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Interleukin (IL) 1-ra is a potent endogenous competitive inhibitor of IL-α and β and has an anti-inflammatory role. Study objectives were: 1) to assess the associations of IL-1RN genetic single nucleotide polymorphism (SNP) (rs419598) with generalized chronic periodontitis (GCP), generalized aggressive periodontitis (GAgP), and absence of periodontitis and 2) to assess its association with the load of five periodontopathogenic bacteria and periodontal clinical variables. A cross-sectional analytic study was conducted in 123 patients with GCP, 60 patients with GAgP, and 20 controls. Reverse hybridization PCR was used for genotyping analysis to detect SNPs in IL-1A (rs1800587), IL-1B (rs1143634), and IL-1RN (rs419598) genes and for determination of the load of five periodontopathogenic bacteria. The severity and extension of periodontitis were assessed. Multinomial logistic regression and mediated regression analyses were performed. Considering results for GCP and GAgP patients together, the presence of polymorphism in IL-1A and/or IL-1B gene was associated with a higher likelihood of periodontitis, (OR = 8.11; 95%CI [1.85-35.48]), but this likelihood was reduced when IL-1RN polymorphism was also present, (OR = 5.91; 95%CI [1.08-32.27]). IL-1RN polymorphism was significantly associated with lower counts of red complex bacteria, specifically Porphyromona gingivalis, Tannerella forsythia, and Prevotella intermedia, which were associated with improved clinical outcomes. The polymorphic expression of IL-1RN (rs419598) gene may be associated with a reduced susceptibility to GAgP and GCP in populations of European descent. This effect may be mediated by a decreased load of Porphyromona gingivalis, Tannerella forsythia, and Prevotella intermedia.

Aggressive Periodontitis (AP) and Feline Chronic Gingivostomatitis (FCGS) are two oral inflammatory diseases in cats with unknown etiology. Both conditions present with severe inflammation of the oral cavity and in FCGS it is found with additional deterioration of the non-keratinized mucosa. The oral microbiome is increasingly implicated in disease progression, but little is known about shifts in the microbial community during the AP and FCGS progression. To that end, we used deep metagenomic sequencing with total RNA on three longitudinal samples of the oral microbiome in a cat first diagnosed with AP that progressed to FCGS. This deep sequencing approach revealed that increased diversity at both the genus and species levels marked the shift from AP to FCGS, including increases in Porphyromonas and Treponema species, and decreased Streptobacillus species. The metatranscriptomes were then probed for expression of antimicrobial resistance genes and virulence factors. Disease-related genes that include cheY, and ompP5 were expressed in early AP and FCGS, while others like galU were only expressed in one or the other disease state. Both genus and species-level shifts were observed along the longitudinal microbiome samples with a noted increase in species diversity in the FCGS-associated microbiome. Corroborating that functional shifts accompany taxonomic changes, the AMR and virulence factor expression similarly changed between the sampling points. Together, these taxonomic and functional shifts indicate that AP and FCGS are potentially linked and may be marked by changes in the oral microbiome, which supports the development of microbial-based clinical diagnostics and therapeutics.

Improved diagnostics remains a fundamental goal of biomedical research. This study was designed to assess cytokine biomarkers that could predict bone loss (BL) in localized aggressive periodontitis. 2,058 adolescents were screened. Two groups of 50 periodontally healthy adolescents were enrolled in the longitudinal study. One group had Aggregatibacter actinomycetemcomitans (Aa), the putative pathogen, while the matched cohort did not. Cytokine levels were assessed in saliva and gingival crevicular fluid (GCF). Participants were sampled, examined, and radiographed every 6 months for 2-3 years. Disease was defined as radiographic evidence of BL. Saliva and GCF was collected at each visit, frozen, and then tested retrospectively after detection of BL. Sixteen subjects with Aa developed BL. Saliva from Aa-positive and Aa-negative healthy subjects was compared to subjects who developed BL. GCF was collected from 16 subjects with BL and from another 38 subjects who remained healthy. GCF from BL sites in the 16 subjects was compared to healthy sites in these same subjects and to healthy sites in subjects who remained healthy. Results showed that cytokines in saliva associated with acute inflammation were elevated in subjects who developed BL (i.e., MIP-1α MIP-1β IL-α, IL-1β and IL-8; p<0.01). MIP-1α was elevated 13-fold, 6 months prior to BL. When MIP-1α levels were set at 40 pg/ml, 98% of healthy sites were below that level (Specificity); whereas, 93% of sites with BL were higher (Sensitivity), with comparable Predictive Values of 98%; p<0.0001; 95% C.I. = 42.5-52.7). MIP-1α consistently showed elevated levels as a biomarker for BL in both saliva and GCF, 6 months prior to BL. MIP-1α continues to demonstrate its strong candidacy as a diagnostic biomarker for both subject and site vulnerability to BL.

Calprotectin, a heterodimer of S100A8 and S100A9 subunits, is associated with inflammatory disorders such as rheumatoid arthritis and cystic fibrosis. Although calprotectin levels are increased significantly in the gingival crevicular fluid (GCF) of periodontitis patients, its effects on periodontal ligament cells (PDLCs) remain largely unknown. The aim of this study was to evaluate calprotectin levels in the GCF of generalized aggressive periodontitis (AgP) patients and to investigate the effects of recombinant human calprotectin (rhS100A8/A9) and its subunits (rhS100A8 and rhS100A9) in PDLCs. Both the concentration and amount of crevicular calprotectin were significantly higher in the AgP group compared with healthy controls. In addition, the GCF calprotectin levels were correlated positively with clinical periodontal parameters including bleeding index, probing depth, and clinical attachment loss. rhS100A8/A9 promoted cell apoptosis, whereas rhS100A8 and rhS100A9 individually exerted little effect on apoptosis in PDLCs. rhS100A9 and rhS100A8/A9 increased the activation of nuclear factor-κB (NF-κB) by promoting the nuclear translocation of p65 in PDLCs, subsequently inducing expression of the pro-inflammatory cytokines IL-6, IL-8, TNFα, and COX2. Treatment with an NF-κB inhibitor partially reversed the rhS100A9- and rhS100A8/A9-induced upregulation of the pro-inflammatory cytokines. rhS100A9, and not rhS100A8, was mainly responsible for the pro-inflammatory role of calprotectin. Collectively, our results suggest that calprotectin promotes apoptosis and the inflammatory response in PDLCs via rhS100A9. These findings might help identify novel treatments for periodontitis.

Background/Aims: CTLA4 has been identified functioning as a protein receptor which functions as an immune checkpoint, downregulating the immune system. Susceptibility to aggressive periodontitis (AgP) is influenced by gene polymorphisms related to the immune response. In this study, we focused on SNPs in the 3’-UTR of CTLA4 among Chinese AgP patients, and investigated any further relationships between the SNPs and miRNAs. Methods: This case–control study included 120 AgP patients and 150 healthy controls. Genotyping was used to detect allele distribution. Cell transfection and the dual luciferase reporter assay were performed to investigate the potential functions of SNPs located in the 3’UTR of CTLA4. Results: The data show that patients with a history of smoking were more susceptible compared to controls, exhibiting deeper probing depth, greater attachment loss and more sites of bleeding on probing. The results of genotyping analysis revealed that individuals with the GA and AA genotypes, and with the A carrier had a decreased risk (P = 0.015, P = 0.03). Furthermore, patients with the G allele might be regulated by miR-105, which caused a down-regulation of CTLA4. The carriers of the GG genotype exhibited the worst results of attachment loss and bleeding on probing. Conclusion: These findings show that rs56102377 in the 3’-UTR of CTLA4 may act as a protective factor by disrupting the regulatory role of miR-105 in CTLA4 expression. Thus, our study highlighted a potential role of these polymorphisms as genetic susceptibility biomarkers of periodontitis in Chinese Han populations.

Periodontal diseases are complex inflammatory diseases and affect up to 20% of the worldwide population. An unbalanced reaction of the immune system toward microbial pathogens is considered as the key factor in the development of periodontitis. Defensins have a strong antimicrobial function and are important contributors of the immune system toward maintaining health. Here, we present the first systematic association study of DEFB1 . Using a haplotype-tagging single nucleotide polymorphism (SNP) approach, including described promoter SNPs of DEFB1 , we investigated the associations of the selected variants in a large population ( N =1337 cases and 2887 ethnically matched controls). The 3′ untranslated region SNP, rs1047031, showed the most significant association signal for homozygous carriers of the rare A allele ( P =0.002) with an increased genetic risk of 1.3 (95% confidence interval: 1.11–1.57). The association was consistent with the specific periodontitis forms: chronic periodontitis (odds ratio=2.2 (95% confidence interval: 1.16–4.35), P =0.02), and aggressive periodontitis (odds ratio=1.3 (95% confidence interval 1.04–1.68), P =0.02). Sequencing of regulatory and exonic regions of DEFB1 identified no other associated variant, pointing toward rs1047031 as likely being the causative variant. Prediction of microRNA targets identified a potential microRNA-binding site at the position of rs1047031.

•Estimate age-at-death is central to determine biological profile and identification.•We propose a new way to evaluate age-at-death of adults cadavers.•Two step procedure (TSP) combines sequentially Lamendin and Suckey Brooks methods.•TSP improves the accuracy of age estimation and remains a user friendly system.•Moreover, inexpensive and fast method preserving body appearance. This paper presents the principles and results of TSP (the two step procedure), a comprehensive (combined) method of age estimation in mature human skeletal remains. The first step consists of the examination of the pubic symphysis using the Suchey–Brooks system for a “pre-choice”. Then for SBS phases I, II, III, (young adults up to about 40) the age estimate is given using the chronological interval corresponding to each phase. For SBS phase is IV, V or VI (mature adults, about 40 to 60), then (second step) the dental method of Lamendin (using single rooted tooth) will be applied alone. Both methods are fast, easy to learn and to use (requiring no preparation except cleaning soft tissues from the pubic bone) and are not expensive, making TSP usable by all pathologists or anthropologists in any Forensic unit. It is also of great practical use in mass disaster and mass grave situation. After 15 years of use, a literature review and four evaluation studies we confirm that TSP is more accurate than any single method for aging adults and at least as good as more complicated combined methods. Despite its advantages TSP is, like all other aging methods, not efficient in adults over 65 years of age.

Age estimation in unknown adult skeletons remains a considerable problem in forensic anthropology. In 1992, Lamendin et al. published a non-destructive method of age estimation on single rooted teeth. With this method, periodontosis and root transparency are judged against root height, and these are then used in regression formulae to estimate age. The aim of this study was to test the accuracy of the Lamendin method on a large sample of canines of South Africans, and if necessary to adapt the formulae for this population. A sample of known sex, age and population group was used. This included 537 upper and lower canines from 498 skulls, and included black males, black females, white males and white females. The age of the individuals ranged from 20 to 90 years. The original formulae gave relatively poor results, and in an attempt to obtain better accuracy the formulae were adapted with the current data. Even after adaptation of the formulae, the highest correlation between estimated age and actual age remained low (R2=0.41), with mean errors ranging between 12 and 15 years. Periodontosis was better correlated with age than root transparency. The accuracy of the method was found to be much lower than what was originally published, but probably reflects biological reality and is on a par with other methods of adult age estimation.

Phosphoinositide-dependent kinase (PDK1) plays a central role in signal transduction mediated by phosphatidylinositol 3-kinases (PI3K) and regulates cellular functions in neutrophils. Neutrophils from individuals diagnosed with localized aggressive periodontitis (LAP) present an in vivo phenotype with depressed chemotaxis. The aim of this study was to test the hypothesis that PDK1 regulates chemotaxis in neutrophils and is responsible for the abnormal neutrophil chemotaxis LAP. Neutrophil chemotaxis was significantly suppressed by the PDK1 inhibitor staurosporine. When cells were transfected with PDK1 siRNA, there was a significant reduction in chemotaxis, while superoxide generation was not significantly affected. In primary neutrophils from persons with LAP, PDK1 expression and activation levels were significantly reduced, and this reduction was associated with the reduced phosphorylation of Akt (Thr308) and chemotaxis. Analysis of these data demonstrates that PDK1 is essential for the chemotactic migration of neutrophils, and in the absence of PDK1, neutrophil chemotaxis is impaired.