Induction of Prostaglandin Release from Macrophages by Bacterial Endotoxin

This review summarizes the role of the monocytic responses to lipopolysaccharide as it relates to periodontal disease severity. Data are presented which illustrate that the levels of prostaglandin E2 (PGE2) secreted by systemic peripheral blood monocytes in culture, in the presence of bacterial endotoxins, are highly correlated with the levels observed in the gingival crevicular fluid. Furthermore, the different periodontal diagnostic categories have varying levels of monocytic and crevicular fluid PGE2, in juxtaposition with clinical disease severity. These data are consistent with the concept that there is close synchrony between the systemic responsiveness of peripheral blood monocytes with regard to prostanoid synthesis and the local levels of mediator present within the gingival crevic

Epigenetics: Connecting Environment and Genotype to Phenotype and Disease

Genetic information is encoded not only by the linear sequence of DNA, but also by epigenetic modifications of chromatin structure that include DNA methylation and covalent modifications of the proteins that bind DNA. These “epigenetic marks” alter the structure of chromatin to influence gene expression. Methylation occurs naturally on cytosine bases at CpG sequences and is involved in controlling the correct expression of genes. DNA methylation is usually associated with triggering histone deacetylation, chromatin condensation, and gene silencing. Differentially methylated cytosines give rise to distinct patterns specific for each tissue type and disease state. Such methylation-variable positions (MVPs) are not uniformly distributed throughout our genome, but are concentrated among genes that regulate transcription, growth, metabolism, differentiation, and oncogenesis. Alterations in MVP methylation status create epigenetic patterns that appear to regulate gene expression profiles during cell differentiation, growth, and development, as well as in cancer. Environmental stressors including toxins, as well as microbial and viral exposures, can change epigenetic patterns and thereby effect changes in gene activation and cell phenotype. Since DNA methylation is often retained following cell division, altered MVP patterns in tissues can accumulate over time and can lead to persistent alterations in steady-state cellular metabolism, responses to stimuli, or the retention of an abnormal phenotype, reflecting a molecular consequence of gene-environment interaction. Hence, DNA epigenetics constitutes the main and previously missing link among genetics, disease, and the environment. The challenge in oral biology will be to understand the mechanisms that modify MVPs in oral tissues and to identify those epigenetic patterns that modify disease pathogenesis or responses to therapy

Dentists' knowledge and opinions of oral-systemic disease relationships: relevance to patient care and education.

Population studies consistently support associations between poor oral (periodontal) health and systemic diseases such as cardiovascular disease (CVD) and diabetes. The aim of this study was to assess the knowledge of dentists and document their opinions regarding the evidence on oral-systemic disease relationships. A survey consisting of 39 items was developed and mailed to 1,350 licensed dentists in North Carolina. After three mailings, 667 dentists (49%) meeting inclusion criteria responded. The respondents were predominantly male (76.3%), in solo practice (59.5%), and in non-rural settings (74%). More than 75% of these dentists correctly identified risk factors like diet, genetics, smoking, obesity, and physical inactivity for CVD and diabetes. The majority rated the evidence linking periodontal disease with CVD and diabetes as strong (71% and 67%, respectively). These dentists were most comfortable inquiring about patients' tobacco habits (93%), treating patients with diabetes (89%) or CVD (84%) and concurrent periodontal disease, and discussing diabetes-periodontal disease risks with patients (88%). Fewer respondents were comfortable asking patients about alcohol consumption (54%) or providing alcohol counseling (49%). Most agreed that dentists should be trained to identify risk factors (96%) or actively manage systemically diseased patients (74%). Over 90% agreed that medical and dental professionals should be taught to practice more collaboratively. These data indicate that these dentists were knowledgeable about oral-systemic health associations, had mixed comfort levels translating the evidence into clinical practice, but expressed support for interprofessional education to improve their readiness to actively participate in their patients' overall health management

Letter to the Editor: Authors’ response:

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141212/1/jper0182.pd

Derivation and Validation of the Periodontal and Tooth Profile Classification System for Patient Stratification

BACKGROUND: The goal of this study is to use bioinformatics tools to explore identification and definition of distinct periodontal and tooth profile classes (PPCs/TPCs) among a cohort of individuals by using detailed clinical measures at the tooth level, including both periodontal measurements and tooth loss. METHODS: Full-mouth clinical periodontal measurements (seven clinical parameters) from 6,793 individuals from the Dental Atherosclerosis Risk in Communities Study (DARIC) were used to identify PPC. A custom latent class analysis (LCA) procedure was developed to identify clinically distinct PPCs and TPCs. Three validation cohorts were used: NHANES (2009 to 2010 and 2011 to 2012) and the Piedmont Study population (7,785 individuals). RESULTS: The LCA method identified seven distinct periodontal profile classes (PPCs A to G) and seven distinct tooth profile classes (TPCs A to G) ranging from health to severe periodontal disease status. The method enabled identification of classes with common clinical manifestations that are hidden under the current periodontal classification schemas. Class assignment was robust with small misclassification error in the presence of missing data. The PPC algorithm was applied and confirmed in three distinct cohorts. CONCLUSIONS: The findings suggest PPC and TPC using LCA can provide robust periodontal clinical definitions that reflect disease patterns in the population at an individual and tooth level. These classifications can potentially be used for patient stratification and thus provide tools for integrating multiple datasets to assess risk for periodontitis progression and tooth loss in dental patients

Preterm low birthweight and the role of oral bacteria

Preterm and low birthweight (PTLBW) continues to be a major cause of mortality and morbidity across the world. In recent years, maternal periodontal disease has been implicated as a risk factor for adverse pregnancy outcomes. There is conflicting evidence to support such an outcome as illustrated by descriptive, case control and randomised controlled trials involving pregnant women from across the world, using different measurement tools to determine the level of periodontal disease. Whilst considering the literature, there is evidence for both arguments, based on the effect of periodontal inflammatory by products. Bacteria associated with periodontal disease are not dissimilar to those known to be associated with genito-urinary bacterial infections and adverse pregnancy outcomes. Several groups have demonstrated the apparent translocation of Fusobacterium nucleatum, Prevotella nigrescens, Prevotella intermedia, Porphyromonus gingivalis, Treponema denticola to the foetal placental unit whereby a maternal or foetal response has been detected resulting in premature birth or low birthweight. The normal process of parturition involves a cascade of events including a build-up of inflammatory mediators as linked to inflammation, whereby the maternal environment becomes hostile and threatens the well-being of the infant, and the foetus expelled. The question remains therefore, is there a greater risk of delivering a PTLBW infant when the mother has detectable periodontal disease, or is the release of inflammatory mediators and their translocation via the haematogenous route sufficient to induce a poor pregnancy outcome? The data investigated would suggest that there is a positive outcome when certain oral gram-negative bacteria create a cumulative effect sufficient to trigger early delivery, which represents the final straw to result in preterm or low birthweight delivery. There is equally sufficient epidemiological evidence that does not support this outcome, but it is agreed that maintaining oral health during pregnancy is beneficial to the mother and her infant

MicroRNA Modulation in Obesity and Periodontitis

The aim of this pilot investigation was to determine if microRNA expression differed in the presence or absence of obesity, comparing gingival biopsies obtained from patients with or without periodontal disease. Total RNA was extracted from gingival biopsy samples collected from 20 patients: 10 non-obese patients (BMI 30 kg/m2), each group with 5 periodontally healthy sites and 5 chronic periodontitis sites. MicroRNA expression patterns were assessed with a quantitative microRNA PCR array to survey 88 candidate microRNA species. Four microRNA databases were used to identify potential relevant mRNA target genes of differentially expressed microRNAs. Two microRNA species (miR-18a, miR-30e) were up-regulated among obese individuals with a healthy periodontium. Two microRNA species (miR-30e, miR-106b) were up-regulated in non-obese individuals with periodontal disease. In the presence of periodontal disease and obesity, 9 of 11 listed microRNAs were significantly up-regulated (miR-15a, miR-18a, miR-22, miR-30d, miR-30e, miR-103, miR-106b, miR-130a, miR-142-3p, miR-185, and miR-210). Predicted targets include 69 different mRNAs from genes that comprise cytokines, chemokines, specific collagens, and regulators of glucose and lipid metabolism. The expression of specific microRNA species in obesity, which could also target and post-transcriptionally modulate cytokine mRNA, provides new insight into possible mechanisms of how risk factors might modify periodontal inflammation and may represent novel therapeutic targets

Antibacterial Efficacy of Exogenous Nitric Oxide on Periodontal Pathogens

Current treatments for periodontitis (e.g., scaling/root planing and chlorhexidine) have limited efficacy since they fail to suppress microbial biofilms satisfactorily over time, and the use of adjunctive antimicrobials can promote the emergence of antibiotic-resistant organisms. Herein, we report the novel application of nitric oxide (NO)-releasing scaffolds (i.e., dendrimers and silica particles) as anti-periodontopathogenic agents. The effectiveness of macromolecular NO release was demonstrated by a 3-log reduction in periodontopathogenic Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis viability. In contrast, Streptococcus mutans and Streptococcus sanguinis, caries-associated organisms, were substantially less sensitive to NO treatment. Both dendrimer- and silica-based NO release exhibited substantially less toxicity to human gingival fibroblasts at concentrations necessary to eradicate periodontopathogens than did clinical concentrations of chlorhexidine. These results suggest the potential utility of macromolecular NO-release scaffolds as a novel platform for the development of periodontal disease therapeutics

Toll-like receptor 4 mediates intrauterine growth restriction after systemic Campylobacter rectus infection in mice: TLR4 mediates IUGR after C. rectus infection

Campylobacter rectus is associated with fetal exposure and low-birth weight in humans. C. rectus also invades placental tissues and induces fetal intrauterine growth-restriction (IUGR) in mice, along with Toll-like receptors (TLR4) overexpression, suggesting that TLR4 may mediate placental immunity and IUGR in mice. To test this hypothesis we examined the effect of in vitroTLR4 neutralization in trophoblastic proinflammatory activity and studied the IUGR phenotype in a congenic TLR4-mutant mouse strain after in vivo C. rectus infection. Human trophoblasts were pretreated with TLR4 neutralizing antibodies and infected with C. rectus; pro-inflammatory cytokine production was assessed by cytokine multiplexing assays. Neutralizing TLR4 antibodies significantly impaired the production of pro-inflammatory cytokines in trophoblastic cells after infection in a dose-dependent manner. We used a subcutaneous chamber model to provide a C. rectus challenge in BALB/cAnPt (TLR4Lps-d) and wild-type(WT) females. Females were mated with WT or TLR4Lps-dmales once/week; pregnant mice were infected at (E)7.5 and sacrificed at (E)16.5 to establish IUGR phenotypes. Maternal C. rectus infection significantly decreased fetal weight/length in infected WT when compared to sham WT controls(PLps-d−/− mice did not show statistically significant differences in fetal weight and length when compared to WT controls(P>0.05). Furthermore, heterozygous TLR4Lps-d −/+fetuses showed IUGR phenotype rescue. We concluded that TLR4 is an important mediator of trophoblastic proinflammatory responses and TLR4-deficient fetuses do not develop IUGR phenotypes after C. rectus infection, suggesting that placental cytokine activation is likely to be mediated by TLR4 during low birth weight/preterm delivery pathogenesis

Multiple Hypothesis Testing for Experimental Gingivitis Based on Wilcoxon Signed Rank Statistics

Dental research often involves repeated multivariate outcomes on a small number of subjects for which there is interest in identifying outcomes that exhibit change in their levels over time as well as to characterize the nature of that change. In particular, periodontal research often involves the analysis of molecular mediators of inflammation for which multivariate parametric methods are highly sensitive to outliers and deviations from Gaussian assumptions. In such settings, nonparametric methods may be favored over parametric ones. Additionally, there is a need for statistical methods that control an overall error rate for multiple hypothesis testing. We review univariate and multivariate nonparametric hypothesis tests and apply them to longitudinal data to assess changes over time in 31 biomarkers measured from the gingival crevicular fluid in 22 subjects whereby gingivitis was induced by temporarily withholding tooth brushing. To identify biomarkers that can be induced to change, multivariate Wilcoxon signed rank tests for a set of four summary measures based upon area under the curve are applied for each biomarker and compared to their univariate counterparts. Multiple hypothesis testing methods with choice of control of the false discovery rate or strong control of the family-wise error rate are examined