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Objective: To evaluate the possible effects of apical periodontitis (AP) on cardiac function, structure, and oxidative stress (OS) in rats with diabetes mellitus type 2 (T2DM)., Design: Forty-eight (Wistar albino, male) rats were randomized into four groups: control healthy (CTRL), normoglycemic with AP (AP), T2DM, and T2DM with AP (T2DM+AP). T2DM was induced by streptozotocin and a high-fat diet. AP was induced by pulp exposure to the oral environment for 4 weeks and analyzed radiographically. In the blood samples insulin and glucose were established. In vivo, cardiac function was evaluated by echocardiography. Ex vivo cardiac function was assessed by the Langendorff technique. Heart tissue was analyzed pathophysiologically. OS was determined in cardiac tissue homogenate and coronary venous effluent, spectrophotometrically., Results: Impaired glycoregulation was observed in the T2DM+AP group compared to the T2DM, AP, and CTRL groups. The T2DM+AP group was associated with disturbed echocardiography and cardiodynamic parameters. The levels of superoxide anion radical, nitrite, and index of lipid peroxidation were significantly increased, while the superoxide dismutase and catalase were significantly decreased in the T2DM+AP group compared to T2DM, AP, and CTRL groups. The radiographic AP area was significantly larger in the T2DM+AP compared to the AP group., Conclusion: AP was associated with increased glucose levels, impaired cardiac function, structure, and OS in diabetic rats. Diabetes was related to an increased radiographic AP area. The study may be a starting point for further research to clarify the effects of AP on cardiac function in various models of systemic diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The maxillary sinus floor is formed by the alveolar process of the maxilla. Frequently, the roots of maxillary molars and premolars may protrude into the sinus cavity, with only a thin membrane separating them. Endodontic infections are characterized by mixed biofilms of anaerobic and proteolytic bacteria that can infect the root canal space and accessory anatomy of those teeth producing apical periodontitis. Due to the close relationship with the maxillary sinus, the persistence of apical periodontitis could potentially lead to odontogenic sinusitis. Understanding maxillary sinus anatomy and its relationship with the posterior maxillary dentition is crucial for diagnosing this entity., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: This prospective study evaluated the effect of immediate functional loading (IFL) of a full-coverage prosthesis on the clinical and radiographic outcome of nonsurgical endodontic therapy (NSET) performed on mandibular molar teeth with pulp necrosis and asymptomatic apical periodontitis., Methods: In 20 subjects, standardized 2-visit NSET was performed in bilateral mandibular first molar teeth (split-mouth model) with a diagnosis of pulp necrosis and asymptomatic apical periodontitis exhibiting a radiographic periapical index (PAI) score ≥3. In each subject, the nonvital bilateral mandibular first molar teeth were randomized to 1 of 2 groups: the IFL group or the functional loading after a time interval of 6 months group. Provisional full-coverage prostheses were provided within 7 days after the completion of endodontic therapy. The cases were followed up clinically and radiographically at 6 and 12 months. Radiographs were assessed for periapical healing based on PAI scores, which were dichotomized as healed (PAI score ≤2) or nonhealed (PAI score ≥3). The data were compared using chi-square and Fisher exact tests., Results: A recall rate of 100% was achieved at the end of 12 months. All teeth in the IFL group and the functional loading after a time interval of 6 months group were clinically asymptomatic. According to an intergroup comparison between the proportion of teeth healed and nonhealed (radiographic), there was a significant difference (P < .05)., Conclusions: IFL of a full-coverage prosthesis in endodontically treated mandibular molar teeth with pulp necrosis and asymptomatic apical periodontitis delayed periapical healing., (Copyright © 2024 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Introduction: The aim of this study was to assess the prevalence and severity of apical periodontitis (AP) in subjects with different stages of chronic kidney disease (CKD) and its association with systemic markers., Methods: In this cross-sectional study, 105 patients with CKD (n = 35 each in the early, predialysis, and hemodialysis groups) and 105 healthy controls were included. The prevalence, number of teeth with AP (endodontic burden [EB]), and the severity of AP were recorded. High- sensitivity C-reactive protein, blood urea, and serum creatinine levels were also recorded. Logistic regression was applied to determine the possible association between CKD and AP in the study population, and linear regression was performed to predict the effect of AP on systemic markers in CKD patients., Results: AP in at least 1 tooth was found in 75.2% of CKD patients and 40.9% of the controls (P < .05). CKD patients were 4 times more likely to have AP than controls (P < .05; odds ratio = 3.954; 95% confidence interval, 2.09-7.45). EB and the severity of AP were also significantly higher in CKD patients than the healthy controls (P < .05). Although higher values of EB and severe AP were observed with the progression of disease, the difference was not significant. The severity of AP was significantly associated with an increase in serum creatinine, blood urea, and a decrease in estimated glomerular filtration rate (P < .05) in CKD patients., Conclusions: AP was significantly more prevalent in the CKD group. The association between the severity of AP and CKD markers suggests that AP could possibly alter the progression of CKD. However, these findings do not establish a cause-and-effect relationship., (Copyright © 2023 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Objectives: To investigate the regulation of inflammatory and osteoclastogenic signaling by 5-lipoxygenase (5-LO) in apical periodontitis induced by oral contamination of dental root canals in mice., Design: Apical periodontitis was induced in 5-lipoxygenase enzyme knockout (129-Alox5 tm1Fun ) and 129 wild-type mice (n = 96) by exposure of the dental root canal to the oral cavity. After 7, 14, 21, and 28 days, the animals were euthanized and the tissues removed (n = 12 teeth per period) for histopathological and histometric analyses (hematoxylin and eosin [HE]), evaluation of osteoclastogenic activity (tartrate-resistant acid phosphatase enzyme [TRAP]), and determination of inflammatory and osteoclastogenic signaling (qRT-PCR)., Results: Oral contamination of dental root canals induced recruitment of neutrophils and osteoclasts to the periodontal ligament, resulting in bone resorption. Absence of 5-LO did not impair neutrophil recruitment while osteoclastic formation was increased. Nonetheless, early bone resorption progressed similarly to lesions in wild-type animals. Interestingly, in the absence of 5-LO, the synthesis of mRNAs for cytokines, chemokines, and their receptors was significantly reduced while that of regulators of osteoclastogenesis (RANK, RANKL, and OPG) was increased in comparison with the corresponding levels in wild-type animals., Conclusions: The 5-LO pathway plays a role in the stimulation of inflammatory mediator synthesis and inhibition of osteoclastogenesis in apical periodontitis in mice. However, the paradoxical inflammatory-osteoclastogenic signaling did not impair inflammatory cell recruitment and bone resorption during early development of the disease., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To investigate the influence of chronic stress and adrenergic blockade in a rat model of apical periodontitis., Methods: Thirty-two Wistar rats were submitted to an animal model of periapical lesion and randomly divided into 4 groups (n = 8): no stress (NS); stress + saline solution (SS); stress + β-adrenergic blocker (Sβ); stress + α-adrenergic blocker (Sα). The SS, Sβ and Sα groups were submitted to an animal model of chronic stress for 28 days and received daily injections of saline solution, propranolol (β adrenergic blocker) and phentolamine (α adrenergic blocker), respectively. After 28 days the animals were euthanized and the following analyses were carried out: a) serum corticosterone levels through Radioimmunoassay; b) measurement of serum levels of IL-1B, IL-6, IL-10 and IL-17 by enzyme-linked immunosorbent assay (ELISA); c) volume of periapical bone resorption by micro-computed tomography; d) histomorphometric analysis by staining with hematoxylin and eosin; e) expression of β-AR, α-AR, receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) by immunohistochemistry; f) tartrate-resistant acid phosphatase (TRAP) staining; g) ex-vivo cytokine release followed by the stimulation with LPS in superfusion system, by ELISA., Results: SS group displayed significantly higher corticosterone levels than NS group (non-stressed). Higher IL-1β serum level was observed in the NS group (p < .05); compared to all stressed groups. Other cytokines were present in similar amounts in the serum of all groups. All groups presented similar periapical lesions. All groups presented moderate inflammatory infiltrate, without statistically significant differences between them. No differences were observed regarding β-AR, α-AR, Rank-L and OPG expression. The number of TRAP-positive cells was significantly decreased in the groups that received daily injections of adrenergic blockers. The IL-1β release followed LPS stimulation was significantly suppressed when the superfusion media contained propranolol (p < .05). Perfusion containing phentolamine induced a greater release of IL-10. TGF-β was significantly suppressed by phentolamine perfusion in the NS group (p < .05)., Conclusions: Chronic stress can significantly change the inflammatory cytokines release. Rank-L/OPG system and periapical lesion volume were not affected following the current method applied. The administration of adrenergic blockers was not able to modulate the inflammatory response but presented effectivity in reducing the number of osteoclasts in the periapical region., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: This study aimed to investigate the role of JAK2-STAT3 (Janus kinase 2/signal transducer and activator of transcription 3) in periapical disease caused by Enterococcus faecalis, as well as the correlation between lipoteichoic acid (LTA) in E. faecalis and the activity of the JAK2-STAT3 signaling pathway and osteoclast formation., Materials and Methods: A rat model of periapical periodontitis induced by E. faecalis was established. Periapical bone resorption was confirmed by HE staining. The expression of JAK2, p-JAK2, STAT3, and p-STAT3 was assessed with immunohistochemical staining. Osteoclasts were observed through enzyme histochemical staining. LTA acted on mouse osteoclast precursor cells (RAW264.7 cells); a JAK2 inhibitor (AG490) was used to inhibit the JAK2-STAT3 pathway in RAW264.7 cells. The expression of proteins in the JAK2-STAT3 pathway and TRAP (tartrate resistant acid phosphatase) in RAW264.7 cells was also detected., Results: Rat periapical periodontitis was successfully established and bone resorption peaked at day 21. The expression of critical components in the JAK2-STAT3 pathway increased with the progression of inflammation. LTA promoted the differentiation of RAW264.7 cells into osteoclasts. NFATc1 was highly expressed and was inhibited by AG490., Conclusions: JAK2-STAT3 signaling pathway plays an important role in the process of periapical bone resorption and osteoclastogenesis., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.)

Introduction: Cardiovascular diseases are the leading cause of mortality worldwide. Apical periodontitis (AP) has been associated with an increased risk of cardiovascular diseases. A correlation has been shown between chronic AP and endothelial dysfunction (ED), but there is no evidence to indicate ED improves after endodontic treatment in patients with periapical lesions. The aim of this study was to investigate vascular and molecular markers of early ED before and after root canal treatment in young adults with chronic AP., Methods: Twenty control subjects and 21 patients with AP were assessed at baseline. The AP patients were also evaluated 2 and 12 months post-treatment. Endothelial flow reserve was assessed via an endothelial function test, and enzyme-linked immunosorbent assays were used to evaluate plasma levels of proinflammatory cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor alpha; vasoconstrictor ED marker endothelin (ET)-1; circulating endothelial adhesion markers intercellular adhesion molecule 1 (ICAM-1)/CD54 and soluble vascular cellular adhesion molecule (sVCAM)-1/CD106; soluble CD14; and the endothelial leukocyte adhesion molecule (E-selectin)., Results: AP was associated with increased serum levels of ET-1, ICAM-1, E-selectin, IL-1, and sCD14, suggesting early vascular ED, with no macroscopic evidence of a reduction in endothelial flow reserve. Root canal treatment ameliorated inflammation and early ED, lowering plasma levels of IL-1, sCD14, ET-1, ICAM-1/CD54, and E-selectin to those of control subjects., Conclusions: Our findings suggest that AP may drive early vascular ED and that the endodontic therapy of AP ameliorates early ED., (Copyright © 2019 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Introduction: The exact mechanisms of periapical bone resorption have not been fully elucidated. This study aimed to analyze the expression of Notch signaling molecules (Notch2, Jagged1, and Hey1) and proinflammatory cytokines (tumor necrosis factor alpha [TNF-α], interleukin [IL]-1β, and IL-6) in human apical periodontitis lesions with different receptor activator of nuclear factor kappa B ligand (RANKL)/osteoprotegerin (OPG) ratios and determine their potential correlation., Methods: The study group consisted of 50 periapical lesions collected in conjunction with apicoectomy. The relative gene expression of the investigated molecules (Notch2, Jagged1, Hey1, RANKL, OPG, TNF-α, IL-1β, and IL-6) in all tissue samples was analyzed using reverse transcriptase real-time polymerase chain reaction. The Student t test, Mann-Whitney U test, and Spearman correlation were used for statistical analysis., Results: Based on the RANKL/OPG ratio, periapical lesions were either RANKL predominant (RANKL > OPG, n = 33) or OPG predominant (RANKL < OPG, n = 17). Symptomatic lesions occurred more frequently in RANKL-predominant compared with OPG-predominant lesions (24 vs 7, P = .029). Notch2, Jagged1, Hey1, and TNF-α were significantly overexpressed in lesions with predominant RANKL compared with lesions with predominant OPG (P = .001, P = .001, P = .027, and P = .016, respectively). Significant correlations were observed between the investigated genes in periapical lesions., Conclusions: Notch signaling appeared to be activated in periapical inflammation. An increase in Notch2, Jagged1, Hey1, and TNF-α expression in RANKL-predominant periapical lesions corroborates their joined involvement in extensive periapical bone resorption., (Copyright © 2018 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Objective: Because the impact of conditioned fear stress on apical bone resorption is unknown, the aim of the current studywas to use a rat model to evaluate the impact of conditioned fear stress on the bone resorption of inflammatory apical periodontitis lesions., Methods: Twenty-five animals were divided into two groups. They underwent a surgical procedure in the first left lower molar tooth to expose the dental pulp and induce inflammatory apical periodontitis lesions through the retention of contamination (bacterial infection) during a 56-day period. The animals in the case group were stressed daily by using electrical stimuli (1.10 mA), whereas the animals in the control group were absent from the stressful stimuli (shocks). The open field test was performed to validate the stress methodology. The jaws were removed and collected for histological and radiographic analyses., Results: Stressed animals presented increased levels of bone loss and inflammatory cells in the root apex in comparison with the control group (P = 0.0001). However, no radiographic differences were observed between the groups (P > 0.05)., Conclusions: Our results demonstrated that conditioned fear stress could modify a periapical lesion by increasing the size of bone loss there. Conditioned fear stress also increased the total number of inflammatory cells compared with the control group. Studies evaluating the impact of conditioned fear stress on human periapical inflammatory lesions should be encouraged., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: The aim of this study was to systematically review the evidence on the cleaning and disinfection of root canals and the healing of apical periodontitis when ultrasonic irrigant activation is applied during primary root canal treatment of mature permanent teeth compared with syringe irrigation., Methods: An electronic search was conducted of the Cochrane Library, Embase, LILACS, PubMed, SciELO, and Scopus databases using both free-text key words and controlled vocabulary. Additional studies were sought through hand searching of endodontic journals and textbooks. The retrieved studies were screened by 2 reviewers according to predefined criteria. The included studies were critically appraised, and the extracted data were arranged in tables., Results: The electronic and hand search retrieved 1966 titles. Three clinical studies and 45 in vitro studies were included in this review. Ultrasonic activation did not improve the healing rate of apical periodontitis compared with syringe irrigation after primary root canal treatment of teeth with a single root canal. Conflicting results were reported by the in vitro microbiological studies. Ultrasonic activation was more effective than syringe irrigation in the removal of pulp tissue remnants and hard tissue debris based on both clinical and in vitro studies. Ultrasonic activation groups were possibly favored in 13 studies, whereas syringe irrigation groups may have been favored in 3 studies., Conclusions: The level of the available evidence was low, so no strong clinical recommendations could be formulated. Future studies should focus on the antimicrobial effect and healing of apical periodontitis in teeth with multiple root canals., (Copyright © 2018 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Introduction: Regeneration of the pulp-dentin complex is the penultimate goal of regenerative endodontic procedures (REPs). Histological outcomes have demonstrated reparative tissue formation in human teeth extracted post-REPs. However, lack of accurate characterization has precluded identification of the true nature of tissues formed post-REP., Methods: Here, we present 2 case reports of tooth #29 and #9 treated with REPs and demonstrate their clinical, radiographic, and histological outcomes., Results: Clinical outcomes revealed healing of apical periodontitis in both teeth and re-establishment of vitality responses in tooth #29. Moreover, radiographic assessments using 2D and 3D-volumetric analyses demonstrate considerable increase in root development for both teeth. Further, histological outcomes evaluated using Hematoxylin and Eosin and immunohistochemical staining demonstrates presence of vascular and lymphatic structures as well as immune cell markers indicative of regeneration of an immunocompetent pulp. Lastly, examination of hard tissue deposition shows dentin-like tissue in parts of tooth #29 demonstrating for the first time, regeneration of a pulp-dentin complex post-REP., Conclusions: Collectively, this is the first study demonstrating recapitulation of several tissues commonly found as part of a pulp-dentin complex in teeth treated with REPs., (Copyright © 2018 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Introduction: We evaluated healing after nonsurgical primary/secondary endodontic treatment of apical periodontitis (AP) in patients with inflammatory bowel diseases (IBDs) treated with anti-tumor necrosis factor alpha biologic medications (BMs)., Methods: Nineteen patients with 22 teeth affected by AP from the gastroenterology unit of the hospital with IBDs under treatment with BMs formed the study group (the IBD group). Fourteen patients with 22 teeth with AP, matched by age and sex, without systemic diseases and not taking medications formed the control group. Teeth underwent primary or secondary root canal treatments and clinical and radiographic follow-up every 3 months for 24 months. The periapical index score was recorded, and 2 trained and calibrated endodontists evaluated and compared radiographs (weighted kappa values, κ = 0.8). The Mann-Whitney, t, chi-square, Fisher, and Bruner-Langer tests and analysis of variance-type statistics were used as appropriate., Results: The recall rate was 100%. All teeth in the IBD patients and 81% in the control patients healed (P = .108). Initial healing was appreciable at 3 months in the IBD group and 6 months in the control group (P = .174). Overall healing was reached at 6 and 10.5 months in the IBD and control groups, respectively (P = .106). At any time of the experiment, teeth in the IBD patients showed a higher probability of healing (P < .05). Both groups exhibited a similar decrement of the periapical index (P = .291), more significant for the IBD at the 3-month follow-up (P < .05). The 2 BMs used showed a similar trend of healing (P = .628)., Conclusions: The treatment of AP in patients taking BMs had no complications; furthermore, it was associated with faster healing than the controls. These results support the possible therapeutic aid of BMs in treating AP., (Copyright © 2018 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Endodontic medicine, which addresses the bidirectional relationship between endodontic infections and systemic diseases, has gained prominence in the field of endodontics. There is much evidence showing that while systemic disease may influence the pathogenesis of endodontic infection, endodontic infection can also cause systemic alterations. These alterations include more severe bone resorption and inflammation in the periapical area as well as enhanced systemic disease symptoms. Similarly, many reports have described the impact of systemic diseases on the tissue responses to dental materials. Conversely, the local use of dental materials may show systemic effects in the form of altered production of biomarkers. Thus, studies to better understand the mechanisms related to those connections are extremely important. In this context, the objective of this review was to analyze and discuss the current literature regarding the connections among these three factors-systemic diseases, endodontic infection, and endodontic dental materials-and determine how these connections may interfere in the systemic health status and the endodontic treatment outcomes, which are represented by periapical wound healing.

Introduction: The aim of the present study was to evaluate the possibility of regaining pulp sensibility in mature necrotic teeth using modified regenerative endodontic procedures by inducing bleeding in root canals and using platelet-rich fibrin (PRF)., Methods: Fifteen patients with necrotic pulp with symptomatic or asymptomatic apical periodontitis were included. At the first visit, the tooth was anesthetized, and an access cavity was performed. Mechanical preparation of root canals was performed using the standardized technique reaching apical canal preparation to K-file size #60-80. Double antibiotic paste was injected into the canal, and the cavity was temporarily sealed using glass ionomer cement. Three weeks from the first visit, regenerative endodontic procedures were performed by inducing bleeding, and a freshly prepared PRF membrane was placed in the canal. White mineral trioxide aggregate was placed directly over the PRF matrix, and the tooth was restored with a glass ionomer cement base and resin composite restoration. The electric pulp test was used to record if the teeth included in the study regained sensibility or not every 3 to 12 months follow-up. Readings at different times were compared as categoric qualitative data using the chi-square test and compared as means and standard deviations using the analysis of variance test., Results: Readings of tooth sensibility revealed a highly significant difference (P < .0001) between baseline and the 12-month follow-up period., Conclusions: The presence of sensibility is indicative of the formation of vital pulplike tissue. Reestablishing real pulp tissue after regenerative endodontic treatment is debatable and still needs high level of evidence with large-scale investigations., (Copyright © 2018 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Introduction: Numerous previously undocumented factors may influence the healing of apical periodontitis (AP). The aim of this cohort study was to analyze the association between statin medication intake during the follow-up period and healing of AP., Methods: Patients who self-reported being on statins during nonsurgical root canal treatment or retreatment and patients who reported never taking statins were included. All patients who received treatment on a tooth with periapical radiolucency in the postgraduate endodontics clinic at the University of Maryland School of Dentistry (2011-2014) were invited for follow-up 2 to 5 years after treatment. Healing was determined using the periapical index (PAI). Two calibrated endodontists assessed outcomes blinded to the statin intake. The association of statin intake and healing of endodontic treatment (ie, healed [PAI 1-2]/not healed [PAI 3-5]) was analyzed using the Fisher exact test. Logistic regression analysis was used to explore the association between statin intake and treatment outcome, controlling for the following confounding variables: diabetes mellitus, cardiovascular disease, and smoking, with confidence intervals set at 95%., Results: A total of 60 cases were included in the final analysis, including 30 patients taking statins and 30 patients not taking statins as the control. The Fisher exact test showed significantly higher healing at the 2-year or greater follow-up in patients taking statins compared with controls (93.0% vs 70%; Fisher exact test, P = .02)., Conclusions: The results of this study show a significant association between long-term statin intake and healing of AP after nonsurgical root canal treatment., (Copyright © 2018 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the effect of exogenous stem cells from apical papillae (SCAP) in the pulp revascularization treatment for the immature permanent tooth with periapical periodontitis in animal model. Methods: After the SCAP were isolated and cultured from the Beagle dogs, stem cell properties of these cells were characterized by analyzing their colony-forming ability, the expression of mesenchymal stem cell markers and the multidifferentiation characteristics including osteogenic, adipogenic, and chondrogenic potentials. Models of young permanent tooth with periapical periodontitis were established in dogs and the infection in each of the model tooth was eliminated by root canal irrigation and intracanal medication. After that, all of the model teeth were randomly divided into 4 groups: Group 1: normal developing teeth with no treatment applied;Group 2: teeth that periapical tissues were irritated to induce blood flowing into the root canals;Group 3: teeth that peripheral blood was delivered into the root canals;Group 4: teeth that SCAP were resuspended in peripheral blood and delivered into the root canals. In Group 2-4, firm coronal seal was performed after revascularization procedure and radiographs were taken periodically in order to observe the development of roots. After a 12-week-period, alveolar samples were collected and observed histologically. Results: The isolated SCAP showed clonogenic ability and multilineage differentiation ability including osteogenic, adipogenic and chondrogenic potentials. These cells also expressed the mesenchymal stem cell markers such as STRO-1 and CD146, while no cytokeratin was detected. The thickening of canal wall was observed radiographically 12 weeks after procedures of infection control and revascularization. Histologically, the newly formed tissues on the inner canal wall were found bone lacuna like structure in Group 2 and 3, and the new tissue formed in the Group 3 seemed easy to separate from the canal wall. The newly formed tissues in Group 4 were much thicker compare to those in the Group 2 and 3, and the dentine tubule like structure instead of bone lacuna was noticed although the orientation of these tubules were various. Conclusions: SCAP seem to play an important role in the tissue regeneration procedure when infection is well controlled in young permanent teeth with periapical periodontitis. It is difficult to achieve real tissue regeneration due to the lack of endogenous SCAP in apical area, therefore delivering adequate exogenous SCAP isolated and cultured in vitro could be a promising approach to overcome the challenge.

Introduction: The purpose of this prospective study was to compare the success of primary root canal treatment between type 2 diabetic and nondiabetic patients and to investigate the effect of periapical healing on glycated hemoglobin (HbA1c) in type 2 diabetic patients with apical periodontitis., Methods: Sixty mandibular molars with necrotic pulps and apical radiolucency (size ≥ 2 mm × 2 mm) were included in the study. Based on the HbA1c levels, patients were divided into 2 groups: type 2 diabetic (HbA1c ≥6.5%) and nondiabetic (HbA1c <6.5%). Forty-six teeth were evaluated at the 12-month follow-up time period. The primary outcome measure was the change in apical bone density as determined by the periapical index., Results: Both the diabetic and nondiabetic group depicted a significant reduction in the periapical score after endodontic treatment at the 12-month follow-up (P < .05). Significantly less periapical healing was observed in the diabetic group (43%) compared with the nondiabetic group (80%) at the 12-month follow-up (P < .05). HbA1c levels in the diabetic group increased at each follow-up after endodontic treatment., Conclusions: Diabetes mellitus may have a negative impact on the outcome of endodontic treatment in terms of periapical healing. Nonsurgical endodontic treatment did not improve HbA1c levels in patients with type 2 diabetes., (Copyright © 2017 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Aim: To evaluate the association between chronic oral inflammatory burden (OIB) - as the combination of periodontal and endodontic disease load - and physical fitness., Methodology: One hundred and twelve nonsmoker male police officers who performed a standardized physical fitness test (PFT) were analysed. Participants underwent oral clinical and periapical radiographic examinations. Periodontal disease was assessed by probing depth (PD) and clinical attachment loss (AL). For radiographic analysis, both apical periodontitis (AP) and root canal treatment (RCT) variables were analysed. Endodontic Burden (EB) was calculated merging the total number of teeth with AP and/or RCT per individual. OIB was calculated combining EB and AL. The outcome of physical fitness was dichotomized according to whether the highest PFT score was 'achieved' or 'not-achieved'. Multivariable logistic regression models were adjusted for age, body mass index and frequency of daily exercise., Results: There was no significant association between AP, RCT and EB with physical fitness whereas PD, AL and OIB were significantly associated with low physical fitness (P < 0.05). Multivariate regression analysis revealed that individuals with OIB = EB ≥ 3 and AL ≥ 4 mm had a 81% lower chance of reaching the highest PFT score (OR = 0.19, 95%CI = 0.04-0.87, P = 0.03) compared to individuals with EB < 3 and and no AL ≥ 4 mm. Individuals with unfavourable periodontal parameters but with low EB (OIB = EB < 3 & AL ≥ 4 mm) showed no significant differences on the chance to reach the highest PFT score compared to participants with favourable periodontal status and low EB (OIB = EB < 3 & no AL ≥ 4 mm)., Conclusions: The OIB - higher levels of EB in periodontal patients - was independently associated with poor physical fitness in males., (© 2016 International Endodontic Journal. Published by John Wiley & Sons Ltd.)

Aim: This randomized controlled trial compared the incidence of post-instrumentation pain associated with Mtwo rotary NiTi files and the self-adjusting file system following canal shaping and cleaning., Methodology: Following sample size estimation, a total of 130 patients were randomized into two groups based on selection criteria [group Mtwo and group SAF (self-adjusting file)]. Root canal treatment was carried out in two appointments. The teeth were endodontically treated with the appropriate allotted systems following the similar clinical parameters. Patients were asked to rate the intensity of pre-instrumentation and post-instrumentation pain (at 2, 4, 6, 8, 24, 48 h) using the VAS score. The Kruskal-Wallis test was carried out for the overall comparisons of the two systems. The Friedman test was used to compare between time-points with each system. Subgroup analyses for independent variables (gender, pulp status and diagnosis) used the Mann-Whitney test and Wilcoxon signed ranks test (P < 0.05)., Results: No significant difference was found between the two groups with respect to post-instrumentation pain. Teeth with pulpal necrosis had significant pain at 8 h compared with teeth with vital pulps (P = 0.04). Teeth with vital pulps in the SAF group had significantly less post-instrumentation pain compared with those in the Mtwo group at 6 h (P = 0.042). Patients who had teeth with nonvital pulps in the SAF group experienced more post-instrumentation pain at 8 h (P = 0.017) and 24 h (P = 0.005)., Conclusion: The incidence of post-instrumentation pain at different time intervals in patients undergoing root canal treatment was similar for both the self-adjusting file and Mtwo file systems., (© 2016 International Endodontic Journal. Published by John Wiley & Sons Ltd.)

Apical periodontitis (AP) is a chronic infection of endodontic origin accompanied with bone destruction around the apical region. Semaphorin3A (Sema3A) and neuropilin-1 (Nrp1) are regarded as a pair of immune regulators in bone metabolism. In this study, we firstly investigated the expression pattern of Sema3A/Nrp1 in apical periodontitis and its correlation with bone destruction. Using rat animal model, we analysed the level of mandibular bone destruction and the expression of Sema3A/Nrp1 on days 0, 7, 14, 21, 28, and 35 after pulp exposure. In addition, clinical samples from apical periodontitis patients were obtained to analyse the expression of Sema3A/Nrp1. These results indicated that the bone destruction level expanded from days 7 to 35. The number of positive cells and level of mRNA expression of Sema3A/Nrp1 were significantly decreased from days 7 to 35, with a negative correlation with bone destruction. Moreover, expression of Sema3A/Nrp1 in the AP group was reduced compared to the control group of clinical samples. In conclusion, decreased expression of Sema3A/Nrp1 was observed in periapical lesions and is potentially involved in the bone resorption of the periapical area, suggesting that Sema3A/Nrp1 may contribute to the pathological development of apical periodontitis.

Introduction: The purpose of this study was to ascertain the regenerative characteristics of apical papilla-derived cells (APDCs) from immature teeth with pulpal and periapical pathosis and thus to provide proof-of-principle evidence for further regenerative endodontic research., Methods: Pulpal and periapical pathosis was induced in immature permanent double-rooted premolars of beagles, which were randomly assigned to experimental treatment groups: group AO (n = 14), pulp disruption and access left open; group PS (n = 14), supragingival plaque suspension-soaked cotton pellet was introduced, and access was sealed; and control (n = 7), untreated. The teeth were extracted at 2- and 4-week periods after experimental treatments. APDCs were cultured from the extracted teeth, and their cellular proliferation, differentiation characteristics, and stemness were assessed. The data were statistically analyzed., Results: After 4 weeks of intentional pulpal and periapical pathosis induction period, all teeth in group PS showed features of apical periodontitis with necrotic pulp, and their APDCs showed significantly increased proliferation rate and osteogenic/odontogenic differentiation capabilities (P < .05). The stemness was maintained in all APDCs, although the stem cell population was smaller in group PS at 2-week period when the inflammatory responses were most fulminant (P < .05)., Conclusions: The APDCs from immature teeth retained the regenerative characteristics with the differences according to their pulpal and periapical pathosis. The results of this study partly provide the evidence for regenerative endodontic research., (Copyright © 2016 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Chronic inflammatory processes in periapical tissues caused by etiological agents of endodontic origin lead to apical periodontitis. Apart from bacteria, two herpesviruses, Epstein-Barr virus (EBV) and Human cytomegalovirus (HCMV) are recognized as putative pathogens in apical periodontitis. Although previous reports suggest the involvement of EBV in the pathogenesis of apical periodontitis, its exact role in periapical bone resorption has not yet been fully elucidated. We hypothesize that EBV infection in apical periodontitis is capable of inducing periapical bone resorption via stimulation of reactive oxygen species (ROS) overproduction. Increased levels of ROS induce expression of receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL). RANKL binding to receptor activator of nuclear factor κB (RANK) present on the surface of preosteoclasts induces their maturation and activation which consequently leads to bone resorption. The potential benefit of antiviral and antioxidant-based therapies in periapical bone resorption treatment remains to be assessed., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Revascularization of immature teeth with necrotic pulps traditionally involves the use of triple antibiotic paste, which may sometimes lead to undesirable complications. The objective of this study was to assess tissue repair in immature dog teeth with apical periodontitis subjected to revascularization, comparing two different pastes used for root canal disinfection. Apical periodontitis was induced in 30 dog premolars. Teeth were randomly divided into three experimental groups: root canals filled with triple antibiotic paste (n = 10); root canals filled with 1% propolis paste (n = 10); and no medication (n = 10). An additional group (n = 10, no intervention) was used as control. After 7 months, the jaws were histologically evaluated for the following variables: newly formed mineralized tissue (present/absent); vital tissue in the canal space (absent/periodontal ligament-like/pulp-like); apical extension of root (present/absent); and severity of inflammatory process (absent/mild/moderate/severe). There were no statistically significant differences among the experimental groups in new mineralized tissue formation and apical root development. The formation of vital tissue in the canal space, in turn, was statistically different between the triple paste and propolis groups: vital tissues were present in all revascularized teeth disinfected with propolis paste (100%), compared to 71% of those disinfected with the triple paste. Severity of inflammatory process was different between the triple paste and no medication groups. The new tissues formed onto canal walls and in the root canal space showed characteristics of cementum and periodontal ligament, respectively. Propolis may have some advantages over the triple paste for the revascularization of immature teeth.

Inflammatory injuries in the maxillary sinus may originate from root canal infections and lead to bone resorption or regeneration. This report describes the radiographic findings of 4 asymptomatic clinical cases of large reactional osteogenesis in the maxillary sinus (MS) associated with secondary root canal infection detected using cone-beam computed tomographic (CBCT) imaging. Apical periodontitis, a consequence of root canal infection, may lead to a periosteal reaction in the MS and osteogenesis seen as a radiopaque structure on imaging scans. The use of a map-reading strategy for the longitudinal and sequential slices of CBCT images may contribute to the definition of diagnoses and treatment plans. Root canal infections may lead to reactional osteogenesis in the MS. High-resolution CBCT images may reveal changes that go unnoticed when using conventional imaging. Findings may help define initial diagnoses and therapeutic plans, but only histopathology provides a definitive diagnosis. Surgical enucleation of the periapical lesion is recommended if nonsurgical root canal treatment fails to control apical periodontitis., (Copyright © 2015 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Enterococcus faecalis is considered a major bacterial pathogen implicated in endodontic infections and contributes considerably to periapical periodontitis. This study aimed to investigate the potential mechanisms by which E. faecalis accounts for the bone destruction in periapical periodontitis in vitro. Osteoclast precursor RAW264.7 cells were treated with E. faecalis ATCC 29212 and a wild strain of E. faecalis derived clinically from an infected root canal. The results showed that, to some extent, E. faecalis induced the RAW264.7 cells to form tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclast-like cells. This pathogen markedly stimulated RAW264.7 cells to express semaphorin 4D (Sema4D), which inhibits bone formation. Once RAW264.7 cells were primed by low-dose receptor activator of nuclear factor-kappa B ligand (RANKL), E. faecalis could significantly increase the production of TRAP-positive multinucleated cells and up-regulate the expression of osteoclast-specific markers, including NFATc1, TRAP and cathepsin K. Both p38 and ERK1/2 MAPK signaling pathways were activated by E. faecalis in RANKL-primed RAW264.7 cells, and meanwhile the expression of Sema4D was highly increased. In conclusion, E. faecalis may greatly contribute to the bone resorption in periapical periodontitis by promoting RANKL-dependent osteoclastogenesis and expression of Sema4D through activation of p38 and ERK1/2 MAPK signaling pathways., (© The Author(s) 2015.)

Introduction: This study evaluates radiographically the efficacy of 4 revascularization protocols in necrotic-infected immature dog teeth with apical periodontitis (AP)., Methods: Forty double-rooted immature premolar teeth from 4 female beagle dogs aged 5 months were used. Four teeth were left untouched as negative controls; the other 36 teeth were infected to develop pulp necrosis and AP following different treatment protocols. Four teeth were left untreated and assigned to the positive control group, and the last 28 teeth were randomly assigned into 4 experimental groups of 8 teeth: A1, sodium hypochlorite (NaOCl) + a blood clot; A2, NaOCl + platelet-rich plasma (PRP); B1, NaOCl + modified triantibiotic paste (mTAP) + a blood clot; and B2, NaOCl + mTAP + PRP. Teeth were monitored radiographically for 6 months regarding healing of periapical radiolucencies, thickening of the dentinal walls, and apical closure of roots., Results: Significant differences (P < .05) between the 4 groups were evident in the percentage of teeth showing improvement of periapical radiolucencies (62.5%), continued radiographic thickening of radicular walls (53.1%), radiographic apical closure (43.8%), and deposition of hard tissue on radicular dentin walls (53.1%). Group B2 showed maximal improvement in the 3 variables assessed (P < .05). Group A1 showed the minimum percentages in the 3 parameters assessed (P < .05)., Conclusions: These results suggest that an intracanal dressing of mTAP and the use of PRP as scaffold improves the success rate of the revascularization procedure., (Copyright © 2015 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Introduction: To investigate the potential link between apical periodontitis (AP) and cardiovascular (CV) function, inflammation markers, endothelial flow reserve (EFR), and levels of asymmetrical dimethylarginine (ADMA), the endogenous inhibitor of nitric oxide synthase (NOS), were measured in young adults with AP aged 20-40 years of both sexes., Methods: Forty men and 41 women (31 ± 5.71 years) free from periodontal disease, CV disease, and traditional CV risk factors were enrolled in the study. Twenty men and 21 women had AP; 40 healthy individuals matched for age, sex, and physical characteristics were also recruited as controls. All subjects underwent dental and complete physical examination, electrocardiography, conventional and tissue Doppler imaging echocardiography, and measurement of EFR. Interleukin (IL)-2, tumor necrosis factor alpha, reactive oxygen species (ROS), and ADMA were also assessed. Data were analyzed using the 2-tailed Student t test, the Pearson t test (or the Spearman t test for nonparametric variables), and multivariate linear regression analysis., Results: Echocardiography excluded any morphologic and functional cardiac alteration in all the subjects studied. Patients with AP of both sexes showed a significant reduction in EFR (P < .05) and a significant increase in IL-2 (men: P < .01, women: P < .05), whereas ROS were increased significantly only in women (P < .05). ADMA levels were unchanged in women with AP, but they were significantly increased in men (P < .05). A significant direct correlation between ADMA and IL-2 (r = 0.67, P < .001) and an inverse correlation between ADMA and EFR (r = -0.42, P < .05) in men and a significant inverse correlation between ROS and EFR (r = -0.71, P < .01) in female patients were observed., Conclusions: The presence of chronic inflammation in young adults with AP may cause early endothelial dysfunction documented by the reduced EFR. AP in men may influence the metabolism of NOS, whereas in women it appears to implicate a more direct detrimental mechanism. This difference is sex dependent and may be attributable to the protective action of estrogen in women., (Copyright © 2015 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Introduction: Enterococcus faecalis is closely associated with refractory apical periodontitis, manifesting periapical lesions and alveolar bone loss. Macrophages playing an important role in the induction of inflammation can differentiate into bone-resorbing osteoclasts. In the present study, we investigated the effect of E. faecalis on the differentiation and function of macrophages as osteoclast precursors., Methods: Bone marrow-derived macrophages (BMMs) were differentiated into osteoclasts with macrophage colony-stimulating factor and receptor activator of nuclear factor kappa B ligand in the presence or absence of heat-killed E. faecalis (HKEF). Tartrate-resistant acid phosphatase-positive multinucleated giant cells were analyzed to determine osteoclast differentiation. Western blotting was performed to examine the expression of c-Fos and NFATc1 transcription factors. Phagocytic capacity was analyzed by measuring uptake of carboxyfluorescein succinimidyl ester-labeled E. faecalis. Secretion of tumor necrosis factor-α, interleukin-6, keratinocyte-derived chemokine, and monocyte chemotactic protein-1 was determined by enzyme-linked immunosorbent assay., Results: Differentiation of BMMs into osteoclasts was attenuated in the presence of HKEF, and expression of c-Fos and NFATc1 was inhibited. HKEF exposure also prevented a reduction in the phagocytic capacity of BMMs after differentiation into osteoclasts. Concomitantly, HKEF induced the expression of chemokines monocyte chemotactic protein-1 and keratinocyte-derived chemokine and proinflammatory cytokines tumor necrosis factor-α and interleukin-6., Conclusions: E. faecalis attenuated macrophages from differentiating into osteoclasts, allowing them to keep their ability to phagocytose and kill pathogens and to induce proinflammatory cytokine and chemokine secretion., (Copyright © 2015 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Some patients experience severe pain following root canal therapy (RCT) despite advancements in care. We sought to identify factors, which can be measured preoperatively, that predict this negative outcome so that future research may focus on preemptive steps to reduce postoperative pain intensity. Sixty-two practitioners (46 general dentists and 16 endodontists) who are members of the National Dental Practice-Based Research Network enrolled patients receiving RCT for this prospective observational study. Baseline data collected from patients and dentists were obtained before treatment. Severe postoperative pain was defined based on a rating of ≥7 on a scale from 0 (no pain) to 10 (pain as bad as can be) for the worst pain intensity experienced during the preceding week, and this was collected 1 wk after treatment. Multiple logistic regression analyses were used to develop and validate the model. A total of 708 patients were enrolled during a 6-m period. Pain intensity data were collected 1 wk postoperatively from 652 patients (92.1%), with 19.5% (n = 127) reporting severe pain. In multivariable modeling, baseline factors predicting severe postoperative pain included current pain intensity (odds ratio [OR], 1.15; 95% confidence interval [CI], 1.07 to 1.25; P = 0.0003), number of days in the past week that the subject was kept from their usual activities due to pain (OR, 1.32; 95% CI, 1.13 to 1.55; P = 0.0005), pain made worse by stress (OR, 2.55; 95% CI, 1.22 to 5.35; P = 0.0130), and a diagnosis of symptomatic apical periodontitis (OR, 1.63; 95% CI, 1.01 to 2.64; P = 0.0452). Among the factors that did not contribute to predicting severe postoperative pain were the dentist's specialty training, the patient's age and sex, the type of tooth, the presence of swelling, or other pulpal and apical endodontic diagnoses. Factors measured preoperatively were found to predict severe postoperative pain following RCT. Practitioners could use this information to better inform patients about RCT outcomes and possibly use different treatment strategies to manage their patients (Clinicaltrials.gov NCT01201681)., (© International & American Associations for Dental Research.)

Introduction: The purpose of this study was to present a new periapical and endodontic status scale (PESS) that is based on the complex periapical index (COPI), which was designed for the identification and classification of periapical bone lesions in cases of apical periodontitis, and the endodontically treated tooth index, which was designed for endodontic treatment quality evaluation by means of cone-beam computed tomographic (CBCT) analysis., Methods: Periapical and endodontic status parameters were selected from the already known indexes and scientific literature for radiologic evaluation. Radiographic images (CBCT imaging, digital orthopantomography [DOR], and digital periapical radiography) from 55 patients were analyzed. All parameters were evaluated on CBCT, DOR, and digital periapical radiographic images by 2 external observers. The statistical analysis was performed with software SPSS version 19.0 (SPSS Inc, Chicago, IL). Chi-square tests were used to compare frequencies of qualitative variables. The level of significance was set at P ≤ .05., Results: Overall intraobserver and interobserver agreements were very good and good, respectively. CBCT analysis found more lesions and lesions of bigger dimension (P < .001). CBCT imaging was also superior in locating lesions in the apical part on the side compared with DOR and in the diagnosis of cortical bone destruction compared with both methods (P < .001). Through CBCT analysis, more root canals and more canals associated with lesions were found. The most informative and reproducible periapical and endodontic status parameters were selected, and a new PESS was proposed., Conclusions: The classification proposed in the present study seems to be reproducible and objective and adds helpful information with respect to the existing indexes. Future studies need to be conducted to validate PESS., (Copyright © 2015 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Introduction: It has been proposed that individual genetic predisposition may contribute to persistent apical periodontitis. Cytokines are associated with levels of inflammation and are involved in caries, pulpal, and periapical tissue destruction. We hypothesized that polymorphisms in cytokine genes may contribute to an individual's increased susceptibility to apical tissue destruction in response to deep carious lesions., Methods: Subjects with deep carious lesions with or without periapical lesions (≥3 mm) were recruited at the University of Pittsburgh, Pittsburgh, PA, and the University of Texas at Houston, Houston, TX. Genomic DNA samples of 316 patients were sorted into 2 groups: 136 cases with deep carious lesions and periapical lesions (cases) and 180 cases with deep carious lesions but no periapical lesions (controls). Nine single-nucleotide polymorphisms in IL1B, IL6, TNF, RANK, RANKL, and OPG genes were selected for genotyping. Genotypes were generated by end point analysis using TaqMan chemistry (Invitrogen, Carlsbad, CA) in a real-time polymerase chain reaction instrument. Allele and genotype frequencies were compared among cases and controls using the PLINK program (http://pngu.mgh.harvard.edu/purcell/plink/). Ninety-three human periapical granulomas and 24 healthy periodontal ligament tissues collected postoperatively were used for messenger RNA expression analyses of IL1B., Results: A single-nucleotide polymorphism in IL1B (rs1143643) showed allelic (P = .02) and genotypic (P = .004) association with cases of deep caries and periapical lesions. We also observed altered transmission of IL1B marker haplotypes (P = .02) in these individuals. IL1B was highly expressed in granulomas (P < .001)., Conclusions: Variations in IL1B may be associated with periapical lesion formation in individuals with untreated deep carious lesions. Future studies could help predict host susceptibility to developing periapical lesions., (Copyright © 2015 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Introduction: The purpose of this prospective clinical study was to evaluate the clinical outcome of endodontic microsurgery on roots exhibiting the presence or absence of dentinal defects at 1-year and 3-year follow-up period., Methods: One hundred fifty-five teeth were treated with periapical microsurgery using a modern microsurgical protocol in a private practice setting. The root apices were resected and inspected for dentinal defects with a surgical operating microscope and a 0.8-mm head diameter light-emitting diode microscope diagnostic probe light. After inspection, root-end preparations were performed using ultrasonic tips, and root-end fillings were placed. Follow-up visits occurred at 1 year and 3 years postoperatively. The primary outcome measure used was the change in the radiographic apical bone density, and the secondary outcome measure used was the absence of clinical symptoms., Results: Of the 155 treated teeth, a total of 134 teeth were assessed at the 1-year follow-up and 127 teeth at the 3-year evaluation. In the "intact" group, 94.8% healed at 1 year, and 97.3% healed at 3 years. In the "dentinal defect" group, 29.8% healed at 1 year, and 31.5% healed at 3 years. The baseline root condition of either "dentinal defect" or "intact" showed a statistical difference in the healing outcome at both 1 and 3 years., Conclusions: This prospective periapical microsurgery study showed a significant superior clinical outcome for intact roots when compared with roots with dentinal defects at both 1 year and at 3 years postoperatively., (Copyright © 2015 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Introduction: Apical root resection is a biologically essential component in endodontic microsurgery. However, because it reduces the total root length and supported root surface, it changes the biomechanical response of the tooth. The purpose of this study was to analyze the biomechanical effect of apical root resection and to compare apical root resection with periodontal bone loss from a biomechanical standpoint., Methods: Finite element models of the maxillary central incisor were reconstructed. First, preoperative and surgically treated models were generated to assess the factors altering the biomechanical response of the tooth. Then, apically resected models with different amounts of resection (3, 4, 5, 6, 7, and 8 mm) were created to estimate the clinically applicable limit of apical root resection. Periodontally destructed models with varying degrees of bone loss (0.5, 1, 1.5, 2, and 3 mm) were also created to compare the effect of apical root resection with periodontal bone loss. Stress distribution, tooth displacement, and effective crown-to-root ratio (α) were analyzed for each condition., Results: Apical root resection did not significantly alter the maximum von Mises stress or tooth displacement until it reached 6 mm (α = 0.67) when the tooth was supported by normal periodontium. In contrast, periodontal bone loss had a greater impact on biomechanical response change compared with apical root resection., Conclusions: For a tooth supported by normal periodontium, 3 mm of apical root resection (α = 1.07) appeared to be mechanically acceptable. The biomechanical influence of apical root resection was weak compared with that of periodontal bone loss., (Copyright © 2014 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Introduction: The purpose of this study was to investigate the effect of conditioned medium (CM) from murine preameloblasts on the cellular differentiation of mesenchymal stem cells (MSCs) in immature teeth with necrotic pulp and apical periodontitis., Methods: Pulp necrosis and apical periodontitis were induced in 30 immature permanent double-rooted premolars of 3 beagles and were randomly assigned to the following treatment groups: group CM (n = 10), revascularization treatment was performed using CM from preameloblasts of C57BL/6 mice apical bud cells; group CR (n = 10), conventional revascularization treatment was performed; positive control group (n = 5), left infected; and negative control group (n = 5), untreated. The dogs were followed up for 12 weeks and assessed for treatment outcomes with radiographic and histologic analyses. The effect of the CM on sequential Runx2 and osterix messenger RNA gene expression during the differentiation of MG63 osteoblastlike cells was analyzed with real-time polymerase chain reaction., Results: The overall treatment outcomes were not significantly different between the 2 treatment groups. However, the teeth in the CM group showed significantly more mature apices and a higher degree of hard tissue formation with projections intercalating into the pre-existing root dentin (P < .05). In CM-treated teeth, regenerated pulplike tissue was more frequently observed (P < .05). During differentiation, the CM induced early peak expression of Runx2 followed by sustained osterix overexpression., Conclusions: CM from preameloblasts rendered a favorable effect in providing a physiologic microenvironment for the differentiation of MSCs after revascularization treatment., (Copyright © 2014 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

The aim of this review was to examine current knowledge of the role of interleukin-6 (IL-6) in apical periodontitis (AP) pathogenesis as an inflammatory or pro-inflammatory cytokine. It also looked at whether IL-6 could serve as a measure for differential diagnosis or as a biomarker that can further predict the progression of bone resorption. A systematic review relating to AP and IL-6 was made via PubMed, BIOSIS, Cochrane, EMBASE and Web of Science databases using keywords and controlled vocabulary. Two independent reviewers first screened titles and abstracts and then the full texts. The reference lists of the identified publications were examined for additional titles. Eighteen papers were studied in total. In vitro studies (n = 6) revealed that IL-6 is present in AP, and its levels are proportional to the size of the periapical lesions. Neutrophils and macrophages resident in these lesions can produce IL-6 in vitro after a bacterial stimulus. Animal studies (n = 5) showed that IL-6 is present in AP and that osteoblasts can produce IL-6 in vivo. On the other hand, two studies using IL-6 knockout mice revealed larger periapical lesions when compared with control groups, demonstrating IL-6's role as an anti-inflammatory cytokine. In human studies (n = 7), IL-6 was identified in AP, and its levels were higher in symptomatic, epithelialized and large lesions than in asymptomatic and small lesions. These data lead to the conclusion that IL-6 may play a pro-inflammatory role, increasing its levels and reabsorbing bone in the presence of infections. When IL-6 is not present, other cytokines such as IL-1 and TNF-α induce bone resorption. Further studies about the relationship between AP development and the cytokine network must be performed to establish the exact role of each cytokine in the inflammatory process., (© 2013 International Endodontic Journal. Published by John Wiley & Sons Ltd.)

Aim: To characterize the formation and progression of experimentally induced periapical lesions in teeth of MyD88 knockout (MyD88 KO) mice compared with wild-type (WT) mice., Methodology: Periapical lesions were induced in the mandibular first molars of 30 WT and 30 MyD88 KO mice. After 7, 21 and 42 days, the animals were euthanized and the mandibles were subjected to histotechnical processing. Histological sections were stained with haematoxylin and eosin (HE), TRAP histoenzymology, Brown and Brenn staining and immunohistochemistry (RANK, RANKL, OPG). Data were subjected to statistical analysis by the nonparametric Mann-Whitney and Kruskal-Wallis tests and the Dunn post-test, using the SPSS software, version 17.0 (α = 0.05)., Results: Regarding the periapical lesion size, the MyD88 KO group had significantly higher values than the WT group in the periods of 7 (P = 0.001) and 21 days (P = 0.05). A larger number of neutrophils in the MyD88 KO group were observed (P = 0.01 at 7 days, P = 0.004 at 21 days and P < 0.001 at 42 days). Regarding the number of osteoclasts, no statistically significant difference was observed between the groups at any of the experimental periods (P = 0.884 at 7 days, P = 0.506 at 21 days and P = 0.211 at 42 days)., Conclusions: In the absence of MyD88, the animals had larger periapical lesions, with a severe inflammatory infiltrate and a significantly larger number of neutrophils., (© 2013 International Endodontic Journal. Published by John Wiley & Sons Ltd.)

Wnt/β-catenin signaling plays an important role in bone biology. The present study investigated the involvement of Wnt/β-catenin signaling in rat periapical bone destruction and whether lithium chloride (LiCl), a glycogen synthase kinase-3β (GSK-3β) inhibitor, promotes bone restoration. Rat bone marrow mesenchymal cells (BMMSCs) treated with Porphyromonas gingivalis lipopolysaccharide (Pg LPS) showed decreased osteogenic potential through inhibited Wnt/β-catenin signaling as quantified by Western blot, immunofluorescence, and luciferase reporter assay. Transient Wnt3a treatment in vitro partially restored mineralization and Runx2/Osx and osteocalcin expression in cultures with Pg LPS-induced osteogenic arrest. Prolonged Wnt3a treatment impaired osteogenic commitment. X-ray microtomography showed dramatically enhanced periapical bone formation in rats gavage-fed with LiCl for 2 wks, while continuous LiCl treatment for 4 wks impaired periapical bone healing. LiCl treatment also increased GSK-3β phosphorylation and osteocalcin expression in periapical tissue. Collectively, these results indicate that Wnt/β-catenin has dichotomous functions in bone homeostasis. Modulation of this signaling pathway by LiCl may be a potential therapeutic option for bone destruction in endodontic disease.

Apical periodontitis in permanent children's teeth with incomplete root development is a challenge for endodontists to treat. It is important that highly efficient therapeutic methods and biologically valuable therapies be developed to prevent the loss of these teeth. The AIM of the study was to review modern literature on revascularization of non-vital permanent teeth with incomplete root development, and to present a clinical case. The literature review herein reflects the modern concept of revascularization of non-vital permanent teeth with incomplete root development. Clinical protocols are presented on cases with and without the formation of a blood clot. The case study reports the treatment of an immature non-vital permanent tooth using the technique of revascularization that utilises formation of a blood clot and use of a two-component antibiotic paste for disinfection. One year after treatment the clinical and radiological data showed absence of subjective complaints, thickening of the root walls, apical closure and no periapical pathology of the revascularized tooth. Literature data and the favorable outcome of our case allow us to further research the revascularization of immature non-vital permanent teeth.

Aim: To evaluate whether the initial healing of apical radiolucencies 1 year after root canal treatment could be quantitatively identified by the change in fractal dimension (FD) values for the eventually completely healed cases., Methodology: Twenty-six patients with successful root canal treatment were recruited. All teeth were associated with complete healing either before or at 1 year following treatment (six of 26) or still undergoing healing at 1 year after treatment but completely healed thereafter (20 of 26). Two radiographs were selected for the same patient, one taken before treatment and the other taken 1 year after treatment. Eight regions of interests (ROIs) were selected from each radiograph, two as the experimental group located close to the infected root apex, two as the control group in the healthy bone and the other four in the healthy bone ensuring the image quality., Results: Based on the FD values of the four ROIs in the healthy bone, the two radiographs were confirmed to have been taken with similar projection angles and exposure. The FD values were shown to significantly increase (P = 0.006) and decrease (P = 0.000) around the root apex and the neighbouring region of the apical lesion, respectively., Conclusion: Changes in fractal dimension values may serve as a necessary condition to quantitatively indicate the initial healing status 1 year after root canal treatment., (© 2012 International Endodontic Journal.)

Introduction: This study evaluated the development of periapical lesions in a rat model of type 2 diabetes and assessed the potential actions of the antioxidant agent tempol in this model., Methods: Male Wistar rats were used; they received tap water (N = 5) or a 20% glucose solution (N = 15) during a period of 9 weeks. At the sixth week, periapical lesions were induced on the first mandibular molars, and the animals were subdivided into 4 groups. The subgroup 1 was composed of nondiabetic rats orally receiving saline solution (10 mL/kg). Chronically glucose-fed rats were divided into the following subgroups: (2) saline-treated animals (10 mL/kg by oral route), and animals treated with tempol by gavage at doses of (3) 50 mg/kg or (4) 100 mg/kg. The body weight was monitored thoroughly. After 21 days of apical periodontitis induction, the animals were killed, and the mandibles were collected and submitted to radiographic and histologic analysis. The livers were collected to determine free radicals, and the blood plasma was used to measure insulin levels., Results: Type 2 diabetic rats displayed a significant decrease of body weight gain and a slight increase of insulin levels, which were allied to reduced levels of the antioxidant components catalase and reduced glutathione; these alterations were reversed by tempol. Concerning the periapical lesions, neither radiographic nor histologic analysis revealed any significant difference between control and type 2 diabetic rats. In diabetic rats, the apical periodontitis was refractory to tempol treatment., Conclusions: The extent and cellularity of periapical lesions in glucose-fed type 2 diabetic rats were similar to those seen in control rats. Despite affecting other parameters related to diabetes, tempol failed to improve the outcome of endodontic lesions in type 2 diabetic animals., (Copyright © 2013 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Introduction: In this study, the role of transcription factor Forkhead/winged helix box protein O3a (FoxO3a) in Cyr61 expression and its modulation by simvastatin were investigated in cultured murine osteoblasts and a rat model of induced apical periodontitis. We also examined the effects of simvastatin on the synthesis of chemokine CCL2 and chemotaxis of macrophages in vitro., Methods: We assessed tumor necrosis factor (TNF)-α-stimulated expression of Cyr61 and phosphorylated inactive FoxO3a (p-FoxO3a) in MC3T3-E1 murine osteoblasts by Western analysis. Forced expression of FoxO3a by lentiviral-based gene transduction was performed, and its effect on Cyr61 expression was evaluated. The modulation of CCL2 secretion and macrophage chemotaxis by simvastatin were examined by enzyme-linked immunosorbent assay and transwell migration assay, respectively. In a rat model of induced apical periodontitis, the relation between disease progression and osteoblastic expression of Cyr61, p-FoxO3a, and CCL2 and macrophage recruitment were studied by radiographic and immunohistochemistry analyses., Results: Western blot analysis showed enhanced expression of Cyr61 and p-FoxO3a after TNF-α treatment in a time-dependent manner. Simvastatin significantly counteracted the actions of TNF-α. Forced expression of FoxO3a reduced TNF-α-stimulated Cyr61 synthesis. Simvastatin and FoxO3a diminished TNF-α-induced CCL2 secretion and macrophage recruitment, whereas Cyr61 partially restored the stimulating action. In rat periapical lesions, simvastatin significantly attenuated bone resorption, reduced osteoblastic expressions of Cyr61, p-FoxO3a, and CCL2, and suppressed macrophage recruitment., Conclusions: Simvastatin may alleviate periapical lesions by enhancing FoxO3a activity to suppress the synthesis of Cyr61 in osteoblasts. Moreover, the downstream effector mechanism of Cyr61 may involve CCL2 production and macrophage recruitment., (Copyright © 2013 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Commonly is accepted that a non-vital tooth has a higher risk of root fracture but there is a relatively little knowledge about the specific biomechanical behavior of non-vital frontal teeth with chronic apical periodontitis. The aim of our study was to evaluate the deformation and tensile generated in these teeth while vertically loading them because it is crucial to assess the moment when the absorbed occlusal forces exceed the elasticity of root dentine. Using the method of finite-element analysis, we highlighted the distribution patterns of the compressive and tension tensile, as well as their concentration areas. The vertical forces of 100 N generate deformations of no clinical risk in teeth with chronic apical periodontitis. The tensile developed in these teeth are higher than those in the vital teeth are but do not exceed the value of the elastic modulus of the radicular dentin. By increasing the force to 300 N occur elastic deformations, which cannot be neglected anymore. Even so, the 300 N forces do not generate deformations of the alveolar bone. The highest tensile at loading with 300 N was generated in vertical direction but in the cervical area of the tooth also developed tensile in lingual and mesiodistal direction that must be taken into consideration because they are near the risk limit of the elasticity modulus. The crack lines or fractures can appear both in case of excessive or even usual but accumulative occlusal forces that gradually alter the mechanical resistance of the tooth.

The pulp-dentin complex is a strategic and dynamic barrier to various insults that plague the dentition. Researchers have yet to understand the complete potential of this shifting junction and its components. The most common cause of injury to the pulp-dentin complex is carious breakdown of enamel and dentin. In recent years, there has been a change in restorative management of caries. The emphasis is on strategies to preserve dentin and protect the pulp. This article provides a brief review of the effect of caries on the pulp, of subsequent events on the periradicular tissues, and of current understanding of treatment modalities., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aim: To monitor radiographically the progress of bone repair within chronic periapical lesions after root canal treatment using digital subtraction radiography (DSR)., Methodology: Twelve patients with 17 single-rooted teeth with chronic apical periodontitis associated with an infected necrotic pulp were selected for root canal treatment. Periapical radiographs were taken before treatment (baseline) and immediately post-treatment, 45, 90, 135 and 180 days after treatment. The radiographic protocol included the use of individualized film holders with silicone bite blocks. The six radiographic images were digitized and submitted to digital subtraction using DSR software, resulting in five subtracted images (SI). Quantitative analysis of these SI was performed using Image Tool software to assess pixel value changes, considering a step-wedge as the gold standard and a cut-off value of 128 pixels. The aim was to identify any increase or decrease in mineral density in the region of the periapical lesion., Results: A minor decrease in mineral density at the canal filling session and a significant progressive mineral gain in the following evaluations (P < 0.001) occurred. Pairwise comparison of pixel grey values revealed that only the 180-day follow-up differed significantly from the previous SI., Conclusion: Digital subtraction radiography is a useful method for evaluating the progress of bone repair after root canal treatment. Noticeable mineral gain was observed approximately 90 days after root canal filling and definite bone repair after 180 days.

Aim: To report the healing of a periradicular lesion and maintaining vitality of the pulp following endodontic treatment of the invaginated canal of a dental invagination., Summary: Dens invaginatus is a developmental malformation resulting from invagination of the tooth crown or root before calcification has occurred. A case of type III dens invaginatus, an invagination that extends from the crown to the apex, in the maxillary right lateral incisor with a healthy pulp and large peri-invagination periodontitis is reported. Non-surgical root canal treatment of the invagination was performed. There appeared to be no communication between the main root canal and the invaginated canal. The invaginated canal was filled by lateral condensation of gutta-percha and a calcium hydroxide sealer. The final restoration of the tooth was completed using composite, and the tooth was reviewed after 1 and 2 years. Non-surgical root canal treatment of the invagination retained the pulp in a health condition and resulted in resolution of a substantial peri-invagination lesion., Key Learning Points: Even though there are no symptoms, radiography should be performed in teeth that exhibit anatomical differences from the contralateral tooth. Even if there is extensive apical pathology in a tooth with type III dens invaginatus, pulp sensibility tests should be performed. Correct diagnosis and treatment planning are fundamental when treating dens invaginatus.

Introduction: Osteoblastic expression of cysteine-rich 61 (Cyr61) correlates with the severity of periapical lesion-associated bone loss, but the regulatory mechanism of Cyr61 expression was not known., Methods: In the study we examined the effect of major histocompatibility complex class II transactivator (CIITA) on tumor necrosis factor (TNF)-alpha-induced Cyr61 synthesis in U2OS human osteoblastic cells by Western blot analysis. In a rat model of bacteria-induced apical periodontitis, we assessed the relation between osteoblastic expressions of CIITA/Cyr61 and disease progression by radiographic and immunohistochemistry studies., Results: We found that forced expression of CIITA suppressed Cyr61 synthesis in U2OS cells. In rat periapical lesions, osteoblastic CIITA decreased as the disease progressed, and expression of CIITA is negatively related to Cyr61 synthesis in osteoblasts., Conclusions: Our data showed that CIITA is a repressor of Cyr61 synthesis in osteoblasts, and it might play a protective role in the pathogenesis of bone resorption in apical periodontitis, possibly through down-regulating the expression of Cyr61 in osteoblasts., (Copyright 2010 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

This study investigated whether teaching undergraduate dental students the diagnosis and management of acute dental pain alongside the underpinning oral physiology helped them to understand the topic better than teaching them acute dental pain as a separate entity. Each of three clinical years of dental students at the same dental school was taught in two groups. Each group was taught the signs/symptoms of five acute dental pain conditions by the same member of the staff. However, the teaching for one group of students in each year reminded the students about the physiology that underpinned the clinical symptoms. One week later, the students completed an open-ended questionnaire that required them to list signs/symptoms of the five dental pain conditions. For each year of dental students that was examined, the mean student marks were significantly higher (p<0.05) for those who were taught dental pain and the underlying physiology compared with students who were only taught dental pain as a stand-alone subject. This suggests that integrating biomedical science and clinical teaching is beneficial.

Aim: To determine the pain experienced by patients during root canal treatment and to correlate with age and gender, pulpal diagnosis, previous periapical status, dental characteristics and length of treatment., Methodology: One hundred and seventy-six patients (68 men and 108 women), with ages ranged from 6 to 83 years, were randomly recruited. Patients completed a 10-cm visual analogue scale (VAS) that ranked the level of pain experienced during root canal treatment., Results: The mean pain level during root canal treatment was 1.2 +/- 0.8 in a VAS between 0 and 10. Fifty-four per cent of patients did not experience pain. There were no significant differences in relation to gender or age groups. Mandibular teeth had a significantly (P < 0.05) higher percentage incidence of pain in comparison with maxillary teeth. Pain was absent in 63% of anterior teeth compared with 44% in posterior ones (P < 0.01). Interventions shorter than 45 min resulted in a significantly higher percentage of pain absence (P < 0.05). Root canal treatment was significantly (P < 0.05) more painful in teeth with irreversible pulpitis and acute apical periodontitis compared to the group with necrotic pulps and chronic apical periodontitis (P = 0.049)., Conclusions: Root canal treatment in teeth with irreversible pulpitis and acute apical periodontitis was more painful. Age, tooth type and length of the treatment were factors associated with increased risk for pain experienced during the procedure. Knowledge of pain levels endured by patients will allow dentists to decide when to use supplemental local anaesthesia.

Introduction: The aim of this study was to determine the effect of age on the process of healing of chronic periapical inflammation., Material and Methods: The study was carried out in 59 patients with accidentally disclosed chronic periapical inflammation and no other pathology. The patients were allocated to two age groups: group I--from 17 to 44 years of age; group II--from 45 to 78 years of age. All teeth with periapical inflammation were endodontically treated. Control radiographs were taken 6 and 12 months later., Results: Radiographs taken after 6 months disclosed partial or complete restoration of periapical tissues in 79.5% of patients in group I and 65.0% of patients in group II. Radiographs after 12 months showed partial or complete healing in 94.8% of patients in group I and 90.0% of patients in group II., Conclusions: The process of healing of chronic periapical inflammation lasted longer in patients aged 45-78 years than in patients aged 17-44 years. The outcome of treatment was similar in both groups.