We assessed the hypothesis that dental caries is associated with ischemic stroke and specific ischemic stroke subtypes in the Atherosclerosis Risk In Communities (ARIC) study.

Background We recently described the association between periodontal disease (PD) and stroke risk. Purpose The purpose of this study was to test the association between PD, dental care utilization and incident atrial fibrillation (AF), as well as AF as a mediator to PD- stroke association. Methods In dental cohort of the Atherosclerosis Risk in Communities Study (ARIC), participants without prior AF underwent full-mouth periodontal measurements. PD was defined on an ordinal scale as healthy (referent), mild, moderate and severe. In ARIC main cohort, participants were classified as regular or episodic dental care users. These patients were followed for AF, over 17 years. Cox proportional hazards models adjusted for AF risk factors were used to study relationships between PD severity, dental care utilization and AF. Mediation analysis was used to test if AF mediated the PD- stroke association. Results In dental ARIC cohort, 5,958 were assessed without prior AF, 754 were found to have AF. Severe PD was associated with AF on both univariable (crude HR, 1.54; 95% CI, 1.26-1.87) and multivariable (adjusted HR, 1.31, 95% CI, 1.06-1.62) analyses. Mediation analysis suggested AF mediates the association between PD and stroke. In the main ARIC cohort, 9,666 participants without prior AF were assessed for dental care use, 1558 were found to have AF. Compared with episodic users, regular users had a lower risk for AF on univariable (crude HR, 0.82, 95% CI, 0.74-0.90) and multivariable (adjusted HR, 0.88, 95% CI, 0.78-0.99) analyses. Conclusions PD is associated with AF. The association may explain the PD-stroke risk. Regular users had a lower risk of incident AF compared with episodic users.

BACKGROUND AND OBJECTIVES Plakophilin-2 (PKP2) is an intracellular desmosomal anchoring protein that has been implicated in a genome-wide association study, in which genetic variants of PKP2 are associated with Porphyromonas gingivalis (P.gingivalis) -dominant periodontal dysbiosis. In this study, we compared the ex vivo PKP2 expression in periodontitis gingival biopsies to periodontitis-free subjects and assessed the in vitro role of PKP2 in gingival epithelial barrier function and the mechanism by which P.gingivalis modulates PKP2 expression. MATERIAL AND METHODS Using reverse transcription quantitative real-time PCR (RT-qPCR), we determined PKP2 mRNA expression levels in gingival biopsies collected from 11 periodontally healthy, 10 experimental gingivitis, and 10 chronic periodontitis subjects. PKP2 protein expression in gingival biopsies was detected by immunohistochemistry. We then challenged primary gingival epithelial cells with bacteria including P.gingivalis, Campylobacter rectus, and various Toll-like receptor agonists. Western blot and immunofluorescence staining were used to detect protein expression. Inhibitors blocking proteases pathways were tested for P.gingivalis-mediated PKP2 protein degradations. We also knocked down endogenous epithelial PKP2 using lentiviral short-hairpin RNA (shRNA) and evaluated cell proliferation, spreading, and barrier function. RESULTS Periodontitis gingival biopsies had approximately twofold less PKP2 mRNA than did healthy controls (p < .05). PKP2 protein was predominantly expressed in gingival epithelium. In primary gingival epithelial cells, P.gingivalis challenge increased PKP2 mRNA levels, while protein expression decreased, which suggests that P.gingivalis has a protein degradation mechanism. Cysteine proteases inhibitors greatly attenuated P.gingivalis-mediated PKP2 protein degradation. Epithelial cells with deficient PKP2 exhibited inhibited cell proliferation and spreading and failed to form monolayers. Finally, P.gingivalis impaired gingival epithelial barrier function. CONCLUSIONS PKP2 appears to be critical in maintaining gingival epithelial barrier function and is susceptible to degradation by cysteine proteases produced by P.gingivalis. Our findings have identified a mechanism by which P.gingivalis impairs epithelial barrier function by promoting PKP2 degradation.

OBJECTIVESPrevious studies on a potential association between endodontic infection (EI) and cardiovascular disease (CVD) produced mixed results. Endodontic treatment (ET) may also be linked to cardiovascular risk, as a marker for prior chronic dental infection and subclinical EI in other teeth. We tested the hypothesis that ET is associated with elevated risk of coronary heart disease (CHD), ischemic stroke (IS), heart failure (HF), or venous thromboembolism (VTE).METHODSARIC participants who completed the dental ancillary study exam 4 (1996-1998; n = 6,638) were included in the analyses. Participants were followed through 2013 for CHD, stroke, and HF and 2011 for VTE. Cox-proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for CHD, IS, HF, and VTE across ET classifications adjusting for age, sex, race/center, education, income, smoking, alcohol consumption, BMI, statin use, family history of CHD, physical activity, diet quality, insurance status, last dental visit, dental visit frequency, having a current dentist, and tooth loss due to gum disease.RESULTSAmong participants, 21.0% reported a single ET, while 28.5% reported multiple ETs. Over a median of 15.8 years of follow-up, there were 506 incident CHD events, 311 IS events, 739 HF events, and 219 VTE events. There were no significant associations between self-reported history of ET and any of our outcomes (HR (95%CI): CHD = 1.16 (0.87,1.44), IS = 0.77 (0.55,1.09), HF = 1.00 (0.81,1.24), VTE = 0.98 (0.67,1.43)) after adjustment.CONCLUSIONSOur results do not support an independent association between ET and development of CHD, IS, HF, or VTE.

Purpose: The purpose of this clinical study was to evaluate the effectiveness of a curved rubber bristle interdental cleaner, as compared to dental floss, in the reduction of gingivitis and plaque.Methods: Gingival Index (GI), Bleeding on Probing (BOP), Periodontal Probing Depth (PPD) and Modified QH Plaque Index (MQH-PI) parameters were evaluated in an examiner-masked, parallel group, controlled clinical study. A total of 50 participants with gingivitis (no site with PPD >4 mm, BOP ≥10% but ≤50%) met the eligibility criteria. Participants were randomly assigned to either the curved rubber bristle interdental cleaner (cRBIC) group or the ADA-accepted dental floss (Floss) group. Participants used the devices for four weeks. Parameters were obtained at 2 and 4 weeks. Participants scored their level of product familiarity, satisfaction and motivation for interdental cleaning.Results: There were no statistically significant differences between the two groups in changes from baseline to 2 or 4 weeks in GI, BOP%, and MQH-PI. However, cRBIC group showed greater reduction of PPD at 4 weeks from baseline, compared with Floss group (p<0.05). The cRBIC group showed overall better compliance level than Floss group. The mean score of "ease of use" of the cRBIC group was significantly greater than that of Floss group. However, Floss group showed higher levels of "satisfaction" than cRBIC group. Motivation for interdental cleaning was higher in cRBIC.Conclusion: The cRBIC was similar to Floss in clinical effectiveness; however, PPD reduction at 4 weeks was greater with the cRBIC. Ease of use of cRBIC may have affected the participants' motivation for interdental cleaning, resulting in better compliance.

Emerging evidence suggests comprehensive immune profiling represents a highly promising, yet insufficiently tapped approach to identify potentially prognostic signatures for periodontitis. In this report, we agnostically identified a periodontitis-associated inflammatory expression network with multiple biomarkers identified within gingival crevicular fluid samples from study participants by applying principal component analysis. We identified an IL-17-dominated trait that is associated with periodontal disease and is inversely modified by the level of IL-10. IL-10 mitigated chemokine CXCL5 and CXCL1 expressions in IL-17-stimulated peripheral blood monocytic cells and peripheral blood monocytic cell-derived macrophages. 1110-deficient mice presented more bone loss, which was associated with more Il17 and IL-17-mediated chemokine and cytokine expression at the transcriptional levels in comparison with control wild-type mice in both the Porphyromonas gingivalis-induced experimental murine periodontitis and ligature-induced alveolar bone-loss models. The dampening effect of IL-10 on the excessive signaling of IL-17 appeared to be mediated by innate immune cells populations rather than by gingival epithelial cells, which are the major cell target for IL-17 signaling. Additionally, elevated IL-17 response in Il10-deficient mice specifically elicited an Ml-skewing macrophage phenotype in the gingiva that was associated with the advanced bone loss in the ligature model. In summary, IL-17 dominated an inflammatory network characteristic of periodontitis, and IL-10 dampens this excessive IL-17-mediated periodontitis trait.

The concept of precision dentistry as it relates to precision medicine is relatively new to the field of oral health. Precision dentistry is a contemporary, multifaceted, data-driven approach to oral health care that uses individual characteristics to stratify similar patients into phenotypic groups. The objective is to provide clinicians with the information that will allow them to improve treatment planning and a patient's response to treatment. Providers that use a precision oral health approach would move away from using an "average treatment" for all patients with a particular diagnosis and move toward more specific treatments for patients within each diagnostic subgroup. Precision dentistry requires a method or a model that places each individual in a subgroup where each member is the same as every other member in relation to the disease of interest. Precision dentistry is a paradigm shift that requires a new way of thinking about diagnostic categories. This approach uses patients' risk factor data (including, but not limited to, genetic, environmental, and health behavioral), rather than expert opinion or clinical presentation alone, to redefine traditional categories of health and disease. We review aspects of current efforts to allow precision dentistry to be realized and focus on one of the major innovations that may help precision dentistry to be practiced by periodontists, the World Workshop Model. Another approach is the Periodontal Profile Class system. These two approaches represent examples of supervised and unsupervised learning systems, respectively. This review compares and contrasts these two learning systems for their ability to classify patients into homogeneous disease and risk groups, as well as their feasibility at achieving the objective of enabling precision dentistry. We conclude that: (a) the World Workshop Model concept of stages and grades works as expected, in that periodontal status appears to be more serious in each successive stage. In addition, the seriousness and the complexity of the disease are greater as the grade increases within each stage. Stages and grades are important for precision dentistry because they consider the risk of future disease and the prognosis, and enable practitioners to use more signs, symptoms, and other associated factors when placing a patient in a diagnostic category; (b) the assignment of stages and grades using unsupervised learning systems is superior to using supervised learning systems for the prediction of 10-year tooth loss and 3-year attachment loss progression. In addition, the unsupervised learning approach (Periodontal Profile Class stages) results in stronger associations between the periodontal phenotypes and systemic diseases and conditions (prevalent diabetes, C-reactive protein, and incident stroke). This probably occurs because an unsupervised learning model produces more data-driven, mutually exclusive, homogeneous groups than a supervised learning model.

Oral mucositis, inflammation, and ulceration that occur in the oral cavity can manifest in significant pain. A formulation was designed to investigate the potential of vitamin E to ameliorate inflammation resulting from Candida albicans in cell-based systems. Human gingival fibroblasts and THP1 cells were stimulated with heat killed C. albicans and Porphyromonas gingivalis LPS (agonists). Unstimulated cells were included as controls. Cells were also simultaneously treated with a novel denture adhesive formulation that contains vitamin E (antagonist). The experimental conditions included cells exposed to the experimental formulation or the vehicle for 2 h for mRNA extraction and analysis, and cells left for 24 h under those experimental conditions for analysis of protein expression by ELISA. ssAffymetrix expression microarray pathway analyses demonstrated that the tested formulation exhibited a statistically significant (p < 0.05) inhibition of the following key inflammatory pathways: TLR 6, IL-1 signaling (IRAK, A20), NF-kappaB, IL-6 signaling (gp130, JK2 and GRB2), TNF signaling (TNF receptor) and Arachidonic acid metabolism (PLA2). Quantitative PCR array analysis confirmed the downregulation of key inflammatory genes when cells under adhesive treatment were challenged with heat killed C. albicans. PGE2 secretion was inhibited by the tested formulation only on THP1 cells after 24 h stimulation with C. albicans. These results suggest that the active formulation containing vitamin E acetate can modulate inflammatory responses, through anti-inflammatory actions as indicated by in vitro experimental conditions.

The in vivo antibacterial activity of NO-releasing hyperbranched polymers was evaluated against Porphyromonas gingivalis, a key oral pathogen associated with periodontitis, using a murine subcutaneous chamber model. Escalating doses of NO-releasing polymers (1.5, 7.5, and 37.5 mg/kg) were administered into a P. gingivalis-infected chamber once a day for 3 days. Chamber fluids were collected on day 4, with microbiological evaluation indicating a dose-dependent bactericidal action. In particular, NO-releasing polymers at 37.5 mg/kg (1170 μg of NO/kg) achieved complete bacterial eradication (>6-log reduction in bacterial viability), demonstrating greater efficacy than amoxicillin (∼4-log reduction in bacterial viability), a commonly used antibiotic. Time-kill assays further revealed that largest dose (37.5 mg/kg; 1170 μg of NO/kg) resulted in ∼3-log killing of P. gingivalis after only a single dose. Based on these results, the potential clinical utility of NO-releasing hyperbranched polymers appears promising, particularly for oral health applications.

Periodontitis is one of the most prevalent chronic inflammatory diseases and is induced by the interaction between oral microorganisms and the host immune system. Plasma cells are of special interest in chronic periodontitis (CP), as they represent ~50% of infiltrated immune cells in periodontal lesions. Plasma cells constitute the only known cell type capable of antibody production; however, recent evidence supports an emerging role for distinct sets of plasma cells in cytokine production. However, the presence of cytokine-producing plasma cells in CP is unknown. In this study, we used immunohistochemistry to detect significantly elevated levels of IL-35 and IL-37 (2 recently identified anti-inflammatory cytokines) in CP gingival tissue as compared with healthy tissue. Remarkably, we demonstrate that CD138+ CD38+ plasma cells are the major immune cell type in CP gingival tissues and that these cells produce IL-35 and IL-37. We used immunofluorescence and confocal microscopy analysis to identify a subset of plasma cells with robust cytoplasmic expression of IL-37—we denote this subset as IL-37-producing plasma cells (CD138+CD38+PIL-37). Another subset of plasma cells coproduces IL-35 and IL-37 and is denoted as IL-37/IL-35-coproducing plasma cells (CD138+CD38+PIL-35/IL-37). We determined that these 2 plasma cell subsets are IgG+plasma cells. Moreover, we show that human recombinant IL-35 and IL-37 exhibit a dose-dependent inhibition of osteoclast formation in vitro (~78.9% and 97.7% inhibition in 300 ng/mL of IL-35 and IL-37, respectively, P < 0.05). Overall, our findings suggest that PIL-37 and PIL-35/IL-37 exist as subsets of plasma cells in CP lesions and that these 2 new types of plasma cells may regulate periodontitis pathogenesis by inhibiting alveolar bone loss through directly blocking osteoclast formation. Importantly, these data suggest a novel role of plasma cells and offer potential new mechanistic and regulatory targets to be investigated in the context of periodontal health and disease.

RATIONALE & OBJECTIVE:Observational studies have suggested that periodontal disease may be a modifiable risk factor for chronic kidney disease (CKD). The Kidney and Periodontal Disease (KAPD) Study was designed to determine the feasibility of conducting a periodontal disease treatment trial among a high-risk (mostly poor and racial/ethnic minority) population and estimate the magnitude and variability of kidney and inflammatory biomarker levels in response to intensive periodontal treatment. STUDY DESIGN:Single-center, unmasked, intention-to-treat, randomized, controlled, pilot trial with 2:1 allocation to the treatment and comparison groups. SETTING & PARTICIPANTS:English- and Spanish-speaking individuals aged 20 to 75 years receiving primary care within the San Francisco Community Health Network with evidence of both moderate to severe periodontal disease and CKD. INTERVENTION:Immediate intensive nonsurgical periodontal treatment versus rescue treatment for progressive disease at baseline and 4, 8, and 12 months. OUTCOMES:Feasibility and process outcomes. Levels of biomarkers of kidney function, kidney injury, and systemic inflammation obtained at baseline and 4 and 12 months. RESULTS:KAPD randomly assigned 51 participants to the immediate (34 participants) or rescue (17 participants) groups. 14% dropped out of the study (4 immediate, 3 rescue) and 80% completed all 4 visits of the 12-month protocol (28 immediate, 13 rescue). Fewer than half the teeth recommended for extraction were extracted and 40% of immediate group visits were outside the protocol window. Bleeding on probing and probing depth improved more in the immediate group than in the rescue group; there was no significant separation in periodontal status. Levels of markers of vascular endothelial and systemic injury declined in both groups. LIMITATIONS:No true control group. CONCLUSIONS:This 12-month, pilot, randomized, controlled trial successfully recruited and retained a high-risk population but was less successful observing treatment adherence, treatment effect, and variability of biomarker levels. Although KAPD did not meet all of its goals, important lessons learned can be applied to future studies. FUNDING:National Institute of Diabetes and Digestive and Kidney Disease (Bethesda, MD; grant number 1K23DK093710-01A1) and Harold Amos Medical Faculty Development Program of the Robert Wood Johnson Foundation, Princeton, NJ. Funders had no role in study design; collection, analysis, or interpretation of data; writing the report; or the decision to submit the report for publication. TRIAL REGISTRATION:NCT01802216.

BACKGROUND:Stroke remains more common in the "buckle" of the stroke belt, and disproportionately impacts African Americans. The reasons for this racial disparity are poorly understood and are not entirely explained by traditional stroke risk factors. The PeRiodontal treatment to Eliminate Minority InEquality and Rural disparities in Stroke (PREMIERS) study will evaluate the effect of periodontal treatment on recurrent vascular events and stroke risk factors among ischemic stroke and transient ischemic attack patients.DESIGN:Eligibility for the trial includes a non-disabling stroke confirmed by neuroimaging or Transient Ischemic Attack (TIA), being at least 18 years of age, having ≥ 5 natural teeth with ≥ 2 interproximal sites with ≥ 4 mm of clinical attachment loss and at least 2 sites with probing depth of ≥ 5 mm, and who are able to provide written informed consent. Within 90 days of the index event, patients are randomly assigned to intensive or initial standard cycle of supragingival mechanical scaling, polishing, and oral health instruction and followed for 1 year. The primary outcome is a composite of death, myocardial infarction and stroke or TIA. Secondary outcomes include A1C, fasting lipid profile, triglycerides, high sensitivity C-reactive protein, carotid intimal medial thickness, and blood pressure. A five year enrollment period followed by an addition one year of follow-up is planned.

Dental caries and periodontitis account for a vast burden of morbidity and healthcare spending, yet their genetic basis remains largely uncharacterized. Here, we identify self-reported dental disease proxies which have similar underlying genetic contributions to clinical disease measures and then combine these in a genome-wide association study meta-analysis, identifying 47 novel and conditionally-independent risk loci for dental caries. We show that the heritability of dental caries is enriched for conserved genomic regions and partially overlapping with a range of complex traits including smoking, education, personality traits and metabolic measures. Using cardio-metabolic traits as an example in Mendelian randomization analysis, we estimate causal relationships and provide evidence suggesting that the processes contributing to dental caries may have undesirable downstream effects on health.

Periodontal medicine is a term used to describe how periodontal infection/inflammation may impact extraoral health. Periodontitis has been linked to over 50 systemic diseases and conditions. As part of the Journal of Dental Research's Centennial Celebration, this narrative review discusses periodontal medicine research done over the past 100 y, with particular focus on the effects of periodontal disease on 3 pathological conditions: cardiovascular disease, diabetes mellitus, and adverse pregnancy outcomes. We selected 29 total studies that were the "first" of their kind, as they provided novel observations or contributed to shifting paradigms as well as important studies that made strong contributions to progress in understanding relationships to the systemic conditions. These studies were organized in an overview timeline and broken down into timelines by topic: cardiovascular disease (n = 10), diabetes (n = 12), and adverse pregnancy outcomes (n = 7). Overall, the majority of cross-sectional, case-control, and longitudinal studies have revealed positive associations between poor periodontal status and cardiovascular disease, diabetes metabolic control, and a number of adverse pregnancy outcomes, and these associations are upheld in systematic reviews. Findings from randomized controlled trials testing the effects of periodontal therapy on systemic health outcomes were conflicting and inconsistent. While there has been a great deal of progress, we highlight lessons learned and make comments and suggestions on a number of key aspects, including the heterogeneity of case definitions of periodontal disease across studies, accounting for features of the periodontal phenotype that are most relevant to the biological link between periodontitis and systemic outcomes, the role of other comorbid inflammatory conditions, selection of study participants, and timing and intensity of the periodontal intervention.

PURPOSE:Denture stomatitis is a common condition manifested by inflammation of the oral mucous membrane beneath a denture. The objective of this study was to compare the transcriptome of human palatal mucosa with chronic oral stomatitis-associated Candida albicans infection to that of healthy oral mucosa. MATERIALS AND METHODS:Oral palatal biopsies were obtained from 17 healthy and 15 C. albicans-infected stomatitis subjects for whole transcriptome analyses. The presence of C. albicans was confirmed by cytology and cultivable methods. The clinical severity of the stomatitis was evaluated by the Newton Classification (Class II or III). For transcriptome analyses a false discovery rate (FDR) of <0.05 was used, and the effects of age, race, and gender were evaluated by principle component analysis (PCA). Specific differentially expressed genes identified by mRNA array data were confirmed by measurements of salivary protein expression using multiplex analyses. RESULTS:Microarray analysis of mRNA expression indicated that in C. albicans stomatitis there were 3034 genes-in-play that were differentially expressed and met the FDR < 0.05 criteria. Two hundred thirty five (235) genes were up-regulated >2-fold, and 71 genes were down-regulated >2-fold. Five of the 6 most significant gene ontology pathways involve inflammation and activation of the immune response with CD28 and CTLA signaling of T cells. There was strong up-regulation of TLR2, CD14, MYD88, IKKA, and NFKB as the dominant toll-like receptor-signaling pathway. The expression of several extracellularly expressed inflammatory protein genes was up-regulated in candidiasis, and 2 were confirmed as up-regulated within the saliva using protein multiplexing analyses. CONCLUSIONS:Neutrophil recruitment and activation, epithelial suppression, and T-cell activation appear as major pathways in chronic oral candidiasis. Tissue up-regulation of TLR2 pathways, as well as potential C. albicans binding proteins, was observed, whereas keratin and adhesion molecule synthesis were down-regulated. Several candidate biomarkers to potentially identify the presence of oral candidiasis were differentially expressed in tissues and saliva.

BACKGROUNDThis study uses multiple, contemporary methodologies to expand our knowledge of the temporal relationship between host-microbial interactions and clinical signs of gingivitis.METHODSSubgingival plaque and crevicular fluid samples were collected from 31 systemically healthy adults with naturally occurring plaque-induced gingivitis. Professional prophylaxis was administered and participants were followed over 7 weeks. Microbial characterization was performed using a bead-based hybridization assay and cytokine analysis using bead-based flow cytometry.RESULTSThe provision of sequential interventions, oral hygiene instruction, and subsequent professional prophylaxis brought about significant reduction of plaque and resolution of gingivitis at all post baseline time points (P < 0.0001). Candidate cytokines that increased significantly (95% level) were interleukin (IL)-1β, matrix metalloproteinases (MMP)-1, MMP-3, MMP-8, MMP-9, from baseline to week 2; regulated on activation, normal T cell expressed and secreted (RANTES) at week 4 and week 8; macrophage inflammatory protein (MIP)-1α and MIP-1β at week 8. Resolution of inflammation was accompanied by a shift in the microbiological flora toward those species associated with health.CONCLUSIONSThis study provides further evidence of the dynamic relationships that exist between the overt clinical signs, the microbial biofilm, and the host response in gingivitis and upon resolution following clinical interventions. Understanding the interactions between the host immune system and subgingival microbial communities during the resolution of established gingivitis continues to evolve as additional knowledge is achieved through using new analytical technologies. The present study confirms a critical effect of oral hygiene measures on restoration of microbial eubiosis in subgingival communities, confirming the important role for home care and professional intervention in maintaining oral health.

Porous tantalum trabecular metal (PTTM) has long been used in orthopedics to enhance neovascularization, wound healing, and osteogenesis; recently, it has been incorporated into titanium alloy dental implants. However, little is known about the biological responses to PTTM in the human oral cavity. We have hypothesized that, compared with conventional titanium alloy, PTTM has a greater expression of genes specific to neovascularization, wound healing, and osteogenesis during the initial healing period. Twelve subjects requiring at least 4 implants in the mandible were enrolled. Four 3 × 5mm devices, including 2 titanium alloy tapered screws and 2 PTTM cylinders, were placed in the edentulous mandibular areas using a split-mouth design. One device in each group was trephined for analysis at 2 and 4 weeks after placement. RNA microarray analysis and ingenuity pathway analysis were used to analyze osteogenesis gene expression and relevant signaling pathways. Compared to titanium alloy, PTTM samples exhibited significantly higher expressions of genes specific to cell neovascularization, wound healing, and osteogenesis. Several genes-including bone morphogenic proteins, collagens, and growth factors-were upregulated in the PTTM group compared to the titanium alloy control. PTTM materials may enhance the initial healing of dental implants by modifying gene expression profiles.

Epigenetic factors are heritable genome modifications that potentially impact gene transcription, contributing to disease states. Epigenetic marks play an important role in chronic inflammatory conditions, as observed in periodontal diseases, by allowing microbial persistence or by permitting microbial insult to play a role in the so-called 'hit-and-run' infectious mechanism, leading to lasting pathogen interference with the host genome. Epigenetics also affects the health sciences by providing a dynamic mechanistic framework to explain the way in which environmental and behavioral factors interact with the genome to alter disease risk. In this article we review current knowledge of epigenome regulation in light of the multifactorial nature of periodontal diseases. We discuss epigenetic tagging in identified genes, and consider the potential implications of epigenetic changes on host-microbiome dynamics in chronic inflammatory states and in response to environmental stressors. The most recent advances in genomic technologies have placed us in a position to analyze interaction effects (eg, between periodontal disease and type 2 diabetes mellitus), which can be investigated through epigenome-wide association analysis. Finally, because of the individualized traits of epigenetic biomarkers, pharmacoepigenomic perspectives are also considered as potentially novel therapeutic approaches for improving periodontal disease status.

Background:While evidence is increasingly consistent with a positive association between periodontitis and cancer risk, most studies have relied on self-reported periodontitis. In this study, we prospectively evaluated the association of periodontal disease severity with cancer risk in black and white older adults in a cohort study that included a dental examination. Methods:Included were 7466 participants in the Atherosclerosis Risk in Communities study cohort who at visit 4 (1996-1998) reported being edentulous or underwent the dental examination. Probing depth and gingival recession were measured at six sites on all teeth; these measurements were used to define periodontal disease severity. Incident cancers (n = 1648) and cancer deaths (n = 547) were ascertained during a median of 14.7 years of follow-up. All statistical tests were two-sided. Results:An increased risk of total cancer (hazard ratio [HR] = 1.24, 95% confidence interval [CI] = 1.07 to 1.44, Ptrend = .004) was observed for severe periodontitis (>30% of sites with attachment loss >3 mm) compared with no/mild periodontitis (<10% of sites with attachment loss >3 mm), adjusting for smoking and other factors. Strong associations were observed for lung cancer (HR = 2.33, 95% CI = 1.51 to 3.60, Ptrend < .001), and elevated risks were noted for colorectal cancer for severe periodontitis, which were significant among never smokers (HR = 2.12, 95% CI = 1.00 to 4.47). Associations were generally weaker, or not apparent among black participants, except for lung and colorectal cancers, where associations were similar by race. No associations were observed for breast, prostate, or hematopoietic and lymphatic cancer risk. Conclusions:This study provides additional evidence that cancer risk, especially for lung and colorectal cancer, is elevated in individuals with periodontitis. Additional research is needed to understand cancer site-specific and racial differences in findings.

Introduction and Hypothesis: Intracranial Atherosclerotic Stenosis (ICAS) is associated with 8-10% of all strokes in the U.S. Although there is evidence in the Asian population that inflammation plays a role in ICAS, it has not been shown in the U.S. population. We hypothesized that midlife sensitivity C-reactive protein (hs-CRP), a marker of inflammation, is associated with late-life ICAS in the U.S. population. Methods: The Atherosclerosis Risk in Communities (ARIC) study recruited participants from four U.S. communities between 1987-1989. In the ancillary Dental ARIC study, dentate subjects from ARIC undergoing full-mouth examination also had blood samples obtained to measure the serum inflammatory marker, hs-CRP (1996-1998). High sensitivity ELISA assay that had been validated against nephelometry, was used to measure hs-CRP. Of this cohort, a subset (N=909) underwent high resolution 3T magnetic resonance angiogram at a follow-up visit (2011-2013). All images were analyzed in a centralized lab and ICAS was graded as no stenosis/<50% stenosis, or ≥50% stenosis/complete occlusion. Crude and adjusted Odds Ratio (OR, adjusted for age, gender, race, body mass index, hypertension, diabetes, low density lipoprotein level, and smoking) were calculated to test the association between hs-CRP (stratified as <1, 1-3 and >3 mg/l), and ICAS. Results: A total of 909 subjects (mean age 62±6, 45% male, 81% Caucasian and 19% African-American), underwent assessment of hs-CRP and ICAS. Compared with the reference group (hs-CRP <1 mg/l) modestly elevated hs-CRP (1-3 mg/l) was not significantly associated with >50% ICAS, on univariate (Crude OR 1.3 95% CI: 0.9-2.0) or multivariable analysis (Adjusted OR 1.3, 95% CI: 0.9-2.0). Elevated hs-CRP (>3mg/l) was significantly associated with >50% ICAS in both univariate (Crude OR 1.6, 95% CI:1.1-2.3) and adjusted model (Adjusted OR 1.6, 95% CI:1.1-2.4). Conclusions: In this US population-based community study, we report a significant and independent association between inflammatory marker hs-CRP and ICAS. Further studies are required to test if anti-inflammatory drugs or diet prevents ICAS.