. Results: Patients with periodontitis had higher risk of osteoarthritis (hazard ratio, HR =1.15, 95% CI =1.12-1.17, p < 0.001) and severe osteoarthritis that led to total knee replacement or total hip replacement (TKR/THR) (HR =1.12, 95% CI =1.03-1.21, p < 0.01) than controls, which was time-dependent (log-rank test p < 0.01). The effect of periodontitis on osteoarthritis was significant in both genders and age subgroups over 30 years-old (all p < 0.001). Among them, females (HR=1.27, 95% CI = 1.13-1.42, p < 0.001) and patients aged over 51 (HR= 1.21, 95% CI =1.10-1.33, p < 0.001) with periodontitis were predisposed to severe osteoarthritis. In addition, periodontitis patients were more likely to have a history of osteoarthritis (odds ratio = 1.11, 95% CI = 1.06 - 1.17, p < 0.001). Conclusions: These findings suggest an association between periodontitis and a higher risk of osteoarthritis, including severe osteoarthritis that led to TKR/THR. Likewise, periodontitis is more likely to develop following osteoarthritis. A bidirectional relationship between osteoarthritis and periodontitis was observed.

Resolvin E1 Reduces Tumor Growth in a Xenograft Model of Lung Cancer.

Inflammation plays a significant role in carcinogenesis and tumor growth. The current study was designed to test the hypothesis that resolvin E1 (RvE1) and overexpression of the receptor for RvE1 (ERV1) will prevent and/or reverse tumor generation in a gain-of-function mouse model of tumor seeding with lung cancer cells. To measure the impact of enhanced resolution of inflammation on cancer pathogenesis, ERV1-overexpressing transgenic (TG) and wild-type FVB mice were given an injection of 1 × 106 LA-P0297 cells subcutaneously and were treated with RvE1 (100 ng; intraperitoneally) or placebo. To assess the impact of RvE1 as an adjunct to chemotherapy, ERV1-TG and wild-type FVB mice were treated with cisplatin or cisplatin + RvE1. RvE1 significantly prevented tumor growth and reduced tumor size, cyclooxygenase-2, NF-κB, and proinflammatory cytokines in TG animals as compared to wild-type animals. A significant decrease in Ki-67, vascular endothelial growth factor, angiopoietin (Ang)-1, and Ang-2 was also observed in TG animals as compared to wild-type animals. Tumor-associated neutrophils and macrophages were significantly reduced by RvE1 in transgenics (P < 0.001). RvE1 administration with cisplatin led to a significant reduction of tumor volume and reduced cyclooxygenase-2, NF-κB, vascular endothelial growth factor-A, Ang-1, and Ang-2. These data suggest that RvE1 prevents inflammation and vascularization, reduces tumor seeding and tumor size, and, when used as an adjunct to chemotherapy, enhances tumor reduction at significantly lower doses of cisplatin.