The prevalence of apical periodontitis in patients prior to hematopoietic cell transplantation: a systematic review.

Objectives: This systematic review addressed the question: "What is the prevalence of apical periodontitis in patients prior to hematopoietic cell transplantation?" Materials and Methods: A systematic search was conducted in MEDLINE/PubMed, Cochrane Library, Scopus, Web of Science, Embase, and Grey Literature Report. Eligibility criteria were based on the condition, content, and population strategy: the condition was the radiographic prevalence of apical periodontitis, the content comprised patients scheduled for hematopoietic stem cell transplantation, and the population consisted of adult and pediatric patients. The revised Risk of Bias in Nonrandomized Studies of Exposure tool was used to assess the quality of studies. The Grading Recommendations Assessments, Development, and Evaluation (GRADE) tool was used to assess the quality of evidence. Results: Eight studies were included in this review. The average number of patients with apical periodontitis was 15.65% (range, 2.1%-43.34%). One study was classified as having a very high risk of bias, 1 with a high risk of bias, and 6 with some concern for bias. GRADE analysis showed a very low certainty of evidence. Significant limitations concerning the absence of control over confounding variables were identified. Conclusions: With the caveat of the very low quality of evidence in the studies reviewed, there was a low to moderate prevalence of apical periodontitis in patients prior to undergoing hematopoietic cell transplantation.

Treatment of retrograde peri-implantitis originating from apical periodontitis of an adjacent tooth: A clinical case letter.

This report aims to present a treatment of retrograde peri-implantitis originating from apical periodontitis of an adjacent tooth in an 84-year-old male. Apical periodontitis of the maxillary left central incisor (#9) extended to the apex of the maxillary left lateral incisor implant (#10), which had been functioning for 16 years. Root canal treatment for #9 was performed, followed by root end surgery to treat the apical periodontitis, which showed a periapical radiolucency measured 1 cm in its greatest dimension. After the root end filling was placed, neither bone substitute materials nor barrier membranes were used to fill and cover the bony defect area. A 2- year postoperative radiograph confirmed the osseous healing around the apices of #9 and #10.

Endodontic Treatment of Chronic Apical Periodontitis Ameliorates Systemic Inflammation and Restores Impaired Cellular Responses to Insulin in an In Vitro Model.

INTRODUCTION: A growing body of research supports an association between periapical inflammation and an increased risk of developing systemic diseases. There is currently no scientific evidence to support a causal effect of inflammation on the onset of insulin resistance (IR) in patients with apical periodontitis (AP). The aim of this in vitro study was to evaluate any association between AP and levels of serum inflammatory factors potentially associated with the onset of IR, and to investigate the effect of root canal treatment (RCT) on these systemic inflammation markers and on the response in vitro to insulin. METHODS: A total of 27 control subjects and 27 patients with AP were enrolled. Patients with AP underwent RCT and were followed-up 6 and 12 months post-treatment. Enzyme-linked immunosorbent assays were used to evaluate serum levels of proinflammatory cytokines interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor (TNF)-α. The response in vitro to insulin was assessed by measuring glucose consumption in a human pancreatic epithelioid carcinoma cell line treated with sera from healthy and AP subjects. RESULTS: At baseline AP was associated with significant higher levels of IL-1, IL-6, and IL-8 in the serum of untreated (AP) patients vs controls (P < .001). Glucose consumption decreased in pancreatic cells incubated with baseline serum from patients with AP, in a manner proportional to total cytokines amount. Notably, endodontic treatment was associated with reduced levels of cytokines (P < .001) and improved response to insulin in AP group (P < .001). CONCLUSIONS: Our findings suggest that AP may promote inflammatory-driven IR in an in vitro model, and that RCT may ameliorate inflammatory mediators in vivo and the cellular response to insulin in vitro.

Endodontic Inflammatory Disease and Future Cardiovascular Events and Mortality: A Report from the PAROKRANK Study.

INTRODUCTION: Prospective studies assessing the relation between endodontic inflammatory disease and subsequent cardiovascular events are few. The present aim was to explore associations between endodontic variables and future cardiovascular events in patients with myocardial infarction and matched controls participating in the PAROKRANK (Periodontitis and Its Relation to Coronary Artery Disease) study. METHODS: Eight-hundred five patients hospitalized for a first myocardial infarction and 805 controls were recruited between 2010 and 2014. Signs of endodontic inflammatory disease were assessed in panoramic radiographs taken at baseline. Mortality and morbidity data during the approximately 8 years of follow up were obtained from national registries. The risk for future cardiovascular events (first of mortality and nonfatal myocardial infarction, stroke, or hospitalization for heart failure) was analyzed with the log-rank test and Cox proportional hazards regression adjusted for the following confounders: sex, age, smoking, myocardial infarction, diabetes, education, marital status, family history of cardiovascular disease, and marginal periodontitis. RESULTS: In total, 285 future events were observed during the follow-up period. Unadjusted analyses revealed that ≥1 root-filled tooth increased the risk of a future event. After adjustment, the number of remaining teeth and non-root-filled teeth decreased the risk of future events, whereas a higher Decayed, Missing and Filled Teeth score increased the risk and ≥1 primary apical periodontitis decreased the risk of suffering cardiovascular events. A higher Decayed, Missing and Filled Teeth score and decayed teeth increased the risk of all-cause mortality. CONCLUSIONS: Tooth loss is a strong indicator of an increased risk for future cardiovascular events. Root-filled teeth seem of limited value as a risk indicator when accounting for other risk factors. The potential effect of dental interventions on future events should be assessed in future research.

The importance of mechanosensitive cell mediated prostaglandin and nitric oxide synthesis in the pathogenesis of apical periodontitis: comparative with chronic periodontitis.

OBJECTIVES: Mechano-sensitive odontoblast cells, which sense mechanical loading and various stresses in the tooth structure, synthesize early signaling molecules such as prostaglandin E2 (PGE2) and nitric oxide (NO) as an adaptive response. It is thought that these synthesized molecules can be used for the diagnosis and treatment of periodontal and periapical diseases. The aim of this study was to investigate the relationship between the severity of apical periodontitis (AP) and chronic periodontitis (CP) and serum (s) TNF-α, IL-10, PGE2 and NO levels, as well as PGE2 and NO levels in gingival crevicular fluid (GCF) samples. MATERIALS & METHODS: A total of 185 subjects were divided into three categories: AP group (n = 85), CP group (n = 50) and healthy control group (n = 50). The AP group was divided into 3 subgroups according to abscess scoring (AS-PAI 1, 2 and 3) based on the periapical index. The CP group was divided into 4 subgroups according to the periodontitis staging system (PSS1, 2,3 and 4). After recording the demographic and clinical characteristics of all participants, serum (s) and gingival crevicular fluid (GCF) samples were taken. TNF-α, IL-10, PGE2 and NO levels were measured in these samples. RESULTS: Unlike serum measurements (sTNF-α, sIL-10, sNO and sPGE2), GCF-NO and GCF-PGE levels of the AP group were significantly higher than the control group in relation to abscess formation (54.4 ± 56.3 vs. 22.5 ± 12.6 µmol/mL, p < 0.001 and 100 ± 98 vs. 41 ± 28 ng/L, p < 0.001, respectively). Confirming this, the GCF-NO and GCF-PGE levels of the AS-PAI 1 group, in which abscesses have not yet formed, were found to be lower than those in AS-PAI 2 and 3, which are characterized by abscess formation [(16.7(3.7-117.8), 32.9(11.8-212.8) and 36.9(4.3-251.6) µmol/mL, p = 0,0131; 46.0(31.4-120.0), 69.6(40.3-424.2) and 74.4(32.1-471.0) ng/L, p = 0,0020, respectively]. Consistent with the increase in PSS, the levels of sTNF [29.8 (8.2-105.5) vs. 16.7(6.3-37.9) pg/mL, p < 0.001], sIL-10 [542(106-1326) vs. 190(69-411) pg/mL, p < 0.001], sNO [182.1(36.3-437) vs. 57.0(15.9-196) µmol/mL, p < 0.001], sPGE2 [344(82-1298) vs. 100(35-1178) ng/L, p < 0.001], GCF-NO [58.9 ± 33.6 vs. 22.5 ± 12.6 ng/L, p < 0.001] and GCF-PGE2 [ 99(37-365) vs. 30(13-119), p < 0.001] in the CP group were higher than the control group. Comparison ROC analysis revealed that the GCF-PGE2 test had the best diagnostic value for both AP and CP (sensitivity: 94.1 and 88.0; specificity: 64.0 and 78.0, respectively; p < 0.001). CONCLUSIONS: GCF-PE2 and GCF-NO have high diagnostic value in the determination of AP and CP, and can be selected as targets to guide treatment. In addition, the measurements of PGE2 and NO in GCF can be used as an important predictor of pulpal necrosis leading to abscess in patients with AP. CLINICAL RELEVANCE: In this article, it is reported that syntheses of early signaling molecules such as PGE2 and NO can be used for the diagnosis and treatment target of periapical and periodontal infections.

Integration of single-cell RNA sequencing of endothelial cells and proteomics to unravel the role of ICAM1-PTGS2 communication in apical periodontitis: A laboratory investigation.

AIM: Endothelial cells (EDs) play a key role in angiogenesis and are associated with granulomatous lesions in patients with chronic apical periodontitis (CAP). This study aimed to investigate the diversity of EDs using single-cell ribonucleic acid sequencing (scRNA-seq) and to evaluate the regulation of intercellular adhesion molecule 1 (ICAM1) on the ferroptosis-related protein, prostaglandin-endoperoxide synthase 2 (PTGS2), in CAP. METHODOLOGY: EDs from the uploaded scRNA-seq data of five CAP samples (GSE181688 and GSE197680) were categorized using distinct marker genes. The interactions between vein EDs (veinEndo) and other cell types were analysed using CellPhoneDB. Differentially expressed proteins in the proteomics of human umbilical vein EDs (HUVECs) and THP-1-derived macrophages infected with Porphyromonas gingivalis were compared with the differentially expressed genes (DEGs) of VeinEndo in scRNA-seq of CAP versus healthy control periodontal tissues. The protein-protein interaction of ICAM1-PTGS2 in macrophages and HUVECs was validated by adding recombinant ICAM1, ICAM1 inhibitor and PTGS2 inhibitor using real-time polymerase chain reaction (PCR), western blotting, and immunofluorescence staining. RESULTS: EDs in patients with CAP were divided into eight subclusters: five vein ED, capillaries, arterials and EC (PLA). There were 29 mutually upregulated DEGs and two mutually downregulated DEGs in vein cells in the scRNA-seq data, as well as differentially expressed proteins in the proteomics of HUVECs. Real-time PCR and immunofluorescence staining showed that ICAM1 and PTGS2 were highly expressed in CAP, infected HUVECs, and macrophages. Recombinant protein ICAM1 may improve PTGS2 expression, reactive oxygen species (ROS), and Fe2+ levels and decrease glutathione peroxidase 4 (GPX4) and SLC7A11 protein levels. ICAM1 inhibitor may inverse the above changes. CONCLUSIONS: scRNA-seq revealed the diversity of EDs in CAP and identified the possible regulation of ICAM1 by the ferroptosis-related protein, PTGS2, in infected HUVECs and macrophages, thus providing a basis for therapeutic approaches that target the inflammatory microenvironment of CAP.

The Role of Macrophage Efferocytosis in the Pathogenesis of Apical Periodontitis.

Macrophages (Mφs) play a crucial role in the homeostasis of the periapical immune micro-environment caused by bacterial infection. Mφ efferocytosis has been demonstrated to promote the resolution of multiple infected diseases via accelerating Mφ polarization into M2 type. However, the Mφ efferocytosis-apical periodontitis (AP) relationship has not been elucidated yet. This study aimed to explore the role of Mφ efferocytosis in the pathogenesis of AP. Clinical specimens were collected to determine the involvement of Mφ efferocytosis in the periapical region via immunohistochemical and immunofluorescence staining. For a further understanding of the moderator effect of Mφ efferocytosis in the pathogenesis of AP, both an in vitro AP model and in vivo AP model were treated with ARA290, a Mφ efferocytosis agonist. Histological staining, micro-ct, flow cytometry, RT-PCR and Western blot analysis were performed to detect the inflammatory status, alveolar bone loss and related markers in AP models. The data showed that Mφ efferocytosis is observed in the periapical tissues and enhancing the Mφ efferocytosis ability could effectively promote AP resolution via facilitating M2 Mφ polarization. Collectively, our study demonstrates the functional importance of Mφ efferocytosis in AP pathology and highlights that accelerating Mφ efferocytosis via ARA290 could serve as an adjuvant therapeutic strategy for AP.

Assessment of Systemic Condition and Smoking Impact Over Incidence of Apical Periodontitis.

This study aimed to assess the prevalence of apical periodontitis in a subset of the population of south-eastern Romania and to analyze the overall health status of the group of patients with apical periodontitis. The medical and dental history, including age, gender, background, presence of smoking, level of education, the total number of teeth present and with apical periodontitis, and the general health status were recorded from a total of 200 patients. The periapical status was analyzed using an orthopantomogram and periapical radiographs of teeth that were diagnosed with periapical lesions by the same dental professional. The periapical status was classified according to the periapical index (PAI), with apical periodontitis being present if the PAI score ≥3. The majority of patients were female (58.5%), with secondary or higher education from urban areas and the mean number of teeth with apical periodontitis was 2.29 ± 1.26, with a median of 2 teeth. A total of 17.1% of patients were smokers, these patients had two more teeth with periapical pathology, and 16% of all patients had general diseases, the most common of which was cardiovascular disease (8.2%). Compared with those without the disease, these patients had a higher number of teeth with apical periodontitis (median = 2.5, IQR = 2-4 vs. median = 2, IQR = 1-3). As a result, this scientific research suggests an association between smoking, cardiovascular disease, and gastritis with apical periodontitis, but no association could be demonstrated between apical periodontitis and other systemic diseases.

Prevalence of Apical Periodontitis in Patients with Autoimmune Liver Diseases on Immune Suppressants and Immune Modulators: A Cross-sectional Study.

INTRODUCTION: Autoimmune liver diseases (ALDs) are chronic conditions generated by an immune-mediated autoaggressive inflammatory reaction in genetically susceptible individuals. The purpose of this study was to evaluate the prevalence of apical periodontitis (AP) in patients suffering from ALDs undergoing treatment with the immune suppressants glucocorticoids, azathioprine, and/or ursodeoxycholic acid. METHODS: The ALD group included 46 patients (11 men and 35 women, average age = 57.9 ± 11.8 years) and 1186 teeth. The control group included 50 healthy patients not taking any medications (15 men and 35 women, average age = 58.6 ± 10.4 years) and 1251 teeth. Demographic data and medical, pharmacologic, and dental history were recorded. Dental and radiographic examinations were performed. The presence of AP; the periapical index score; decayed, missing, and filled teeth; quality of restoration, and root canal treatment were evaluated. The influence of the medications the patients were taking on the prevalence of AP was also tested. RESULTS: The prevalence of AP was significantly lower in ALDs than in the control group at the patient (P = .019) and tooth level (P = .014). Smoking and age were associated with a significant increase in AP in cases and controls (P = .045 and P = .001, respectively). In both groups, endodontically treated teeth showed a higher prevalence of AP. CONCLUSIONS: Considering the limitations because of the observational nature of the study, the patients affected by ALDs liver diseases and undergoing treatment with immune suppressors (often associated with immune modulators) were found to exhibit a lower prevalence of AP.

Comparation of the effectiveness of conventional needle irrigation and photon-induced photoacoustic streaming with sodium hypochorite in the treatment of teeth with apical periodontitis: a randomized clinical trial.

Photon-initiated photoacoustic streaming (PIPS) with an Er: YAG laser has been introduced in root canal treatment to improve irrigation and facilitate the removal of bacteria in the root canal system. This study aimed to compare the antibacterial effectiveness of two different root canal irrigation techniques, conventional needle irrigation (CNI) and PIPS, using 1% sodium hypochlorite (NaOCl), in the treatment of teeth with apical periodontitis. Sixty patients with a total of sixty teeth affected by apical periodontitis were included in this study. The teeth underwent root canal therapy, and after mechanical instrumentation, they were randomly assigned to two groups (n = 30) based on the final irrigation protocol: CNI or PIPS with 1% NaOCl. Bacterial suspensions in the root canals were evaluated using Adenosine 5'-triphosphate (ATP) assay kit after mechanical instrumentation and after final irrigation. Then, a follow-up was conducted after 7 days. The results revealed that final irrigation significantly reduced ATP values in both the CNI and PIPS groups (P < 0.001). The ATP values after final irrigation was greater in the CNI group compared to the PIPS group (P < 0.001). After a 7-day follow-up, percussion tenderness and fistula were significantly resolved in both groups (P < 0.05). A multivariate linear regression model was used to identify the factors that influence post irrigation ATP values. The analysis demonstrated that pre-operative percussion tenderness (P = 0.006), the presence of a fistula (P < 0.001) and the method used in the final irrigation (P < 0.001) had a significant impact on the ATP value after final irrigation. These results indicate that employing PIPS with 1% NaOCl as the final irrigation protocol exhibited superior antibacterial effectiveness and has the potential to enhance clinical outcomes in the treatment of teeth afflicted with apical periodontitis.

Prognostic Factors Affecting the Outcome of Surgical Root Canal Treatment-A Retrospective Cone-Beam Computed Tomography Cohort Study.

Aim: To assess the association between demographic and clinical variables and the outcome of root-end surgery using digital periapical radiographs (PA) and cone-beam computed tomography (CBCT). Methodology: One hundred and fifty teeth that received endodontic microsurgery were clinically and radiographically examined (PA and CBCT scans) after 1 and 2 years. Two calibrated endodontists evaluated the radiographic healing based on a six-point outcome classification. The outcome was classified using both strict (healed) and loose (healing) criteria. The success rates were calculated, and several outcome prognostic factors were assessed. Results: One hundred and fifty teeth were assessed with both radiographic systems. When "loose" success criteria were applied using PA, 90% (n = 135) of teeth were assessed as having had a favourable outcome (90%; 95% CI: 85.2-94.8%), whereas 90.7% (n = 136) of teeth showed a successful outcome when assessed with CBCT (90.7%; 95% CI: 86.0-95.3%). When "strict" success criteria were applied, there was a statistically significant difference (p = 0.018) between the success rates of mineral trioxide aggregate (MTA) (63.7%) and Biodentine (95.5%). Conclusions: Within the limitations of this study, endodontic microsurgery showed a high success rate. Among all the demographic and clinical variables assessed, in the multiregression analysis, only the use of Biodentine was associated with a higher proportion of "complete" healings compared to MTA or Intermediate Restorative Material (IRM) when assessed using CBCT. MTA and Biodentine performed similarly when "incomplete" healings were regarded as successful outcomes.

Metformin switches cell death modes to soothe the apical periodontitis via ZBP1.

Apical periodontitis (AP) is a disease caused by pathogenic microorganisms and featured with the degradation of periapical hard tissue. Our recent research showed the crucial role of Z-DNA binding protein 1 (ZBP1)-mediated necroptosis and apoptosis in the pathogenesis of AP. However, the specific regulatory mechanisms of ZBP1 in AP are not fully elucidated. It was found that metformin has a regulatory role in cell necroptosis and apoptosis. But whether and how metformin regulates necroptosis and apoptosis through the ZBP1 in the context of AP remains unknown. This study provided evidence that lipopolysaccharide (LPS) promotes the synthesis of left-handed Z-nucleic acids (Z-NA), which in turn activates ZBP1. Knockout of Zbp1 by CRISPR/Cas9 technology significantly reduced LPS-induced necroptosis and apoptosis in vitro. By using Zbp1-knockout mice, periapical bone destruction was alleviated. Moreover, type I interferon induced the expression of interferon-stimulated genes (ISGs), which serve as a major source of Z-NA. In addition, the RNA-editing enzyme Adenosine Deaminase RNA specific 1 (ADAR1) prevented the accumulation of endogenous Z-NA. Meanwhile, metformin suppressed the ZBP1-mediated necroptosis by inhibiting the expression of ZBP1 and the accumulation of ISGs. Metformin also promoted mitochondrial apoptosis, which is critical for the elimination of intracellular bacterial infection. The enhanced apoptosis further promoted the healing of infected apical bone tissues. In summary, these results demonstrated that the recognition of Z-NA by ZBP1 plays an important role in AP pathogenesis. Metformin suppressed ZBP1-mediated necroptosis and promoted apoptosis, thereby contributing to the soothing of inflammation and bone healing in AP.

Revolutionizing Endodontics: Innovative Approaches for Treating Mature Teeth With Closed Apices and Apical Lesions: A Report of Two Cases.

INTRODUCTION: Modern tissue engineering strategies have elucidated the potential of regenerative endodontic treatment (RET) as an alternative for treating mature teeth. METHODS: Here, we report two cases in which cell-based RET (CB-RET) using encapsulated allogeneic umbilical cord mesenchymal stem cells (UC-MSCs) in a platelet-poor plasma (PPP)-based scaffold was used in two mature teeth with pulp necrosis and apical periodontitis. RESULTS: After 5 years of follow-up, the healing response was satisfactory in both cases, with evidence of pulp revitalization. CONCLUSIONS: This is the first study to report the success of an extended, 5-year follow-up for allogeneic CB-RET. This report presents an innovative and sustainable solution to challenging endodontic scenarios.

STING inhibition alleviates bone resorption in apical periodontitis.

AIM: The goal of this study was to investigate the potential effects of an immunotherapeutic drug targeting STING to suppress the overreactive innate immune response and relieve the bone defect in apical periodontitis. METHODOLOGY: We established an apical periodontitis mouse model in Sting-/- and WT mice in vivo. The progression of apical periodontitis was analysed by micro-CT analysis and H&E staining. The expression level and localization of STING in F4/80+ cells were identified by IHC and immunofluorescence staining. RANKL in periapical tissues was tested by IHC staining. TRAP staining was used to detect osteoclasts. To clarify the effect of STING inhibitor C-176 as an immunotherapeutic drug, mice with apical periodontitis were treated with C-176 and the bone loss was identified by H&E, TRAP, RANKL staining and micro-CT. Bone marrow-derived macrophages (BMMs) were isolated from Sting-/- and WT mice and induced to osteoclasts in a lipopolysaccharide (LPS)-induced inflammatory environment in vitro. Moreover, WT BMMs were treated with C-176 to determine the effect on osteoclast differentiation by TRAP staining. The expression levels of osteoclast-related genes were tested using qRT-PCR. RESULTS: Compared to WT mice, the bone resorption and inflammatory cell infiltration were reduced in exposed Sting-/- mice. In the exposed WT group, STING was activated mainly in F4/80+ macrophages. Histological staining revealed the less osteoclasts and lower expression of osteoclast-related factor RANKL in Sting-/- mice. The treatment of the STING inhibitor C-176 in an apical periodontitis mice model alleviated inflammation progression and bone loss, similar to the effect observed in Sting-/- mice. Expression of RANKL and osteoclast number in periapical tissues were also decreased after C-176 administration. In vitro, TRAP staining showed fewer positive cells and qRT-PCR reflected decreased expression of osteoclastic marker, Src and Acp5 were detected during osteoclastic differentiation in Sting-/- and C-176 treated BMMs. CONCLUSIONS: STING was activated and was proven to be a positive factor in bone loss and osteoclastogenesis in apical periodontitis. The STING inhibitor C-176 administration could alleviate the bone loss via modulating local immune response, which provided immunotherapy to the treatment of apical periodontitis.

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Alveolar bone, the protruding portion of the maxilla and the mandible that surrounds the roots of teeth, plays an important role in tooth development, eruption, and masticatory performance. In oral inflammatory diseases, including apical periodontitis, periodontitis, and peri-implantitis, alveolar bone defects cause the loosening or loss of teeth, impair the masticatory function, and endanger the physical and mental health of patients. However, alveolar bone restoration is confronted with great clinical challenges due to the the complicated effect of the biological, mechanical, and chemical factors in the oral microenvironment. An in-depth understanding of the underlying molecular regulatory mechanisms will contribute to the exploration of new targets for alveolar bone restoration. Recent studies have shown that Notch, Wnt, Toll-like receptor (TLR), and nuclear factor-κB (NF-κB) signaling pathways regulate the proliferation, differentiation, apoptosis, and autophagy of osteoclasts, osteoblasts, osteocytes, periodontal ligament cells, macrophages, and adaptive immune cells, modulate the expression of inflammatory mediators, affect the balance of the receptor activator for nuclear factor-κB ligand/receptor activator for nuclear factor-κB/osteoprotegerin (RANKL/RANK/OPG) system, and ultimately participate in alveolar bone restoration. Additionally, alveolar bone restoration involves AMP-activated protein kinase (AMPK), phosphatidyl inositol 3-kinase/protein kinase B (PI3K/AKT), Hippo/YAP, Janus kinase/signal transducer and activator of transcription (JAK/STAT), and transforming growth factor ß (TGF-ß) signaling pathways. However, current studies have failed to construct mature molecular regulatory networks for alveolar bone restoration. There is an urgent need for further research on the molecular regulatory mechanisms of alveolar bone restoration by using new technologies such as single-cell transcriptome sequencing and spatial transcriptome sequencing.

Experimental apical periodontitis alters salivary biochemical composition and induces local redox state disturbances in the salivary glands of male rats.

OBJECTIVES: The objective was to evaluate the effects of experimental apical periodontitis on the inflammatory, functional, biochemical, and redox parameters of the parotid and submandibular glands in rats. MATERIALS AND METHODS: Twenty 12-week-old male Wistar rats were randomly divided into two groups (n = 10): a control group and apical periodontitis group. After 28 days, the saliva was collected for salivary flow rate and biochemistry composition. Both glands were sampled for quantification of the tumor necrosis factor-alpha (TNF-α) and biochemical analyses of redox state. RESULTS: TNF-α concentrations were higher in both salivary glands adjacent to the periapical lesions in animals with apical periodontitis and also compared to the control group. The apical periodontitis group increased the salivary amylase, chloride, potassium, calcium, and phosphate. The total oxidant capacity increased in the parotid gland adjacent to the periapical lesions in the same rat and compared to the control group. Conversely, the total antioxidant capacity of the parotid glands on both sides in the apical periodontitis group was lower than that in the control group. Furthermore, glutathione peroxidase activity increased in the submandibular gland adjacent to the apical periodontitis group compared to the control group. CONCLUSIONS: Experimental apical periodontitis alters salivary biochemical composition, in addition to increasing inflammatory marker and inducing local disturbances in the redox state in the parotid and submandibular glands of male rats. CLINICAL RELEVANCE: Apical periodontitis could exacerbate the decline in oral health by triggering dysfunction in the salivary glands.

Correlation Between Proinflammatory Cytokine Expression and Clinical Data in Apical Granuloma.

INTRODUCTION: This study was intended to evaluate the expression of inflammatory cytokines commonly secreted by CD4+ T cells (IL-2, IL-5, IL-17, TGF-ß, TNF-α, and IFN-γ) in apical granulomas and correlate with the clinical conditions and time elapsed since root canal treatment. METHODS: Eighteen biopsy specimens obtained by periradicular surgery of teeth with post-treatment apical periodontitis and diagnosed as apical granuloma were available from the oral pathology laboratory. Silanized slides containing paraffin sections were used for immunohistochemical reactions. Images were analyzed by using an optical microscopy and each slide was subdivided into 5 fields at high magnification. RESULTS: IFN-γ and TGF-ß were the cytokines with the highest expression levels. There were statistically significant differences when comparing IL-2 and IFN-γ (P < .05), and IL-2 and TGF-ß (P < .05). Comparison between the detected cytokines and clinical data and time of treatment demonstrated significant correlation (P < .05) between lower expression of IL-2 and the presence of painful symptoms, absence of sinus tract, and treatments performed more than 4 years before. It was also possible to observe a significant correlation between lower expression of IL-5 and treatments performed less than 4 years before (P < .05). CONCLUSION: IFN-γ and TGF-ß were highly expressed in apical granulomas. However, only IL-2 and IL-5 levels were associated with clinical data and time since previous root canal treatment.

Association between apical periodontitis and secondary outcomes of atherosclerotic cardiovascular disease: A case-control study.

AIM: To evaluate the association between apical periodontitis (AP) and atherosclerotic cardiovascular disease (ASCDV). METHODOLOGY: A total of 65 periodontally and systemically healthy patients (age ≥ 40 years) were included in the study. Periapical status was assessed through dental examination and periapical radiographs; 33 subjects had AP (AP+), while 32 acted as control (AP-). Moreover, data regarding their periapical index (PAI) score and the Decayed, Missing, and Filled Teeth (DMFT) index were recorded. All subjects underwent echo-colour Doppler assessment of carotid intima-media thickness (CIMT), carotid plaques, degree of stenosis using the North American Symptomatic Carotid Surgery Trial (NASCET) method, maximum diameter of the abdominal aorta (maximum AA) and common iliac arteries (CIA) diameters. Furthermore, peripheral blood flow was also measured using the ankle-brachial index (ABI). Simple and multiple regression analyses were performed. RESULTS: Among AP+ patients, 57.58% disclosed at least one sign of subclinical carotid atherosclerosis. Multiple regression analysis identified AP as a significant risk indicator for carotid plaques [OR = 4.87 (1.27, 18.98; p = .021)] and marked carotid intima-media thickenings (OR = 14.58 [1.22, 176.15], p = .035). A significant association was established between AP and other cardiovascular (CV) variables (CIMT, NASCET, and maximum AA). On the contrary, a higher PAI score does not correlate to increased odds of carotid alterations, and the presence of AP did not prove any significant change in CIA and ABI. No significant correlation was established between DMFT and other variables. CONCLUSIONS: Results from the current study highlight that the presence of AP may be regarded as a risk indicator for ASCVD, with AP being associated with 5-fold increased odds of having carotid plaques and 15-fold increased odds of having marked carotid intima-media thickenings. Further studies should be conducted in order to verify whether AP treatment could be beneficial for ASCVD signs.

Primary apical periodontitis correlates to elevated levels of interleukin-8 in a Swedish population: A report from the PAROKRANK study.

AIM: To explore associations between root filled teeth, primary and secondary apical periodontitis, and levels of inflammatory markers in blood from patients with a first myocardial infarction and matched controls. METHODOLOGY: Between May 2010 and February 2014, 805 patients with a first myocardial infarction and 805 controls, matched for sex, age, and postal code area, were recruited to the multicentre case-control study PAROKRANK (periodontitis and its relation to coronary artery disease). All participants underwent a physical and oral examination, as well as blood sampling. Using panoramic radiography, root filled teeth, primary apical periodontitis, and secondary apical periodontitis were assessed by three independent observers. Blood samples were analysed with enzyme-linked immunosorbent assay method for the following inflammatory markers: interleukin-1ß (IL-1ß), IL-2, IL-6, IL-8, IL-12p70, tumour necrosis factor-α, and high-sensitivity C-reactive protein (hsCRP). Additionally, white blood cell count and plasma-fibrinogen were analysed. Associations between endodontic variables and the levels of inflammatory markers were statistically analysed with Mann-Whitney U-test and Spearman correlation, adjusted for confounding effects of baseline factors (sex, age, myocardial infarction, current smoking, diabetes, family history of cardiovascular disease, education, marital status, and periodontal disease). RESULTS: Mean age of the cohort was 62 years, and 81% were males. Root fillings were present in 8.4% of the 39 978 examined teeth and were associated with higher levels of hsCRP, fibrinogen, and leukocyte count, but lower levels of IL-2 and IL-12p70. After adjusting for confounders, root filled teeth remained associated with higher levels of fibrinogen, but lower levels of IL-1ß, IL-2, IL-6, and IL-12p70. Primary apical periodontitis was found in 1.2% of non-root filled teeth and associated with higher levels of IL-8 (correlation 0.06, p = .025). Secondary apical periodontitis was found in 29.6% of root filled teeth but did not relate to the levels of any of the inflammatory markers. CONCLUSIONS: This study supports the notion that inflammation at the periapex is more than a local process and that systemic influences cannot be disregarded. Whether the observed alterations in plasma levels of inflammatory markers have any dismal effects on systemic health is presently unknown but, considering the present results, in demand of further investigation.

Comparison of Cytokine RANTES/CCL5 Inflammation in Apical Periodontitis and in Jawbone Cavitations - Retrospective Clinical Study.

Background: Apical periodontitis (AP) is one of the most common endodontic diseases associated with osteo destructive cytokine production. The literature also reports cytokine studies in fatty degenerative osteonecrotic bone marrow defects (BMDJ/FDOJ) independent of AP. Objective: We compare the RANTES/CCL5 (R/C) chemokine production between AP and BMDJ/FDOJ. For both pathologies, the R/C expression was also compared to radiographic diagnosis in 2D-OPG, 3D-CBCT/DVT. Material and Methods: Postoperative samples were collected and divided in three different groups: HB (healthy jawbone) (n=19), APs (n=19), and BMDJ/FDOJ (n=7). The R/C expression was evaluated using multiplex analysis. In addition, two clinical cases from AP and BMDJ/FDOJ groups were randomly selected and radiographic diagnosis in 2D-OPG and 3D-CBCT/DVT was compared to TAU measurements and R/C expression in AP and in BMDJ/FDOJ. Results: BMDJ/FDOJ showed the highest R/C expression (2498.71 pg/mL), followed by AP (841.85 pg/mL) and HB (149.85 pg/mL) (AP vs BMDJ/FDOJ = p=0.01; AP vs HB = p=<0.01; BMDJ/FDOJ vs HB = p=<0.01). In both clinical cases, the radiographic findings depict the AP areas in OPG and CBCT/DVT, in contrast to the BMDJ/FDOJ areas. Conversely, the systemic immunological R/C expressions are threefold and fivefold excessive in both cases. Discussion: AP is recognized as a pathology requiring treatment, while the pathogenesis of BMDJ/FDOJ is controversially discussed in the literature, despite stronger potential systemic immunological effects (breast cancer (case 1) and multiple sclerosis (case 2)). The inadequate radiographic representation of reduced bone density in BMDJ/FDOJ areas could be a reason for this contradiction. Conclusion: The data presented provide the first quantitative analysis of R/C expression in AP and BMDJ/FDOJ. BMDJ/FDOJ showed high R/C expression than AP, besides the diagnostic through radiographs being extremely poor. To cover this imprecision, a radiation-free TAU device is available.