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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. Il10-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 M1-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.

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., Graphical abstract

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.

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.

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.

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.

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-m ediated 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.

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 &lt, 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.

Periodontitis is one of the most common inflammatory diseases, with a prevalence of 11% worldwide for the severe forms and an estimated heritability of 50%. It is classified into the widespread moderate form chronic periodontitis (CP) and the rare early-onset and severe phenotype aggressive periodontitis (AgP). These different disease manifestations are thought to share risk alleles and predisposing environmental factors. To obtain novel insights into the shared genetic etiology and the underlying molecular mechanisms of both forms, we performed a two step-wise meta-analysis approach using genome-wide association studies of both phenotypes. Genotypes from imputed genome-wide association studies (GWAS) of AgP and CP comprising 5,095 cases and 9,908 controls of North-West European genetic background were included. Two loci were associated with periodontitis at a genome-wide significance level. They located within the pseudogene MTND1P5 on chromosome 8 (rs16870060-G, P = 3.69 × 10(−9), OR = 1.36, 95% CI = [1.23–1.51]) and intronic of the long intergenic non-coding RNA LOC107984137 on chromosome 16, downstream of the gene SHISA9 (rs729876-T, P = 9.77 × 10(−9), OR = 1.24, 95% CI = [1.15–1.34]). This study identified novel risk loci of periodontitis, adding to the genetic basis of AgP and CP.

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.

Non-alcoholic fatty liver disease (NAFLD) prevalence is greater among Hispanics/Latinos than other racial/ethnic groups and prevalence is further reported to vary among Hispanic/Latino background groups. Experimental animal and human studies demonstrate associations between periodontitis and NAFLD, not yet reported among Hispanics/Latinos. This study examined periodontitis as a novel risk factor that may contribute to the burden of NAFLD among Hispanics/Latinos.Data came from 11,914 participants of the Hispanic Community Health Study/Study of Latinos. Periodontitis was defined as the extent (none, 30%, ≥30%) of periodontal sites with clinical attachment level (CAL) of ≥3 mm or probing pocket depth (PD) of ≥4 mm. Elevated serum transaminases indicative of suspected NAFLD were defined as having alanine aminotransferase levels (ALT) 40 IU/L or aspartate aminotransferase (AST) 37 IU/L for men and ALT 31 IU/L or AST 31 IU/L for women. Survey-logistic regression models estimated prevalence odds ratios (POR) and 95% confidence intervals (CI) for the association between periodontitis and suspected NAFLD.The overall age-standardized percentage of study participants with 30% of sites with CAL ≥3 mm or PD ≥4 mm was 53.5% and 58.6%, respectively, while participants with ≥30% sites with CAL ≥3 mm or PD ≥4 mm comprised 16% and 5.72%, respectively. The overall age-standardized prevalence (95% CI) of suspected NAFLD was 18.1% (17.1-19.0). For the entire cohort, we observed a dose-response (i.e. graded) association between PD ≥4 mm and the prevalence odds of suspected NAFLD, whereby participants with 30% affected had a crude POR = 1.19 (95% CI: 1.03, 1.38) while participants with ≥30% affected had a crude POR = 1.39 (95% CI: 1.02, 1.90). These crude estimates were attenuated toward the null and rendered non-significant upon covariate adjustment. No differences were found by Hispanic/Latino background group.Previously reported associations between periodontitis and NAFLD were marginal to null in this study of a diverse group of Hispanics/Latinos.

A new periodontitis classification scheme has been adopted, in which forms of the disease previously recognized as "chronic" or "aggressive" are now grouped under a single category ("periodontitis") and are further characterized based on a multi-dimensional staging and grading system. Staging is largely dependent upon the severity of disease at presentation as well as on the complexity of disease management, while grading provides supplemental information about biological features of the disease including a history-based analysis of the rate of periodontitis progression; assessment of the risk for further progression; analysis of possible poor outcomes of treatment; and assessment of the risk that the disease or its treatment may negatively affect the general health of the patient. Necrotizing periodontal diseases, whose characteristic clinical phenotype includes typical features (papilla necrosis, bleeding, and pain) and are associated with host immune response impairments, remain a distinct periodontitis category. Endodontic-periodontal lesions, defined by a pathological communication between the pulpal and periodontal tissues at a given tooth, occur in either an acute or a chronic form, and are classified according to signs and symptoms that have direct impact on their prognosis and treatment. Periodontal abscesses are defined as acute lesions characterized by localized accumulation of pus within the gingival wall of the periodontal pocket/sulcus, rapid tissue destruction and are associated with risk for systemic dissemination.

The purpose of this study was to evaluate the associations between interdental cleaning behavior and the prevalence of caries and periodontal disease and numbers of missing teeth, with data from the National Health and Nutrition Examination Survey (2011 to 2012 and 2013 to 2014). Analysis included the following parameters: interproximal clinical attachment level (iCAL) ≥3 mm, interproximal probing depth (iPD) ≥4 mm, number of coronal and interproximal caries, number of missing teeth, ≥1 surfaces with coronal caries, and periodontal profile classes (PPCs). Chi-square was used for bivariate associations. Associations of interdental cleaning with outcomes were assessed with multiple linear regression and generalized logit regression, adjusting for age, race, sex, diabetes, smoking, education, dental visits, and sugar consumption. Nonusers had a significantly higher percentage of sites with iCAL ≥3 mm and iPD ≥4 mm as compared with individuals who used interdental cleaning devices ( P < 0.0001). Individuals with a higher frequency of cleaning (4 to 7×/wk) had a significantly lower extent of sites with iCAL ≥3 mm as compared with lower-frequency cleaning (1 to 3×/wk; P ≤ 0.05). Interdental cleaning users showed lower numbers of coronal caries, interproximal coronal caries, and missing teeth as compared with nonusers ( P < 0.0001). Nonusers had 1.73-times (95% confidence interval, 1.53 to 1.94) higher odds for having ≥1 surfaces of coronal caries as compared with interdental cleaning users, regardless of the weekly frequency. Individuals were less likely to be in diseased PPCs if they were interdental cleaning users. Low-frequency cleaners (1 to 3×/wk) had significantly greater odds (1.43; 95% confidence interval, 1.08 to 1.88) to have severe disease (PPC-G) versus health (PPC-A) than were high-frequency cleaners (4 to 7×/wk). Interdental cleaning users showed lower levels of periodontal disease and caries and lower numbers of missing teeth. Higher frequency of interdental cleaning was correlated with increased periodontal health. Individuals with severe periodontal disease could show additional oral health benefits by increasing cleaning frequency. The data support the use of interdental cleaning devices as an oral hygiene behavior for promoting health.

Background and Purpose— Periodontal disease is independently associated with cardiovascular disease. Identification of periodontal disease as a risk factor for incident ischemic stroke raises the possibility that regular dental care utilization may reduce the stroke risk. Methods— In the ARIC (Atherosclerosis Risk in Communities) study, pattern of dental visits were classified as regular or episodic dental care users. In the ancillary dental ARIC study, selected subjects from ARIC underwent fullmouth periodontal measurements collected at 6 sites per tooth and classified into 7 periodontal profile classes (PPCs). Results— In the ARIC study 10 362 stroke-free participants, 584 participants had incident ischemic strokes over a 15-year period. In the dental ARIC study, 6736 dentate subjects were assessed for periodontal disease status using PPC with a total of 299 incident ischemic strokes over the 15-year period. The 7 levels of PPC showed a trend toward an increased stroke risk (χ 2 trend P Conclusions— We confirm an independent association between periodontal disease and incident stroke risk, particularly cardioembolic and thrombotic stroke subtype. Further, we report that regular dental care utilization may lower this risk for stroke.

Background Current periodontal disease taxonomies have limited utility for predicting disease progression and tooth loss; in fact, tooth loss itself can undermine precise person-level periodontal disease classifications. To overcome this limitation, the current group recently introduced a novel patient stratification system using latent class analyses of clinical parameters, including patterns of missing teeth. This investigation sought to determine the clinical utility of the Periodontal Profile Classes and Tooth Profile Classes (PPC/TPC) taxonomy for risk assessment, specifically for predicting periodontal disease progression and incident tooth loss. Methods The analytic sample comprised 4,682 adult participants of two prospective cohort studies (Dental Atherosclerosis Risk in Communities Study and Piedmont Dental Study) with information on periodontal disease progression and incident tooth loss. The PPC/TPC taxonomy includes seven distinct PPCs (person-level disease pattern and severity) and seven TPCs (tooth-level disease). Logistic regression modeling was used to estimate relative risks (RR) and 95% confidence intervals (CI) for the association of these latent classes with disease progression and incident tooth loss, adjusting for examination center, race, sex, age, diabetes, and smoking. To obtain personalized outcome propensities, risk estimates associated with each participant's PPC and TPC were combined into person-level composite risk scores (Index of Periodontal Risk [IPR]). Results Individuals in two PPCs (PPC-G: Severe Disease and PPC-D: Tooth Loss) had the highest tooth loss risk (RR = 3.6; 95% CI = 2.6 to 5.0 and RR = 3.8; 95% CI = 2.9 to 5.1, respectively). PPC-G also had the highest risk for periodontitis progression (RR = 5.7; 95% CI = 2.2 to 14.7). Personalized IPR scores were positively associated with both periodontitis progression and tooth loss. Conclusions These findings, upon additional validation, suggest that the periodontal/tooth profile classes and the derived personalized propensity scores provide clinical periodontal definitions that reflect disease patterns in the population and offer a useful system for patient stratification that is predictive for disease progression and tooth loss.

Aim Several papers have considered the potential relationship between periodontitis and lipid parameters. The present systematic review, meta-analysis and meta-regression study focused on investigating whether serum lipid parameter levels were elevated in patients with periodontal disease (PD) (without altered systemic conditions) in comparison with periodontally healthy subjects. Materials and Methods Eligible studies were those with data about serum lipid parameter levels in non-smoking subjects with and without chronic periodontitis, who are generally healthy and not taking any medication for dyslipidemia. Mean differences and 95% confidence intervals for total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol were obtained from all the selected studies. Results 19 publications were included for meta-analysis. Participants with chronic periodontitis presented significantly higher serum levels of LDL and triglycerides (p=0.003 and p

Background Periodontal disease (PD) is associated with recurrent vascular event in stroke or transient ischemic attack (TIA). In this study, we investigated whether PD is independently associated with aortic arch atheroma (AA). We also explored the relationship PD has with AA plaque thickness and other characteristics associated with atheroembolic risk among patients with stroke or TIA. Finally, we confirmed the association between AA and recurrent vascular event in patients with stroke or TIA. Methods In this prospective longitudinal hospital-based cohort study, PD was assessed in patients with stroke and TIA. Patients with confirmed stroke and TIA (n = 106) were assessed by calibrated dental examiners to determine periodontal status and were followed over a median of 24 months for recurrent vascular events (stroke, myocardial infarction, and death). The extent of AA and other plaque characteristics was assessed by transesophageal echocardiography. Results Within our patient cohort, 27 of the 106 participants had recurrent vascular events (including 16 with stroke or TIA) over the median of 24-month follow-up. Severe PD was associated with increased AA plaque thickness and calcification. The results suggest that PD may be a risk factor for AA. In this cohort, we confirm the association of severe AA with recurrent vascular events. Conclusions In patients with stroke or TIA, severe PD is associated with increased AA plaque thickness, a risk factor for recurrent events. Further studies are needed to confirm this finding and to determine whether treatment of PD can reduce the rate of AA plaque progression and recurrent vascular events.

An association between periodontitis and nonalcoholic fatty liver disease (NAFLD) has been reported by experimental animal and epidemiologic studies. This study investigated whether circulating levels of serum C-reactive protein (CRP) and a weighted genetic CRP score representing markers of inflammatory burden modify the association between periodontitis and NAFLD. Data came from 2,481 participants of the Study of Health in Pomerania who attended baseline examination that occurred between 1997 and 2001. Periodontitis was defined as the percentage of sites (0%, 3 mg/L. Periodontitis was positively associated with higher prevalence odds of NAFLD, and this relationship was modified by serum CRP levels.

Objective To investigate racial differences in the associations between periodontitis and 10-year self-reported incident tooth loss in a biracial, community-based cohort of US late middle-aged and older adults. Methods Subjects were 3,466 dentate men and women aged 53-74 who underwent dental examinations from 1996 to1998. In 2012-2013, telephone interviewers asked participants about tooth loss in the preceding 10 years. Separate multivariable ordinal logistic regression models were used to calculate proportional odds ratios (OR) and 95% confidence intervals (CI) as estimates of association between periodontitis and tooth loss for Whites and African-Americans (AAs). Results The majority of participants were White (85 percent) and female (57 percent) with 23 teeth on average at enrollment. Approximately half the Whites (56 percent) and AAs (49 percent) had periodontitis. At follow-up, approximately 44 percent of AAs and 38 percent of Whites reported having lost ≥1 tooth. In multivariable models, severe periodontitis (OR = 3.03; 95% CI = 2.42-3.80) and moderate periodontitis (OR = 1.64; 95% CI= 1.39-1.94) were significant risk factors of incident tooth loss among Whites. For AAs, severe but not moderate periodontitis increased the odds of incident tooth loss (OR = 2.22; 95% CI = 1.37-3.59). In the final model, education was inversely associated with incident tooth loss among AAs, while lower income was associated with greater odds of tooth loss among Whites. Conclusions In this population-based cohort, there is racial heterogeneity in the association between periodontitis and tooth loss. Interventions to reduce the impact of periodontitis on tooth loss need to consider these differences.

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.

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 P. gingivalis-infected chamber once a day for three 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.

Objectives Previous 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). Methods ARIC 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. Results Among 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. Conclusions Our results do not support an independent association between ET and development of CHD, IS, HF, or VTE.

AimThe intronic variant rs4252120 in the plasminogen gene (PLG) is known to be associated with aggressive periodontitis (AgP) and atherosclerosis. Here, we examined the chromosomal region spanning PLG for associations with both chronic periodontitis (CP) and AgP. Materials and MethodsThe association of PLG candidate rs4252120 was tested in a German case–control sample of 1,419 CP cases using the genotyping assay hCV11225947 and 4,562 controls, genotyped with HumanOmni BeadChips. The German and Dutch sample of AgP cases (N = 851) and controls (N = 6,836) were genotyped with HumanOmni BeadChips. The North American CP sample (N = 2,681 cases, 1,823 controls) was previously genotyped on the Genome‐Wide Human SNP Array 6.0. Genotypes were imputed (software Impute v2), and association tests were performed using an additive genetic model adjusting for sex and smoking. ResultsRs4252120 was not associated with CP. However, a haplotype block downstream of PLG and not in linkage disequilibrium with rs4252120 (r2 = .08) was associated with both AgP (rs1247559; p = .002, odds ratio [OR] = 1.33) and CP (p = .02, OR = 1.15). That locus was also significantly associated with PLG expression in osteoblasts (p = 6.9 × 10−5). ConclusionsOur findings support a role of genetic variants in PLG in the aetiology of periodontitis.

An increasing body of evidence suggests a significant genetic regulation of inflammatory response mechanisms; however, little is known regarding the genetic determinants of severe gingival inflammation (GI). We conducted a genome-wide association study of severe GI among 4,077 European American adults, participants in the Dental Atherosclerosis Risk in Communities cohort. The severe GI trait was defined dichotomously with the 90th percentile of gingival index ≥2 extent score. Genotyping was performed with the Affymetrix 6.0 array platform, and an imputed set of 2.5 million markers, based on HapMap Phase II CEU build 36, was interrogated. Genetic models were based on logistic regression and controlled for ancestry (10 principal components), sex, age, and examination center. One locus on chromosome 17 met genome-wide statistical significance criteria—lead single-nucleotide polymorphism: rs11652874 (minor allele frequency = 0.06, intronic to ASIC2 [acid-sensing ionic channel 2, formerly named ACCN1]; odds ratio = 2.1, 95% confidence interval = 1.6 to 2.7, P = 3.9 × 10-8). This association persisted among subjects with severe periodontitis and was robust to adjustment for microbial plaque index. Moreover, the minor (G) allele was associated with higher levels of severe GI in stratified analyses among subsets of participants with high load of either “red” or “orange” complex pathogens, although this association was not statistically significant. While these results will require replication in independent samples and confirmation by mechanistic studies, this locus appears as a promising candidate for severe GI. Our findings suggest that genetic variation in ASIC2 is significantly associated with severe GI and that the association is plaque independent. Knowledge Transfer Statement: Persistent gingival inflammation reflected by bleeding usually precedes ongoing attachment loss or periodontal disease progression. Our findings suggest that genetic variation in ASIC2 that is associated with severe gingival inflammation might be used as a genetic marker to identify people at higher risk for periodontal disease. Ongoing studies to uncover the mechanistic link between ASIC2 and gingival inflammation could lead to novel therapeutic interventions.

Genome-wide association studies (GWAS) of chronic periodontitis (CP) defined by clinical criteria alone have had modest success to-date. Here, we refine the CP phenotype by supplementing clinical data with biological intermediates of microbial burden (levels of eight periodontal pathogens) and local inflammatory response (gingival crevicular fluid IL-1β) and derive periodontal complex traits (PCTs) via principal component analysis. PCTs were carried forward to GWAS (∼2.5 million markers) to identify PCT-associated loci among 975 European American adult participants of the Dental ARIC study. We sought to validate these findings for CP in the larger ARIC cohort (n = 821 participants with severe CP, 2031-moderate CP, 1914-healthy/mild disease) and an independent German sample including 717 aggressive periodontitis cases and 4210 controls. We identified six PCTs with distinct microbial community/IL-1β structures, although with overlapping clinical presentations. PCT1 was characterized by a uniformly high pathogen load, whereas PCT3 and PCT5 were dominated by Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis, respectively. We detected genome-wide significant signals for PCT1 (CLEC19A, TRA, GGTA2P, TM9SF2, IFI16, RBMS3), PCT4 (HPVC1) and PCT5 (SLC15A4, PKP2, SNRPN). Overall, the highlighted loci included genes associated with immune response and epithelial barrier function. With the exception of associations of BEGAIN with severe and UBE3D with moderate CP, no other loci were associated with CP in ARIC or aggressive periodontitis in the German sample. Although not associated with current clinically determined periodontal disease taxonomies, upon replication and mechanistic validation these candidate loci may highlight dysbiotic microbial community structures and altered inflammatory/immune responses underlying biological sub-types of CP.

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.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) of0.05 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.Microarray analysis of mRNA expression indicated that in C. albicans stomatitis there were 3034 genes-in-play that were differentially expressed and met the FDR0.05 criteria. Two hundred thirty five (235) genes were up-regulated2-fold, and 71 genes were down-regulated2-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.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.

Aim Periodontal disease is a cardiovascular disease (CVD) risk factor but few studies have considered the relationship between periodontal disease and venous thromboembolism (VTE). We hypothesized that periodontal disease is independently associated with increased risk of incident VTE. Materials and methods We used data from 8,092 participants of the Atherosclerosis Risk in Communities (ARIC) study to examine periodontal disease in 1996-1998 and incident VTE through 2011. Periodontal disease was determined using self-reported tooth loss due to gum disease and dental examinations. Cox proportional hazards regression models were used to estimate hazard ratios for VTE and 95% confidence intervals adjusted for relevant confounders. Results and conclusions Participants were on average 62.7 years old at baseline and 13.9% self-reported tooth loss from gum disease. Over a mean of 12.9 years of follow-up, there were 313 incident VTE events. Self-reported tooth loss due to gum disease was associated with 30% higher VTE risk (HR = 1.29 (0.96, 1.73) after adjusting demographic factors, SES, periodontal risk factors, oral hygiene, and access to dental care variables. No statistically significant associations between clinical measures of periodontitis and VTE were observed after adjustment. Further research is needed to elucidate whether a relationship between periodontal disease and VTE exists.

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.

Periodontal diseases are Gram-negative anaerobic infections that can occur in women of childbearing age (18 to 34 years). In the present investigation we sought to determine whether the prevalence of maternal periodontal infection could be associated with preterm low birth weight (PLBW), controlling for known risk factors and potential covariates. A case-control study of 124 pregnant or postpartum mothers was performed. PLBW cases were defined as a mother with a birth of less than 2,500 g and one or more of the following: gestational age

This paper was prepared by the Research, Science and Therapy Committee of the American Academy of Periodontology. It is intended to provide information for the dental profession and other interested parties. The purpose of this paper is to provide a general overview of oral reconstructive and corrective procedures used in periodontal therapy. It is not intended to be a comprehensive review of this subject.

BACKGROUND This study uses multiple, contemporary methodologies to expand our knowledge of the temporal relationship between host-microbial interactions and clinical signs of gingivitis. METHODS Subgingival 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. RESULTS The 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

BACKGROUND This paper focuses on the Periodontal Profile Class (PPC) System that may be more informative and representative of periodontitis phenotypes than current case definitions of periodontitis. This study illustrates the unique aspects of the PPC compared with other periodontal indices for studying associations between periodontal disease and prevalent systemic conditions. METHODS We computed odds ratios and 95% confidence intervals to compare associations between periodontal disease and prevalent systemic conditions using our new PPC and two traditional indices. We used the Bayesian Information Criterion (BIC) to determine the fit of the model and the magnitude of the contribution attributable to periodontal disease beyond traditional risk factors. The Atherosclerosis Risk in Communities (ARIC) Study (1996-1998) results were compared with results from the combined National Health and Nutrition Examination Survey 2009-2014 datasets. RESULTS In the ARIC Study, high gingival inflammation, tooth loss, severe tooth loss, and severe disease PPC components were significantly associated with diabetes, coronary heart disease (CHD), high-sensitivity C-reactive protein, and interleukin (IL)-6, while only severe disease was associated with stroke. Severe disease was associated with CHD using the Centers for Disease Control/American Academy of Periodontology index, and the European Periodontal index was associated with CHD and IL-6. CONCLUSIONS The addition of the PPC to traditional variables associated with prevalent diabetes, stroke, CHD, and systemic measures of inflammation resulted in very strong improvement of the overall models, while the traditional indices were less likely to be associated and, if present, the associations were weaker. The PPC system provides specific insight into the individuals and periodontal characteristics of the phenotype that are associated with systemic conditions that may be useful in designing treatment interventions.

Background This paper focuses on Periodontal Profile Class (PPC), a component of the Periodontal Profile Phenotype (P3 ) System that may be more representative of the periodontitis phenotype than current case definitions of periodontitis. Data illustrate the unique aspects of the PPC compared with other commonly used periodontal classification indices. Methods Latent Class Analysis (LCA) identified discrete classes of individuals grouped by tooth-level clinical parameters. The analysis defined seven distinct periodontal profile classes (PPC A through G) and seven distinct tooth profile classes (TPC A through G). This LCA classification was an entirely data-derived agnostic process without any preconceived presumptions of what constituted disease. Results Comparing the PPC with the Centers for Disease Control/American Academy of Periodontology (CDC/AAP) and European indices, the PPC is unique in that it contains four disease classes not traditionally used. Less than half of individuals classified as Healthy by both the CDC/AAP and European indices were Healthy using the PPC. About 25% of those classified as Severe by CDC/AAP and European indices were PPC-Severe. The remainder spread out over the High Gingival Index, Posterior Disease, Tooth Loss, and Severe Tooth Loss phenotypes. Conclusions The PPC classification provides a significant departure from the traditional clinical case status indices that have been used, but has resulted in clinical phenotypes that are quite familiar to most clinicians who take notice of the distribution of missing teeth, areas of recession, diminished periodontal support, and other aspects of the dentition while conducting a periodontal examination. The mutually exclusive categories provided by the PPC system provide periodontal clinical summaries that can be an important component of precision dentistry.

Purpose To determine the prevalence of third molars in the US population and to report the differences in prevalence of visible third molars in the most recent National Health and Nutrition Examination Survey (NHANES) population of 2011 through 2012 by participant, jaw, and demographics. Materials and Methods The number of visible third molars in the NHANES data was assessed in nonclinical settings by trained, calibrated dental hygienists by decade of age beginning in the 20- to 29-year-old cohort through the 70- to 79-year-old cohort. Cross-sectional analyses of third molar data were conducted by the authors from the NHANES databases of 2001 through 2002, 2009 through 2010, and 2011 through 2012 to compare data for similarity of outcomes on third molar prevalence in the US population. Outcomes on third molar prevalence also were assessed from the NHANES of 2011 through 2012 by participant, jaw, and demographics: gender, race or ethnicity (Caucasian, African American, other), and education (less than high school, high school graduate, some college, college graduate). Results Data on the mean number of third molars from NHANES of 2001 through 2002, 2009 through 2010, and 2011 through 2012 were similar. The number of visible third molars in the NHANES of 2011 through 2012 decreased progressively from a mean of 1.48 in the 20- to 29-year-old cohort to 0.81 in the 60- to 69-year-old cohort, No visible third molars were observed in 47% of the 20- to 29-year-old cohort compared with 53% in the 50- to 59-year-old cohort. Participants who were male, non-Caucasian, and had less than a high school education were more likely to have a visible third molar in all age cohorts. No data were collected by NHANES examiners to determine why third molars were absent. Conclusion Third molar prevalence did not appear to differ in the US population during the first decade of the 21st century. Numbers of visible third molars, prevalent in young adults, decreased progressively through each successive age cohort. Demographic differences exist for prevalence of third molars in the US population.

In a previous report, we demonstrated the inverse association of high serum 8-isoprostane levels, a marker for oxidative stress, with decreased serum IgG antibodies to oral bacteria. The association between increased serum IgG with increased plaque and periodontitis (increased probing depths) was attenuated by high systemic oxidative stress. Other investigations have reported a role for systemic oxidative stress as a stimulus of hepatic C-reactive protein (CRP) response. These observations led us to hypothesize that the reported relationship of periodontitis to elevated serum CRP, a systemic inflammatory marker, may be modified by oxidative stress and that the levels of serum antibodies to oral bacteria might be an intermediary explanatory variable linking the association of systemic oxidative stress, periodontal disease, and levels of CRP. This hypothesis was explored as a secondary analysis of the Dental ARIC (Atherosclerosis Risk in Communities) study using serum levels of CRP, serum IgG levels to 16 oral organisms, serum levels of 8-isoprostane, and periodontal status. The findings indicate periodontitis is associated with high CRP in the presence of elevated oxidative stress that serves to suppress the IgG response. Only within the highest 8-isoprostane quartile was periodontitis (pocket depth) associated with increased serum CRP levels ( P = 0.0003). Increased serum IgG antibody levels to oral bacteria were associated with lowered serum CRP levels. Thus, systemic oxidative stress, which has been demonstrated to be associated with increased levels of CRP in other studies, appears to be associated with the suppression of bacterial-specific IgG levels, which in the presence of periodontal disease can result in an enhanced systemic CRP response. Conversely, individuals with increased serum IgG antibodies to plaque bacteria exhibit lowered serum CRP levels. These 2 factors, oxidative stress and the serum IgG response, appear to function in opposing directions to modify serum levels of CRP and the association with periodontitis.

Objective To assess whether partial-mouth protocols (PRPs) result in biased estimates of the associations between smoking, alcohol, obesity and diabetes with periodontitis. Methods Using a sample (n = 6129) of the 1996–1998 Atherosclerosis Risk in Communities study, we used measures of probing pocket depth and clinical attachment level to identify moderate-severe periodontitis. Adjusting for confounders, unconditional binary logistic regression estimated prevalence odds ratios (POR) and 95% confidence limits. Specifically, we compared POR for smoking, alcohol, obesity and diabetes with periodontitis derived from full-mouth to those derived from 4-PRPs (Ramfjord, National Health and Nutrition Examination survey-III, modified-NHANES-IV and 42-site-Random-site selection-method). Finally, we conducted a simple sensitivity analysis of periodontitis misclassification by changing the case definition threshold for each PRP. Results In comparison to full-mouth PORs, PRP PORs were biased in terms of magnitude and direction. Holding the full-mouth case definition at moderate-severe periodontitis and setting it at mild-moderate-severe for the PRPs did not consistently produce POR estimates that were either biased towards or away from the null in comparison to full-mouth estimates. Conclusions Partial-mouth protocols result in misclassification of periodontitis and may bias epidemiologic measures of association. The magnitude and direction of this bias depends on choice of PRP and case definition threshold used.

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/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 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.

We evaluated whether first-trimester high-sensitivity C-reactive protein (hsCRP), a suggested marker of pregnancy-associated hyperglycemia, predicts third-trimester impaired glucose tolerance (IGT) in a secondary analysis of a prospective cohort of nondiabetic singletons enrolled at26 weeks gestation.We measured the association between hsCRP collected at14 weeks among women classified as IGT (gestational diabetes screening results, 135 to200 mg/dL) and those among normoglycemic women. Multivariable modeling estimated the association between log hsCRP and IGT, adjusted for maternal body mass index (BMI).Among 300 women, 13% (39 of 300) had IGT. The hsCRP was positively associated with glucose (P = .005). Compared with normoglycemic women, women with IGT had higher log hsCRP (0.87 ± 0.66 vs 0.67 ± 0.60, P = .04), but the association was not significant in adjusted models (adjusted odds ratio 1.20, 95% confidence interval 0.65-2.21). The hsCRP did not predict third-trimester IGT in this analysis when BMI is considered.Early identification of women at risk of IGT remains a priority, but the contribution of maternal BMI appears greater than hsCRP.

Background Non-alcoholic fatty liver disease (NAFLD) affects 20-30% of adults with risk factors like obesity and insulin resistance putatively acting through chronic low-grade inflammation. Because periodontitis elicits low-grade inflammation, we hypothesized that it could contribute to NAFLD occurrence. Objective To investigate epidemiologic associations between periodontitis and the incidence of NAFLD among 2,623 participants of the Study of Health in Pomerania Methods Periodontitis at baseline was defined as the percentage of sites (0%, 1-30%, ≥30%) with 1) clinical attachment level (CAL) ≥3mm; 2) probing pocket depth (PD) ≥4mm. Incident NAFLD was defined as a significant increase in liver echogenicity on ultrasound relative to the kidneys, with the diaphragm indistinct OR the echogenic walls of the portal veins invisible Results After a median 7·7 years of follow-up, 605 incident NAFLD cases occurred at a rate of 32·5 cases per 1,000 person-years. Relative to participants without CAL ≥3mm, NAFLD incidence was elevated slightly in participants with 1

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 ( 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.

An increasing body of evidence suggests a significant genetic regulation of inflammatory response mechanisms; however, little is known regarding the genetic determinants of severe gingival inflammation (GI). We conducted a genome-wide association study of severe GI among 4,077 European American adults, participants in the Dental Atherosclerosis Risk in Communities cohort. The severe GI trait was defined dichotomously with the 90th percentile of gingival index ≥2 extent score. Genotyping was performed with the Affymetrix 6.0 array platform, and an imputed set of 2.5 million markers, based on HapMap Phase II CEU build 36, was interrogated. Genetic models were based on logistic regression and controlled for ancestry (10 principal components), sex, age, and examination center. One locus on chromosome 17 met genome-wide statistical significance criteria—lead single-nucleotide polymorphism: rs11652874 (minor allele frequency = 0.06, intronic to ASIC2 [acid-sensing ionic channel 2, formerly named ACCN1]; odds ratio = 2.1, 95% confidence interval = 1.6 to 2.7, P = 3.9 × 10-8). This association persisted among subjects with severe periodontitis and was robust to adjustment for microbial plaque index. Moreover, the minor (G) allele was associated with higher levels of severe GI in stratified analyses among subsets of participants with high load of either “red” or “orange” complex pathogens, although this association was not statistically significant. While these results will require replication in independent samples and confirmation by mechanistic studies, this locus appears as a promising candidate for severe GI. Our findings suggest that genetic variation in ASIC2 is significantly associated with severe GI and that the association is plaque independent.

Objectives The long-term success of dental implants is established by literature. Although clinically well defined, the complex genetic pathways underlying osseointegration have not yet been fully elucidated. Furthermore, patients with osteopenia/osteoporosis are considered to present as higher risk for implant failure. Porous tantalum trabecular metal (PTTM), an open-cell porous biomaterial, is suggested to present enhanced biocompatibility and osteoconductivity. The goal of this study was to evaluate the expression patterns of a panel of genes closely associated with osteogenesis and wound healing in osteopenic patients receiving either traditional titanium (Ti) or PTTM cylinders to assess the pathway of genes activation in the early phases of osseointegration. Material and methods Implant cylinders made of Ti and PTTM were placed in osteopenic volunteers. At 2- and 4 weeks of healing, one Ti and one PTTM cylinder were removed from each subject for RT-PCR analysis using osteogenesis PCR array. Results Compared to Ti, PTTM-associated bone displayed upregulation of bone matrix proteins, BMP/TGF tisuperfamily, soluble ligand and integrin receptors, growth factors, and collagen genes at one or both time points. Histologically, PTTM implants displayed more robust osteogenesis deposition and maturity when compared to Ti implants from the same patient. Conclusions Our results indicate that PTTM properties could induce an earlier activation of genes associated with osteogenesis in osteopenic patients suggesting that PTTM implants may attenuate the relative risk of placing dental implants in this population.

Introduction: Prior epidemiological studies have shown that periodontal disease (PD), also referred to as gum disease, is an independent risk factor for ischemic stroke. We assessed the hypothesis that users of regular dental care may have a lower risk for incident ischemic stroke and specific stroke subtype when compared with users of episodic dental care. Methods: In this prospective, longitudinal community-based cohort study, participants without prior stroke were assessed for dental care utilization represented by patient-reported responses to questionnaires. The pattern of dental care utilization was classified as regular use (every year), episodic use (as needed), or no use (never). Episodic visits, or visits as needed, are considered signs of inadequate utilization of dental care. These participants were followed for incident ischemic strokes. Ischemic stroke diagnoses were defined as sudden onset of neurological deficit(s) lasting ≥24 hours along with neuroimaging confirmation. Strokes were further classified according to etiologic subtype as thrombotic, lacunar, or cardioembolic stroke subtype according to criteria adopted from the National Survey of Stroke. Results: Of 11,242 participants (mean age±SD=62.8±5.6, 56% female, 78% white and 22% African-American) assessed for dental care utilization at the fourth ARIC visit (1996-1998). Over a 15-year follow-up period a total of 583 participants had incident ischemic stroke events, of who 19% were lacunar, 29% were cardioembolic and 45% were of the thrombotic stroke subtype. After adjustment for confounders (race/center, age, gender, BMI, hypertension, diabetes, LDL level, smoking, and education), regular dental care utilization was associated with lower risk for ischemic stroke overall compared with episodic dental users (adjusted HR 0.77, 95% CI 0.63-0.94). Regular dental care specifically lowered the risk of thrombotic stroke subtype (adjusted HR 0.75, 95% CI 0.56-0.99). Conclusions: Results from this prospective cohort study demonstrates an independent association between regular dental care utilization with a lower ischemic stroke risk. Further, we report the highest impact of regular dental care in lowering risk of the thrombotic stroke subtype.