Three dimensional (3D) gingival models in periodontal research: a systematic review.

The aim of this study is to systematically appraise the evidence on available full thickness 3D gingival and mucosal models (3D culture in scaffold base system) and their application in periodontal and peri-implant research. This study involved a systematic review of twenty-two studies obtained from searching from five electronic databases: MEDLINE-OVID, EMBASE, EBSCOhost, Web of Science Core Collection and LILACS, as well as a hand search of eligible articles up to September 2022. A total of 2338 studies were initially identified, after removal of duplicates (573), abstracts/title selection (1765), and full text screening (95), twenty-two studies were included, thirty-seven models were identified. Several cellular markers were reported by the studies included. The expression of keratinocytes differentiation markers (K4, K5, K10, K13, K14, K16, K17, K18, K19, involucrin, laminin5), proliferation marker (Ki67, CD90), and vimentin, Type I, II and IV collagen produced by fibroblasts were investigated in thirty models. No quantitative analyses were performed, and results of the review confirmed a substantial level of heterogeneity across experiments. In conclusion, there is currently insufficient evidence to conclude that the available 3D gingival and mucosal models can entirely recapitulate the human gingival tissue/mucosa and provide a useful research tool for periodontal and peri-implant research. This review also highlighted the lack of a standardized protocol to construct and characterize 3D gingival models. A new protocol is proposed for the characterization of in vitro gingival models for future research.

Is systemic inflammation a missing link between periodontitis and hypertension? Results from two large population-based surveys.

OBJECTIVE: The primary objective was to investigate the relationship between periodontitis and hypertension in two independent large surveys. The secondary objective was to ascertain whether systemic inflammation had a mediation effect in the association. METHODS: This cross-sectional study analysed representative samples of the US (n = 3460; NHANES 2009/10) and Korean (n = 4539; 2015 KNHANES VI-3) populations. The association between periodontitis (exposure), hypertension (outcome) and inflammatory markers [C-reactive protein (CRP) and white blood cell counts (WBC)] (mediators) was assessed using multivariate linear and logistic regression models and mediation analysis. RESULTS: Participants with periodontitis were more likely to have hypertension (NHANES: OR = 1.3, 95% CI: 1.0-1.6, P = 0.025; KNHANES: OR = 1.2, 95% CI: 1.0-1.4, P = 0.041) and actual systolic blood pressure ≥ 140 mmHg (NHANES: OR = 1.6, 95% CI: 1.1-2.3, P < 0.001; KNHANES: OR = 1.3, 95% CI :1.0-1.6, P < 0.031) than those without the disease. These associations were independent of age, gender, BMI, education level, smoking, alcohol consumption, creatinine, physical activity, presence of other comorbidities and confirmed in participants not taking antihypertensive medications. Diagnosis of periodontitis was directly associated with WBC (in both surveys: NHANES: ß ± SE = 0.3 ± 0.1, P < 0.004; KNHANES: ß ± SE = 0.3 ± 0.1, P < 0.001) and with CRP levels (in one survey: NHANES: ß ± SE = 0.1 ± 0.03, P < 0.007; KNHANES: ß ± SE = 0.1 ± 0.04, P > 0.213). Mediation analyses confirmed that CRP acted as a mediator in the association between periodontitis and hypertension in both populations (mediated effect: NHANES: ß ± SE = 0.010 ± 0.003, P < 0.001; KNHANES: ß ± SE = 0.003 ± 0.001, P = 0.015). WBC acted as a mediator in the KNHANES (mediated effect: ß ± SE = 0.004 ± 0.001, P = 0.004) whilst in the NHANES, its effect was dependent of CRP inclusion in the model (mediated effect WBC + CRP: ß ± SE = 0.002 ± 0.001, P = 0.001). CONCLUSIONS: These findings suggest that periodontitis is closely linked to hypertension and systemic inflammation is, in part, a mediator of this association.

miR-30e* is an independent subtype-specific prognostic marker in breast cancer.

BACKGROUND: Breast cancer clinical outcome is affected by tumor molecular features, and the identification of subtype-specific prognostic biomarkers is relevant for breast cancer translational research. Gene expression signatures proved to be able to complement prognostic information provided by classical clinico-pathological features. Recently, microRNAs (miRNAs) have been causally linked to tumorigenesis and cancer progression and have been associated with patient outcome, also in breast cancer. METHODS: MicroRNAs associated with the development of distant metastasis were identified in a cohort of 92 ESR1+/ERBB2- lymph node-negative breast cancers from patients not receiving adjuvant treatment. Results were confirmed and further investigated in a total of 1246 miRNA and gene expression profiles of the Molecular Taxonomy of Breast Cancer International Consortium data set. Moderated t-test, univariable and multivariable Cox regression models were used for statistical analyses. RESULTS: miR-30e* was identified as independent protective prognostic factor in lymph node-negative untreated patients with ESR1+/ERBB2- tumours and retained a significant association with a good prognosis in treated patients with the same tumor subtype as well as in the ERBB2+ subtype, but not in ESR1-/ERBB2- tumours. CONCLUSIONS: We highlighted a relevant and subtype-specific role in breast cancer for miR-30e* and demonstrated that adding miRNA markers to gene signatures and clinico-pathological features can help for a better prognostication.

Lipid subclasses profiles and oxidative stress in aggressive periodontitis before and after treatment.

BACKGROUND AND OBJECTIVE: Associations between dyslipidaemia, oxidative stress and periodontitis have emerged in recent years. However, there is a lack of studies investigating these associations in aggressive periodontitis (AgP) cases. The aim of this study was to investigate the lipid and oxidative stress profiles in patients with AgP, and to relate them to clinical variables and interleukin (IL)-6 genetic variants. MATERIAL AND METHODS: Twelve non-smoking Caucasian patients with AgP selected based on their IL6 haplotypes underwent periodontal non-surgical and surgical treatment. Peripheral blood samples taken at baseline and at six different time-points after treatment were processed to determine IL-6 circulating levels, lipid profiles (cholesterol, triglycerides, high-density lipoprotein [HDL] and low-density lipoprotein [LDL] subclasses) and oxidative stress markers (glutathione and total lipid hydroperoxide levels). RESULTS: HDLs were the most prevalent lipoproteins, followed by intermediate-density lipoprotein, very-low-density lipoprotein and LDL. The LDL subclasses consisted mainly of the less atherogenic large LDL. The lipid profile did not consistently change after treatment up to 3 mo after surgery. Periodontal disease severity was associated with LDL levels and size. The IL6 haplotypes were associated with total cholesterol, triglycerides, HDL and LDL subclasses after adjusting for confounders. IL-6 circulating levels were associated with both very-low-density lipoprotein and lipid hydroperoxide levels. CONCLUSION: Based on these data, we conclude that both periodontal disease severity and IL6 haplotypes may influence lipid profiles in AgP.

Preliminary study of video imaging of blood vessels in tissues lining the gingival sulcus in periodontally healthy individuals.

BACKGROUND AND OBJECTIVE: The aim of this study was to obtain in vivo images of the microcirculation in tissues lining the gingival crevice in periodontally healthy volunteers and to assess the repeatability of the parameters measured. MATERIAL AND METHODS: Video microscopy images of the microcirculation of tissues lining the gingival crevice were obtained from 20 periodontally healthy volunteers. Images were obtained with a single 1 mm diameter 1 pitch gradient index lens with a high numerical aperture and with a plain glass lens and illumination with a green 525 nm light-emitting diode and recorded using a video microscope. RESULTS: The morphological features of the vessels (including vessel diameter, vessel density, loops, branches, dilated vessels) were similar to those described previously in other mammals. The Kappa values for the assessment of morphology of the vessels using the gradient index lens range from 0.83 for branching to 0.91 for dilated and using the glass lens 0.47 for branching and 0.38 for dilated. CONCLUSIONS: This novel system allowed for a consistent and repeatable assessment of the gingival microvasculature. However, there was some evidence of possible pressure artefacts in those cases where the measurements of separation between vessels exceeded 150 µm.

Influence of IL-6 haplotypes on clinical and inflammatory response in aggressive periodontitis.

OBJECTIVES: The aim of this study was to investigate the inflammatory response in aggressive periodontitis (AgP) patients after periodontal therapy and associate these changes to subjects' interleukin-6 (IL-6) genetic variants. MATERIALS AND METHODS: Twelve non-smoking UK Caucasian patients with AgP were selected based on their IL6 haplotypes (six haplotype positive and six haplotype negative based on polymorphisms rs 2069827 and rs 2069825) and underwent full mouth non-surgical periodontal therapy, followed by open flap surgery. Gingival crevicular fluid (GCF) and peripheral blood samples were taken at baseline and at six different time points after treatment. Gingival biopsy samples were harvested during surgery and underwent immunohistochemical analysis for identification of IL-6. RESULTS: An overall improvement in clinical periodontal parameters was observed following periodontal therapy. Haplotype status was associated with clinical presentation, Aggregatibacter actinomycetemcomitans counts in subgingival plaque samples, white cell count, neutrophils, red cell count and haemoglobin. GCF IL-6 concentrations increased dramatically 1 day after surgery and IL-6 haplotype-positive subjects exhibited a higher magnitude in this increase. CONCLUSIONS: IL6 haplotypes may have an effect on clinical presentation and magnitude and kinetics of local and systemic inflammatory responses following non-surgical and surgical periodontal therapy in aggressive periodontitis. CLINICAL RELEVANCE: Detecting IL-6 haplotype-positive periodontitis patients might become helpful in identifying subjects prone to excessive inflammatory response and increased periodontal breakdown.

Interleukin-6 in oral diseases: a review.

Interleukin-6 (IL-6) is a pleomorphic cytokine involved in a number of physiologic and pathologic processes including response to trauma and infection and development and progression of inflammation and malignancy. IL-6 is emerging as an important mediator and novel therapeutic target for chronic inflammatory diseases and cancer. The present study reviews the available evidence regarding the association between IL-6 and a range of oral diseases including infections (periodontal disease and endodontic infections), immunologically mediated disorders (oral lichen planus and Sjögren's syndrome) and malignancy (oral cancer and precancer). The role of common genetic variants of IL-6 in determining individual susceptibility to certain oral diseases, as well as novel therapeutic strategies based on IL-6 inhibition are also discussed.

Periodontal status in oral mucous membrane pemphigoid: initial results of a case-control study.

OBJECTIVE: To evaluate the periodontal status of mucous membrane pemphigoid (MMP) patients and compare it with that of healthy controls. METHODS: A prospective study was undertaken to examine the impact of gingival MMP lesions on the human periodontium of 29 patients. Parameters evaluated included full mouth plaque score (FMPS), full mouth bleeding upon probing scores, probing depths (PD), gingival recession, clinical attachment level (CAL), mobility score, furcation involvement, number of missing teeth and Machtei criteria. RESULTS: All periodontal parameters recorded were increased in cases when compared to controls in univariate statistics. The mean differences between groups in PD (0.8±0.2mm, 95% CI 0.3-1.3), CAL (1.3±0.4mm, 95% CI 0.4-2.2), FMPS (41.0±6.2%, 95% CI 28.7-53.4), FMBS (16.2±6.6%, 95% CI 3.0-29.4) and tooth loss (2±1 teeth, 95% CI 1-3) were all statistically significant (P<0.01 for all). Substantial differences in domiciliary oral hygiene routines were observed (P<0.0001). In multivariate models when FMPS was included as covariate the difference between groups in all clinical periodontal parameters was no longer statistically significant. CONCLUSIONS: Our results showed that periodontal status is worse in MMP patients if compared with healthy controls due to a substantial difference in oral hygiene. Oral health should be promoted in MMP.

Periodontal therapy and biomarkers related to cardiovascular risk.

In the last 15-20 years the association between periodontitis and cardiovascular diseases has received greater attention. Clinical evidence also suggests that periodontitis is associated with a systemic host response and with a low-grade inflammatory state, as assessed by raised serum levels of CRP and endothelial dysfunction. This is a perturbation of the normal function of the endothelial cells that are responsible for a normal vascular function (dilatation, constriction). The objective of this review was to systematically appraise the available evidence on the effect of periodontal therapy on systemic biomarkers related to cardiovascular risk. An electronic search was conducted using MEDLINE via PubMed to identify published literature. The electronic search identified 836 references, of which 643 were considered irrelevant for this review. Full texts of 183 possible relevant articles were assessed, with exclusion of 174. Nine studies were included in the review. The overall effect of periodontal therapy was associated with a reduction in CRP of 0.50 mg/ml (95% CI 0.15, 0.85) (P=0.005). In conclusion, this review supports the hypothesis of an association between periodontitis and systemic inflammation. Further research is needed on the possible impact of periodontitis on cardiovascular disease events.

Periodontitis and Cardiovascular Diseases. Consensus Report.

Background: In Europe cardiovascular disease (CVD) is responsible for 3.9 million deaths (45% of deaths), being ischaemic heart disease, stroke, hypertension (leading to heart failure) the major cause of these CVD related deaths. Periodontitis is also a chronic non-communicable disease (NCD) with a high prevalence, being severe periodontitis, affecting 11.2% of the world's population, the sixth most common human disease. Material and Methods: There is now a significant body of evidence to support independent associations between severe periodontitis and several NCDs, in particular CVD. In 2012 a joint workshop was held between the European Federation of Periodontology (EFP) and the American Academy of Periodontology to review the literature relating periodontitis and systemic diseases, including CVD. In the last five years important new scientific information has emerged providing important emerging evidence to support these associations. Results and Conclusions: The present review reports the proceedings of the workshop jointly organised by the EFP and the World Heart Federation (WHF), which has updated the existing epidemiological evidence for significant associations between periodontitis and CVD, the mechanistic links and the impact of periodontal therapy on cardiovascular and surrogate outcomes. This review has also focused on the potential risk and complications of periodontal therapy in patients on anti thrombotic therapy and has made recommendations for dentists, physicians and for patients visiting both the dental and medical practices.

Association between periodontitis and common variants in the promoter of the interleukin-6 gene.

We recently reported an association between interleukin-6 (IL6) polymorphisms (SNPs) and haplotypes and aggressive periodontitis (AgP). The aim of this study was to investigate this association in a larger cohort of subjects, affected by either aggressive or chronic periodontitis. Five IL6 SNPs were analyzed in 765 subjects (167 generalized aggressive periodontitis, 57 localized aggressive, 310 chronic periodontitis and 231 periodontally healthy). Among Caucasians (n=454) there were moderate associations for -1363T allele (p=0.011) and for -174GG and -1363GG genotypes with diagnosis of periodontitis (respectively, p=0.044, OR=1.6, 95% CI=1.0-2.4, and p=0.017, OR=1.8, 95% CI=1.1-2.8, adjusted for age, gender and smoking). Haplotypes containing the -174G>C, -1363G>T and -1480C>G polymorphisms were associated with diagnosis of periodontitis (p=0.02). Subgroup analysis by disease phenotype showed associations for the localized AgP (LAgP) group and -1480C>G and -6106A>T SNPs (p=0.007 and 0.010, respectively). Among Caucasians the genotypes IL6 -1480 CC and -6106 TT increased the adjusted OR for LAgP (OR=3.09 and 2.27, respectively). This study supports the hypothesis that IL6 polymorphisms and haplotypes are moderately associated with periodontitis, possibly acting through influencing tissue levels of IL6. This association is stronger for LAgP than for other periodontal disease phenotypes.

Molecular markers relevant to myocardial injury following dental extraction in patients with or without coronary artery disease.

OBJECTIVES: The aim of this study was to characterize biological changes following dental extractions in patients with or without coronary artery disease (CAD). MATERIALS AND METHODS: Forty-five patients (36 males and 9 females) referred for dental extraction underwent treatment and provided blood samples before, immediately after, and 24 h after the procedure. A broad array of biomarkers was employed to assess myocardial injury (highly sensitive troponin T, hs-TnT), bacterial burden (LPS endotoxin activity), and systemic inflammation (CRP, fibrinogen, IFN-γ, IL-1ß, IL-6, IL-8, IL-10, IL-12, and TNF-α). RESULTS: Dental extraction in patients with or without CAD was associated with rises in hs-TnT (p = 0.013), hs-CRP (p < 0.001), fibrinogen (p = 0.005), endotoxin activity (p < 0.001), IFN-γ (p < 0.001), IL-6 (p < 0.001), IL-8 (p = 0.011), and IL-12 (p < 0.001) at 24 h compared with immediately post procedure. Changes in systemic inflammation and endotoxin activity were more evident in those with hs-TnT rise. CONCLUSIONS: Simple dental extractions may cause mild increase in hs-TnT, indicating minor myocardial injury in both patients with or without CAD. Acute systemic inflammation and endotoxemia could represent a possible link between invasive dental treatment and increased risk of acute cardiovascular events. These findings indicate that invasive dental treatment (as simple as a single dental extraction) may impact negatively on clinical outcomes in dental patients, especially those with CAD.

Are paediatric headaches in the emergency department increasing? An Italian experience.

The aim of this study was to assess admissions, for headache, to the emergency department (ED) of the Di Cristina Children's Hospital in Palermo over a decade. The total number of ED admissions for headache was retrospectively analysed considering two 24- month periods: 2009-2010 and 2017-2018. Total admissions to the ED decreased from 55,613 to 50,096 (-10%) between the two periods considered, while the number of admissions for headache increased by 63.56% (p < 0.0001). There was also a significant increase in the number of multiple ED admissions by single children (9.5% versus 17.98% of the patients accessing the ED for headache). This significant increase in admissions for paediatric headache is probably due to limited efficacy of the Italian and international guidelines and of the educational strategies implemented in this setting, and also to communication difficulties, both with patients and between primary care networks and hospitals.

Risk of Myocardial Infarction and Ischemic Stroke after Dental Treatments.

The association between invasive dental treatments (IDTs) and a short-term risk of myocardial infarction (MI) and ischemic stroke (IS) remains controversial. Bacterial dissemination from the oral cavity and systemic inflammation linked to IDT can induce a state of acute vascular dysfunction. The aim of study is to investigate the relation of IDTs to MI and IS by using case-only study designs to analyze data from a large Taiwanese cohort. A nationwide population-based study was undertaken by using the case-crossover and self-controlled case series design to analyze the Taiwanese National Health Care Claim database. Conditional logistic regression model and conditional Poisson regression model were used to estimate the risks of MI/IS. In addition, we used burn patients as negative controls to explore the potential effect of residual confounding. In total, 123,819 MI patients and 327,179 IS patients in the case-crossover design and 117,655 MI patients and 298,757 IS patients were included in the self-controlled case series design. Results from both study designs showed that the risk of MI within the first 24 wk after IDT was not significantly different from or close to unity except for a modest risk during the first week for patients without other comorbidities (odds ratios [95% confidence intervals] of 1.31 [1.08-1.58] and 1.15 [1.01-1.31] for 3 d and 7 d, respectively). We also observed no association between IDTs and IS, or the risk ratio was close to unity. IDTs did not appear to be associated with a transient risk of MI and IS in the Taiwanese population, with consistent findings from both case-only study designs. However, we cannot exclude that dental infections and diseases may yield a long-term risk of MI and IS.

Disease severity associated with presence in subgingival plaque of Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Tannerella forsythia, singly or in combination, as detected by nested multiplex PCR.

This study used a nested multiplex PCR method to detect three periodontal pathogens in subgingival plaque collected before treatment and at 2 and 6 months posttreatment from 107 patients with severe, generalized periodontitis. The proportions of the patients who harbored these bacteria before periodontal treatment were as follows: Tannerella forsythia, 81%; Porphyromonas gingivalis, 78%; and Aggregatibacter (formerly Actinobacillus) actinomycetemcomitans, 47%. At 2 months posttreatment there was a significant reduction in the numbers of patients harboring P. gingivalis (46%; P < 0.001) or T. forsythia (63%; P = 0.043) but not A. actinomycetemcomitans (50%) compared to pretreatment data. At 6 months posttreatment, significantly fewer patients harbored P. gingivalis (43%; P < 0.001); A. actinomycetemcomitans, (31%; P = 0.025), or T. forsythia (63%; P = 0.030). Interestingly, at baseline and at 2 months posttherapy, subjects who harbored only a single pathogen had a greater level of periodontal disease than subjects who harbored two, or all three, of these periodontal pathogens. These data suggest that a reduction in the number of species present may be associated with an increase in the severity of periodontal diseases.

Evidence summary: The relationship between oral diseases and diabetes.

Introduction This paper is the third of four rapid reviews undertaken to explore the relationships between oral health and general medical conditions in order to support teams within Public Health England, health practitioners and policymakers.Aims This review aimed to explore the nature of the association between poor oral health and diabetes when found in the same individuals or populations, having reviewed the most contemporary evidence in the field.Methods The reviews were undertaken by four groups each comprising consultant clinicians from medicine and dentistry, trainees, public health and academics. The methodology involved a streamlined rapid review process and synthesis of the findings.Results The results identified a number of systematic reviews of low to high quality suggesting that diabetes is associated with periodontal disease, tooth loss, and oral cancer in particular, and that the management of oral diseases, most notably periodontal care, has a short-term beneficial influence on metabolic outcomes related to diabetes; however, there is no evidence that this is sustained over the long-term and reduces the prevalence of the long-term complications.Conclusion Current evidence, of mixed quality, suggests a number of associations between oral diseases and diabetes mellitus (diabetes). Further high quality research is required in this field.

Systemic Inflammation after Third Molar Removal: A Case-Control Study.

Third molar extraction is one of the most frequent interventions in dentistry. Nevertheless, there is scarce evidence on the host response of individuals with impacted or semi-impacted third molars and the possible effects of surgical removal. A case-control study of 40 patients was designed to evaluate 1) the differences in biomarkers of systemic inflammation, vascular function, and metabolism (high-sensitive C-reactive protein, lipids, fibrinogen, oxidative stress, and endothelial function analysis) and 2) the acute and short-term effects of surgical removal in patients with bilateral impacted or semi-impacted third molars compared to controls with no third molars. Patients undergoing third molar extraction exhibited greater levels of systemic inflammation, oxidative stress, and triglycerides than controls. Raised white blood cell counts as well as peaks of serum levels of C-reactive protein and fibrinogen were noticed in the first postoperative week. Three months after the extraction, all markers returned to baseline values. Malondialdehyde, an indicator of oxidative stress indicator, was significantly reduced after third molar removal. Semi-impacted or impacted third molars are associated with higher systemic inflammation, and their removal may represent a useful human model to study acute inflammation and determine beneficial systemic effects ( ClinicalTrials.gov NCT03048175).

Perioperative dexamethasone reduces post-surgical sequelae of wisdom tooth removal. A split-mouth randomized double-masked clinical trial.

The effect of endo-alveolar and sub-mucosal administration of dexamethasone sodium phosphate to prevent inflammatory sequelae after surgical removal of lower third molars was studied. Forty-three patients underwent bilateral extractions of lower third molars and were randomly assigned to receive either dexamethasone 4 mg (group A) or 10 mg (group B) as endo-alveolar powder or 10 mg as sub-mucosal injection (group C) unilaterally. The controlateral site served as control and did not receive any steroid administration. Facial edema, trismus and pain perception were evaluated at the 2nd and 7th postoperative day. A multivariate analysis revealed that treatment and ostectomy time were both significantly positively associated with the degree of postoperative trismus and edema. Other baseline classification variables (e.g., molar classification) were also predictive of the degree of change in all clinical parameters. Test sites treated (any steroid application) showed greater reductions in all clinical parameters recorded compared to control. No statistically significant differences were observed between the three test groups. Both sub-mucosal and endo-alveolar administration of dexamethasone are effective in reducing postoperative sequelae of surgical removal of lower wisdom teeth.

Short-term effects of intensive periodontal therapy on serum inflammatory markers and cholesterol.

Severe periodontitis has been associated with increased systemic inflammation. In a three-arm preliminary randomized trial, we investigated the impact of standard (SPT) and intensive periodontal therapy (IPT) on serum inflammatory markers and cholesterol levels. Medical and periodontal parameters, C-reactive protein (CRP), interleukin-6 (IL-6), total cholesterol, and LDL cholesterol were evaluated in 65 systemically healthy subjects suffering from severe generalized periodontitis. Two months after treatment, both SPT and IPT resulted in significant reductions in serum CRP compared with the untreated control (0.5 +/- 0.2 mg/L for SPT, P = 0.030 and 0.8 +/- 0.2 mg/L for IPT, P = 0.001). Similar results were observed for IL-6. Changes in inflammation were independent of age, gender, body mass index, and ethnicity, but a significant interaction between cigarette smoking and treatment regimen was found. The IPT group also showed a decrease in total and LDL cholesterol after 2 months. Analysis of these data indicates that periodontitis causes moderate systemic inflammation in systemically healthy subjects.