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Introduction Factors that influence clinical outcomes for regenerative endodontic procedures (REPs) are unknown. This retrospective study aimed to assess tooth healing, root development, pulp vitality, and esthetics post-REPs and categorize them into clinician- and patient-centered outcomes. Furthermore, this study identified significant predictors affecting such outcomes. Methods Immature permanent teeth diagnosed with pulp necrosis treated with REPs between 2008 and 2018 with a minimum of 1-year follow-up were included. Outcomes included success and survival rates, changes in root development using 2-dimensional radiographic root area (RRA) and 3-dimensional measurements, pulp vitality, and tooth discoloration. Predictor variables of success included age, sex, etiology of pulp necrosis (PN), type of medicament, sodium hypochlorite (NaOCl) concentration, type of biomaterial used over the blood clot, and preoperative apical diagnosis. Statistical analyses included Cox proportional hazard analyses and generalized regression models. Results Fifty-one teeth with an average of 2.1 years of follow-up satisfied the criteria. The survival rate was 92%. The success rate was 84.3% with age, etiology of PN, type of medicament, and NaOCl concentration being significant predictors of failure. Root development occurred in 91.4% of cases with age, sex, etiology of PN, type of medicament, NaOCl concentration, and apical diagnosis being significant predictors for RRA change. Positive pulp sensibility responses were associated with greater RRA change, and, finally, the type of biomaterial was a significant predictor for tooth discoloration after treatment. Conclusions : REPs provide a high survival rate. Patient and clinical factors may affect outcomes, and this knowledge may help to define the criteria for optimal treatment planning of REPs.

Introduction The outcomes of an immature tooth with necrotic pulp treated with regenerative endodontic procedures (REPs) were assessed clinically and radiographically. Root maturation is an important outcome of REPs, and several radiographic measurement methods have been used to measure this. The aim of this study was to compare radiographic measurement methods, measuring root maturation in immature teeth with necrotic pulp treated with REPs. Methods Seventy-one radiographic images of REP cases were measured and compared using 3 radiographic measurement methods described by Bose et al (2009), Alobaid et al (2014), and Flake et al (2014). The intraclass correlation coefficient values were evaluated using the intra- and interobserver reliability test and the effect of the stage of root development. Results The intra- and interobserver reliability for Alobaid et al's method and Flake et al's method were slightly higher than Bose et al's method as quantified by the intraclass correlation coefficient without a significant difference (P > .05). The stage of root development did not affect the reliability of the measurement methods. A high level of agreement was found among the 3 stages of root development for all 3 quantitative radiographic measurement methods. Conclusions All 3 quantitative radiographic measurement methods exhibited high agreement regarding reliability. The stage of root development did not have an impact on the reliability of the measurement methods.

Chronic pain is the leading cause of disability worldwide1 and is commonly associated with comorbid disorders2. However, the role of diet in chronic pain is poorly understood. Of particular interest is the Western-style diet, enriched with ω-6 polyunsaturated fatty acids (PUFAs) that accumulate in membrane phospholipids and oxidise into pronociceptive oxylipins3,4. Here we report that mice administered an ω-6 PUFA-enriched diet develop persistent nociceptive hypersensitivities, spontaneously active and hyper-responsive glabrous afferent fibres and histologic markers of peripheral nerve damage reminiscent of a peripheral neuropathy. Linoleic and arachidonic acids accumulate in lumbar dorsal root ganglia, with increased liberation via elevated phospholipase (PLA)2 activity. Pharmacological and molecular inhibition of PLA2G7 or diet reversal with high levels of ω-3 PUFAs attenuate nociceptive behaviours, neurophysiologic abnormalities and afferent histopathology induced by high ω-6 intake. Additionally, ω-6 PUFA accumulation exacerbates allodynia observed in preclinical inflammatory and neuropathic pain models and is strongly correlated with multiple pain indices of clinical diabetic neuropathy. Collectively, these data reveal dietary enrichment with ω-6 PUFAs as a new aetiology of peripheral neuropathy and risk factor for chronic pain and implicate multiple therapeutic considerations for clinical pain management. Boyd and LoCoco et al. link ω-6 polyunsaturated fatty acid–rich diet to development of peripheral nerve damage in mice, revealing diet as a risk factor for chronic pain.

ObjectivesInforming research participants of the results of studies in which they took part is viewed as an ethical imperative. However, there is little guidance in the literature about how to do this. The Fluoxetine Or Control Under Supervision trial randomised 3127 patients with a recent acute stroke to 6 months of fluoxetine or placebo and was published in the Lancet on 5 December 2018. The trial team decided to inform the participants of the results at exactly the same time as the Lancet publication, and also whether they had been allocated fluoxetine or placebo. In this report, we describe how we informed participants of the results.DesignIn the 6-month and 12-month follow-up questionnaires, we invited participants to provide an email address if they wished to be informed of the results of the trial. We re-opened our trial telephone helpline between 5 December 2018 and 31 March 2019.SettingUK stroke services.Participants3127 participants were randomised. 2847 returned 6-month follow-up forms and 2703 returned 12-month follow-up forms; the remaining participants had died (380), withdrawn consent or did not respond.ResultsOf those returning follow-up questionnaires, a total of 1845 email addresses were provided and a further 50 people requested results to be sent by post. Results were sent to all email and postal addresses provided; 309 emails were returned unrecognised. Seventeen people replied, of whom three called the helpline and the rest responded by email.ConclusionIt is feasible to disseminate results of large trials to research participants, though only around 60% of those randomised wanted to receive the results. The system we developed was efficient and required very little resource, and could be replicated by trialists in the future.Trial registration numberISRCTN83290762; Post-results.

Chronic pain is the leading cause of disability worldwide1 and commonly associated with comorbid disorders2. However, the role of diet in chronic pain is poorly understood. Of particular interest is the Western-style diet, enriched with ω-6 polyunsaturated fatty acids (PUFAs) that accumulate in membrane phospholipids and oxidize into pronociceptive oxylipins3,4. Here we report that mice administered a diet enriched with ω-6 PUFAs develop persistent nociceptive hypersensitivities, spontaneously-active and hyper-responsive glabrous afferent fibers, and histologic markers of peripheral nerve damage reminiscent of a peripheral neuropathy. Linoleic and arachidonic acids accumulate in lumbar dorsal root ganglia, with increased liberation via elevated PLA2 activity. Pharmacological and molecular inhibition of PLA2g7 or diet reversal with high ω-3 PUFAs attenuate nociceptive behaviors, neurophysiologic abnormalities, and afferent histopathology induced by high ω-6 intake. In addition, ω-6 accumulation exacerbates the intensity or duration of allodynia observed in preclinical inflammatory and neuropathic pain models, as well as in clinical diabetic neuropathy. Collectively, these data reveal diet as a novel etiology of peripheral neuropathy and risk factor for chronic pain, and implicate multiple therapeutic considerations for clinical pain management.

The recent spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated coronavirus disease has gripped the entire international community and caused widespread public health concerns. Despite global efforts to contain the disease spread, the outbreak is still on a rise because of the community spread pattern of this infection. This is a zoonotic infection, similar to other coronavirus infections, that is believed to have originated in bats and pangolins and later transmitted to humans. Once in the human body, this coronavirus (SARS-CoV-2) is abundantly present in nasopharyngeal and salivary secretions of affected patients, and its spread is predominantly thought to be respiratory droplet/contact in nature. Dental professionals, including endodontists, may encounter patients with suspected or confirmed SARS-CoV-2 infection and will have to act diligently not only to provide care but at the same time prevent nosocomial spread of infection. Thus, the aim of this article is to provide a brief overview of the epidemiology, symptoms, and routes of transmission of this novel infection. In addition, specific recommendations for dental practice are suggested for patient screening, infection control strategies, and patient management protocol.

Neovascular retinopathies are major causes of vision loss; yet treatments to prevent the condition are inadequate. The role of regulatory T cells in neovascular retinopathy is unknown. Here we show that in retinopathy regulatory T cells are transiently increased in lymphoid organs and the retina, but decline when neovascularization is established. The decline is prevented following regulatory T cells expansion with an IL-2/anti-IL-2 mAb complex or the adoptive transfer of regulatory T cells. Further, both approaches reduce vasculopathy (vaso-obliteration, neovascularization, vascular leakage) and alter the activation of Tmem119+ retinal microglia. Our in vitro studies complement these findings, showing that retinal microglia co-cultured with regulatory T cells exhibit a reduction in co-stimulatory molecules and pro-inflammatory mediators that is attenuated by CTLA-4 blockade. Collectively, we demonstrate that regulatory T cells are recruited to the retina and, when expanded in number, repair the vasculature. Manipulation of regulatory T cell numbers is a previously unrecognized, and promising avenue for therapies to prevent blinding neovascular retinopathies.The local immune responses in the eye are attenuated to preserve sight. Surprisingly, Deliyanti et al. show that regulatory T cells (Tregs) take an active role in protecting the eye from neovascularization in oxygen-induced retinopathy, and that interventions that augment the retinal Treg numbers reduce neovascular retinopathy in mice.

Background and Overview Immature teeth are susceptible to infections due to trauma, anatomic anomalies, and caries. Traditional endodontic therapies for immature teeth, such as apexification procedures, promote resolution of the disease and prevent future infections. However, these procedures fail to promote continued root development, leaving teeth susceptible to fractures. Regenerative endodontic procedures (REPs) have evolved in the past decade, being incorporated into endodontic practice and becoming a viable treatment alternative for immature teeth. The authors have summarized the status of regenerative endodontics on the basis of the available published studies and provide insight into the different levels of clinical outcomes expected from these procedures. Conclusions Substantial advances in regenerative endodontics are allowing a better understanding of a multitude of factors that govern stem cell–mediated regeneration and repair of the damaged pulp-dentin complex. REPs promote healing of apical periodontitis, continued radiographic root development, and, in certain cases, vitality responses. Despite the clinical success of these procedures, they appear to promote a guided endodontic repair process rather than a true regeneration of physiological-like tissue. Practical Implications Immature teeth with pulpal necrosis with otherwise poor prognosis can be treated with REPs. These procedures do not preclude the possibility of apexification procedures if attempts are unsuccessful. Therefore, REPs may be considered first treatment options for immature teeth with pulpal necrosis.

This paper presents the preliminary results of the application of the ocean model (FVCOM) to replicate the hydrodynamic flows experienced within Lake El-Manzala, Egypt. The construction of this model is used to characterize the ecosystem of this shallow brackish lake and assess a range of sustainable water management strategies. Lake El-Manzala is the largest of the Egyptian shallow coastal lakes on the fringe of the Mediterranean Sea. The lake currently supports 30% of the fresh water fish farm production of Egypt. In recent years the aquatic health of the lake has significantly deteriorated due to an increase in the contamination of the lake by polluted inflows and over intensive aquaculture. The focus of this study is to develop a model that may be employed to investigate the causes, effects and potential solutions to the pollutant loads imposed on the lake. The model has been used to study the hydrodynamic effect that a 40% reduction in the polluted drain water inflows to the lake due to a diversion of this water towards the Sinai for land development. This study concluded that in the western zone of the lake this action slightly changed the magnitude and direction of the water flows and an increase in the salinity levels. Several other lake management scenarios were proposed and the environmental effects on the lake water quality are under investigation. It is concluded that the hydrodynamic models developed may be used to study the cause and effects of other aquatic pollution problems and permit the investigation of potential engineering solutions to improve water quality management.

Chemotherapy induced peripheral neuropathy (CIPN), a side effect of many anti-cancer drugs including the vinca alkaloids, is characterized by a severe pain syndrome that compromises treatment in many patients. Currently there are no effective treatments for this pain syndrome except for the reduction of anti-cancer drug dose. Existing data supports the model that the pain associated with CIPN is the result of anti-cancer drugs augmenting the function of the peripheral sensory nociceptors but the cellular mechanisms underlying the effects of anti-cancer drugs on sensory neuron function are not well described. Studies from animal models have suggested a number of disease etiologies including mitotoxicity, axonal degeneration, immune signaling, and reduced sensory innervations but these outcomes are the result of prolonged treatment paradigms and do not necessarily represent the early formative events associated with CIPN. Here we show that acute exposure to vinca alkaloids results in an immediate pain syndrome in both flies and mice. Furthermore, we demonstrate that exposure of isolated sensory neurons to vinca alkaloids results in the generation of an inward sodium current capable of depolarizing these neurons to threshold resulting in neuronal firing. These neuronal effects of vinca alkaloids require the transient receptor potential ankyrin-1 (TrpA1) channel, and the hypersensitization to painful stimuli in response to the acute exposure to vinca alkaloids is reduced in TrpA1 mutant flies and mice. These findings demonstrate the direct excitation of sensory neurons by CIPN-causing chemotherapy drugs, and identify TrpA1 as an important target during the pathogenesis of CIPN.

Regenerative endodontic procedures are rapidly gaining the attention of clinicians and investigators alike. However, it is often challenging to understand various regenerative studies and to interpret their results. The present review addresses this problem by focusing on recent strategies for developing standardized clinical protocols, understanding the full spectrum of clinical and translational research and its relationship to selection of proper outcome measures, as well as reviewing the fundamental role of paradigms in designing and interpreting regenerative studies.

Introduction Outcome studies of endodontic treatment of necrotic immature permanent teeth rely on radiographic measures as surrogates of whether the treatment achieved regeneration/revascularization/revitalization. An increase in radiographic root length and/or width is thought to result in a better long-term prognosis for the tooth. In this study, a method to measure radiographic outcomes of endodontic therapies on immature teeth was developed and validated. Methods A standardized protocol was developed for measuring the entire area of the root of immature teeth. The radiographic root area (RRA) measurement accounts for the entire surface area of the root as observed on a periapical radiograph. Reviewers were given instructions on how to measure RRA, and they completed measurements on a set of standardized radiographs. Results The intraclass correlation between the 4 reviewers was 0.9945, suggesting a high concordance among reviewers. There was no effect of the reviewer on the measured RRA values. High concordance was also observed when 1 rater repeated the measurements, with an intraclass correlation value of 0.9995. There was no significant difference in RRA values measured at the 2 sessions by the same rater. Furthermore, significant differences in RRA were detectable between clinical cases that showed obvious continued root development and cases that did not demonstrate discernible root development. Conclusions These results suggest that RRA is a valid measure to assess radiographic outcomes in endodontically treated immature teeth, and RRA should be useful in future clinical studies of regenerative endodontic outcomes.

We sought to understand pregnant women’s product preference and likelihood of use of topical microbicides for bacterial vaginosis (BV) prevention and treatment. Pregnant women (N = 196) in a obstetrics clinic completed a survey between June 2014 and January 2015 about vaginal product use for BV. This cross-sectional study explored product preferences, likelihood of product use for BV management and father of the baby (FOB) involvement. Most participants were under 30 (68%) and underrepresented minorities (47% Hispanic, 21% African-American). Most women preferred the gel (69%). Only 30% were likely to use either product for prevention of BV; 76% if high risk for BV; 83% treatment of BV. Anticipated FOB involvement in decision-making included that 46% would ask his opinion, 38% would inform him of the decision and 7% would need approval. Most (87%) would ask the FOB for reminders and 66% for insertion help. Those under 30 were more likely to agree to ask the FOB for reminders (p

Tissue injury, such as burns or inflammation, can lead to the generation of oxidized lipids capable of regulating hemodynamic, pulmonary, immune, and neuronal responses. However, it is not known whether traumatic injury leads to a selective upregulation of transcripts encoding oxidative enzymes capable of generating these mediators. Here, we analyzed microarrays taken from circulating leukocytes of 187 trauma subjects compared with 97 control volunteers for changes in the expression of 105 oxidative enzymes and related receptors. The results indicate that major blunt trauma triggers a selective change in gene expression, with some transcripts undergoing highly significant upregulation (e.g., CYP2C19), while others display significantly reduced expression (e.g., CYP2U1). This pattern in gene expression was maintained for up to 28 days after injury. In addition, the level of expression of CYP2A7, CYP2B7P1, CYP2C19, CYP2E1, CYP4A11, CYP4F3, CYP8B1, CYP19A1, CYP20A1, CYP51A1, HMOX2, NCF1, NCF2, and NOX1 and the receptors PTGER2 and ESR2 were correlated with clinical trauma indices such as APACHE II, Max Denver Scale, and the Injury Severity Score. Demonstration of a selective alteration in expression of transcripts encoding oxidative enzymes reveals a complex molecular response to major blunt trauma in circulating leukocytes. Furthermore, the association between changes in gene expression and clinical trauma scores suggests an important role in integrating pathophysiologic responses to blunt force trauma.

Endodontic management of immature permanent teeth with necrotic pulps is both a clinical problem for dental practitioners and a public health care problem. Although it is feasible to perform apexification procedures, the long-term survival of these teeth is questionable due to thin, incompletely formed dentinal walls. Regenerative endodontic procedures have emerged as a viable treatment alternative for these teeth. This review summarizes the evolution of these procedures while presenting recent advances, including treatment protocol modifications based on translational studies and future bioengineering approaches.

Introduction There are numerous challenges in treating immature permanent teeth with a diagnosis of pulp necrosis. Three general treatment options are calcium hydroxide apexification, mineral trioxide aggregate (MTA) apexification, and revascularization. The objective of this retrospective study was to evaluate radiographic and clinical outcomes of immature teeth treated with 1 of these 3 methods. Methods Clinical outcome data and radiographs were collected from 61 cases (ie, 22 calcium hydroxide apexification cases, 19 MTA apexification cases, and 20 revascularization cases). Both tooth survival and clinical success rates were analyzed. In addition, the preoperative and recall radiographs were analyzed to calculate the percentage increase in root width and length. Results The percentage change of root width was significantly greater in the revascularization group (28.2%) compared with the MTA apexification (0.0%) and calcium hydroxide apexification groups (1.5%). In addition, the percentage increase of root length was significantly greater in the revascularization group (14.9%) compared with the MTA (6.1%) and calcium hydroxide apexification groups (0.4%). Moreover, the survival rate of the revascularization-treated teeth (100%) and MTA apexification−treated teeth (95%) were greater than the survival rates observed in teeth treated with calcium hydroxide (77.2%). Conclusions In this study, revascularization was associated with significantly greater increases in root length and thickness in comparison with calcium hydroxide apexification and MTA apexification as well as excellent overall survival rates.

Randomized Clinical Trial of Intraosseous Methylprednisolone Injection for Acute Pulpitis Pain Khaly Bane, Emmanuel Charpentier, Francois Bronnec, Vianney Descroix, Fatou Gaye-N'diaye, Abdoul Wahabe Kane, Rafael Toledo, Pierre Machtou, Jean Azerad The Effect of Foraminal Enlargement of Necrotic Teeth with the Reciproc System on Postoperative Pain: A Prospective and Randomized Clinical Trial Jose Artero Cruz Junior, Marcelo Santos Coelho, Augusto Shoji Kato, Nilton Vivacqua-Gomes, Carlos Eduardo Fontana, Daniel Guimaraes Pedro Rocha, Carlos Eduardo da Silveira Bueno

Intracanal disinfection is a crucial step in regenerative endodontic procedures. However, this novel endodontic treatment lacks standardization, and numerous treatment protocols have been reported without knowledge of the effect of disinfection protocols on the survival of stem cells. The aim of this study was to test the hypothesis that different root canal irrigation protocols alter survival of stem cells from the apical papilla (SCAP).SCAP were isolated from immature human third molars, and a subpopulation of STRO-1 expressing cells was selected and expanded in vitro. Standardized human root segments (n = 5/group) were irrigated with 1 of 4 protocols: (1) 17% ethylenediaminetetraacetic acid (EDTA), (2) 6% NaOCl/17% EDTA/6% NaOCl, (3) 17% EDTA/2% chlorhexidine (CHX), or (4) 6% NaOCl/17% EDTA/6% NaOCl/isopropyl alcohol/2% CHX. Subsequently, STRO-1-enriched SCAP were mixed with platelet-rich-plasma, seeded into the root tips, and cultured for 21 days. Roots were then decalcified, processed for immunohistochemistry, and stained for vimentin and TO-PRO-3. The proportion of viable (vimentin-positive) cells was calculated on the basis of the total cell counts (TO-PRO-3) for each group.Irrigation with 17% EDTA best supported cell survival (89% viability; P.001 versus all other groups), followed by irrigation with 6% NaOCl/17% EDTA/6% NaOCl (74%; P.001 versus the 2 groups containing 2% CHX). Conversely, protocols that included 2% CHX lacked any viable cells.Collectively, the results suggest that irrigants alone greatly affect the survivability of STRO-1-enriched SCAP within the root canal environment and that inclusion of EDTA in irrigation protocols might be beneficial in regenerative procedures.

Prolactin (PRL) is a hormone and a neuromodulator. PRL sensitizes TRPV1 responses in sensory neurons, but it is not clear whether peripheral inflammation results in the release of endogenous PRL, or whether endogenous PRL is capable of acting as an inflammatory mediator in a sex-dependent manner. To address these questions, we examined inflammation-induced release of endogenous PRL, and its regulation of thermal hyperalgesia in female and male rats. PRL is expressed in several types of peripheral neuronal and non-neuronal cells, including TRPV1-positive nerve fibers, preadipocytes and activated macrophages/monocytes localized in the vicinity of nerves. Evaluation of PRL levels in hindpaws and plasma indicated that complete Freund’s adjuvant (CFA) stimulates release of peripheral, but not systemic PRL within 6–48h in both ovariectomized females with estradiol replacement (OVX-E) and male rats. The time course of release varies in OVX-E and male rats. We next employed the prolactin receptor (PRL-R) antagonist, Δ1-9-G129R-hPRL to assess the role of locally-produced PRL in nociception. Applied at a ratio of 1:1 (PRL:Δ1-9-G129R-hPRL; 40nM each), this antagonist was able to nearly (≈80%) reverse PRL-induced sensitization of capsaicin responses in rat sensory neurons. CFA-induced inflammatory thermal hyperalgesia in OVX-E rat hindpaws was significantly reduced in a dose-dependent manner by the PRL-R antagonist at the 6h, but not the 24h time point. In contrast, PRL contributed to inflammatory thermal hyperalgesia in male rats at 24h, but not 6h. In summary, these findings indicate that inflammation leads to accumulation of endogenous PRL in female and male rats. Further, PRL acts as an inflammatory mediator at different time points for female and male rats.

Introduction Immature teeth with open apices treated with conventional nonsurgical root canal treatment often have a poor prognosis as a result of the increased risk of fracture and susceptibility to recontamination. Regenerative endodontics represents a new treatment modality that focuses on reestablishment of pulp vitality and continued root development. This clinical procedure relies on the intracanal delivery of a blood clot (scaffold), growth factors (possibly from platelets and dentin), and stem cells. However, to date, the clinical presence of stem cells in the canal space after this procedure has not been demonstrated. The purpose of this clinical study was to evaluate whether regenerative endodontic procedures are able to deliver stem cells into the canal space of immature teeth in young patients and to identify the possible tissue origin for these cells. Methods After informed consent, the first appointment consisted of NaOCl irrigation and treatment with a triple antibiotic paste. One month later, the root canal space was irrigated with sterile saline, and bleeding was evoked with collection of samples on paper points. Real-time reverse-transcription polymerase chain reaction and immunocytochemistry were conducted to compare the gene transcripts and proteins found in the root canal sample with levels found in the systemic circulation. Results Molecular analyses of blood collected from the canal system indicated the significant accumulation of transcripts for the stem cell markers CD73 and CD105 (up to 600-fold), compared with levels found in the systemic blood. Furthermore, this effect was selective because there was no change in expression of the differentiation markers ALK-P, DSPP, ZBTB16, and CD14. Histologic analyses demonstrated that the delivered cells expressed both CD105 and STRO-1, markers for a subpopulation of mesenchymal stem cells. Conclusions Collectively, these findings demonstrate that the evoked-bleeding step in regenerative procedures triggers the significant accumulation of undifferentiated stem cells into the canal space where these cells might contribute to the regeneration of pulpal tissues seen after antibiotic paste therapy of the immature tooth with pulpal necrosis.

Introduction The purpose of this study was to evaluate the biocompatibility of gray mineral trioxide aggregate (MTA) mixed with selected accelerants by examining the inflammatory response through histological analysis after implantation into rat mandibles. Methods Sixty rats were randomly divided into experimental groups of calcium chloride (CaCl 2 ), calcium nitrite/nitrate (CaN/N), or calcium formate (CaF) mixed with MTA and compared with controls of MTA mixed with sterile water (MTA control) and unfilled osteotomies. Material was implanted into an osteotomy prepared between the roots of the mandibular molars and the incisors in the mandible. After 2 or 8 weeks, tissues were collected and processed for hematoxylin and eosin staining and light microscopic evaluation. Blinded evaluators graded the inflammatory response along the MTA-bone interface on an ordinal scale. Data were analyzed using the Kruskal-Wallis test, and interobserver agreement was determined by the kappa analysis. Results Interobserver agreement was good with κ = 0.72. No statistically significant differences were noted between experimental and control groups at the 2-week time point ( p > 0.05). At this time, all groups displayed a range of inflammatory responses from none to severe with mostly mild to moderate reactions. At the 8-week time point, the inflammatory reaction of CaF mixed with MTA was statistically different from the controls ( p = 0.03). CaCl 2 and CaN/N were not statistically different from the controls, and the MTA control displayed no inflammation at this time point. Conclusions The findings of this study indicate that MTA mixed with accelerants may be a biocompatible alternative when a rapid set is indicated clinically.

Introduction Diagnostic terminology used in endodontics has been based on historical use, textbook and glossary terms, best-available science, and personal conviction. There is minimal evidence that establishes an absolute set of terms that can be used to make a definitive diagnosis. As a component of the Consensus Conference on Diagnostic Terminology held in October 2008, an online survey was conducted to invitees to assess their opinions on diagnosis. Methods Thirty-six questions were developed by the oversight committee and chairs of the subcommittees. Most questions used a modified Likert scale to generate a response. At least a 51% agreement or disagreement to the statement was considered a consensus, and a response greater than 25% but less than 51% generated a minority report. Results Thirty-one of the 36 questions were designed to determine consensus. All 31 generated a consensus response, with 14 of those generating a minority report. Minority reports suggest that there was still greater than 25% of the respondents who did not follow consensus. Possible explanations were provided for those statements that generated a minority report. Conclusions Data from the online survey provided trends and preferences toward particular diagnostic terms and beliefs. The limitations of such a survey are multiple including the limited size and nature of the respondent group, responses based on opinion, and question design. The online survey results suggest an awareness for the specialty to develop better diagnostic tools and terminology that are biologically and metric based.

The mechanisms underlying trigeminal pain conditions are incompletely understood. In vitro animal studies have elucidated various targets for pharmacological intervention; however, a lack of clinical models that allow evaluation of viable innervated human tissue has impeded successful translation of many preclinical findings into clinical therapeutics. Therefore, we developed and characterized an in vitro method that evaluates the responsiveness of isolated human nociceptors by measuring basal and stimulated release of neuropeptides from collected dental pulp biopsies. Informed consent was obtained from patients presenting for extraction of normal wisdom teeth. Patients were anesthetized using nerve block injection, teeth were extracted and bisected, and pulp was removed and superfused in vitro. Basal and capsaicin-evoked peripheral release of immunoreactive calcitonin gene-related peptide (iCGRP) was analyzed by enzyme immunoassay. The presence of nociceptive markers within neurons of the dental pulp was characterized using confocal microscopy. Capsaicin increased the release of iCGRP from dental pulp biopsies in a concentration-dependent manner. Stimulated release was dependent on extracellular calcium, reversed by a TRPV1 receptor antagonist, and desensitized acutely (tachyphylaxis) and pharmacologically by pretreatment with capsaicin. Superfusion with phorbol 12-myristate 13-acetate (PMA) increased basal and stimulated release, whereas PGE2 augmented only basal release. Compared with vehicle treatment, pretreatment with PGE2 induced competence for DAMGO to inhibit capsaicin-stimulated iCGRP release, similar to observations in animal models where inflammatory mediators induce competence for opioid inhibition. These results indicate that the release of iCGRP from human dental pulp provides a novel tool to determine the effects of pharmacological compounds on human nociceptor sensitivity.

Pulpitis pain might be triggered by a cold stimulus, yet the cellular mechanisms responsible for this phenomenon are largely unknown. One possible mechanism involves the direct activation of cold-responsive thermoreceptors. The purpose of this study was to evaluate the possible role of the TRPM8 thermoreceptor in cold-mediated noxious pulpal pain mechanisms by comparing expression patterns in pulpal nerves from healthy control molars to cold-sensitive painful molars with irreversible pulpitis. Samples were identically processed with the indirect immunofluorescence method, and images were obtained with confocal microscopy. The immunofluorescence intensity and area occupied by TRPM8 within N52/PGP9.5-identified nerve fibers were quantified. Results showed that relative to normal samples, TRPM8 nerve area expression was significantly less in the cold-sensitive painful samples (34.9% vs 8%, P

In contrast to the high long-term survival rates (> 93%) of conventional endodontic treatment applied to mature permanent teeth, the treatment of the immature permanent tooth with a necrotic root canal system and apical periodontitis is challenging, due in part to incomplete root development leading to thin dentinal walls and reduced overall length. Conventional apexification procedures treat apical periodontitis in immature teeth, but the cases often have a poor prognosis due to weak root structures. Recent studies have employed a tissue engineering approach designed to regenerate a pulp-like tissue, resulting in continued radiographic root development, healing of apical periodontitis, and improved overall tooth survival. This chapter reviews the biological basis of regenerative endodontics and provides a perspective to interpret ongoing research in this dynamic area.

The intra-operative control of pain and hemorrhage represents significant factors that are required for modern, effective, and efficient endodontic surgical procedures. This review focuses on these important issues and emphasizes the level of clinical evidence of various studies reporting on interventions to alter pain or hemorrhage. To accomplish this goal, the review will provide an overview of the fundamental properties of local anesthetics and hemostasis and then build upon this foundation to provide evidence-based recommendations for treatment considerations.

Recent advances in the understanding of pain physiology and pharmacology have provided dental practitioners with more reliable information upon which clinical decisions in the treatment of endodontic pain can be based. This article provides practical treatment strategies based upon current scientific evidence and uses information presented in the prior articles of this issue of Endodontic Topics to make treatment recommendations for given patient scenarios.

Although many studies have evaluated analgesic strategies for control of postendodontic pain, there have been no systematic reviews of this literature. This article describes the process for conducting a systematic review and uses this method to analyze the use of non-steroidal anti-inflammatory drugs (NSAIDs) for treatment of postendodontic pain.

Many patients fear endodontic procedures due to a concern about pain. Although pain treatment is well managed in many endodontic patients, there exists a group of patients who do not receive adequate local anesthesia. This article reviews the mechanisms of local anesthetic failure and focuses on available evidence for developing effective and efficient approaches in local anesthesia.

The continued development of more effective and predictable methods for pain control is a process that combines the best efforts of basic and clinical scientists. This review explores the developing themes of clinical pain management strategies that are emerging from molecular, cellular, and physiologic research into pain mechanisms and emphasizes the unique opportunity that several years of well-controlled clinical trials affords the dental education community to provide evidence-based learning in pain treatment strategies.

The endodontic management of permanent immature teeth is fraught with challenges. Although treatment modalities for vital pulp therapy in these teeth provide long-term favorable outcome, the outcomes from the treatment of pulp necrosis and apical periodontitis are significantly less predictable. Immature teeth diagnosed with pulp necrosis have been traditionally treated with apexification or apexogenesis approaches. Unfortunately, these treatments provide little to no benefit in promoting continued root development. Regenerative endodontic procedures have emerged as an important alternative in treating teeth with otherwise questionable long-term prognosis because of thin, fragile dentinal walls and a lack of immunocompetency. These procedures rely heavily on root canal chemical disinfection of the root canal system. Traditionally, irrigants and medicaments have been chosen for their maximum antimicrobial effect without consideration for their effects on stem cells and the dentinal microenvironment. Translational research has been crucial to provide evidence for treatment modifications that aim to increase favorable outcome while steering away from common pitfalls in the currently used protocols. In this review, recent advances learned from translational research related to disinfection in regenerative endodontics are presented and discussed.

Background Bacterial vaginosis (BV) is the most common reproductive tract infection (RTI) and is a significant risk factor for preterm birth. Microbicides could be an option for the prevention and treatment of BV in pregnancy, and understanding use of the product will be crucial. The present study explored attitudes of women in the third trimester of pregnancy regarding topical microbicide use for the prevention and treatment of BV. Methods: Twenty-six women in their third trimester were interviewed regarding their knowledge and beliefs about RTIs during pregnancy and attitudes concerning the use of topical microbicides for prevention and treatment of BV. Results: Participants had a mean age of 24.9 years, were largely under-represented minorities and the majority had had past pregnancies. Participants had knowledge and experience with RTIs but not BV. They were open to the use of microbicides for prevention or treatment of BV, but believed that women requiring treatment would be more motivated. Rationales for acceptability were most commonly related to the baby’s health. Practical issues that may interfere with use were often, but not always, related to pregnancy. There was a range of attitudes about partner involvement in decision-making and the practicalities of product use. Conclusion: Pregnant women are knowledgeable about RTIs but not necessarily BV. The women in this study found microbicide use acceptable, particularly for treatment. To improve acceptability and use, education would be needed about BV and possible complications, how to overcome practical problems and the value of involving partners in the decision.

One of the main culprits in modern drug discovery is apparent cardiotoxicity of many lead-candidates via inadvertent pharmacologic blockade of K+, Ca2+ and Na+ currents. Many drugs inadvertently block hERG1 leading to an acquired form of the Long QT syndrome and potentially lethal polymorphic ventricular tachycardia. An emerging strategy is to rely on interventions with a drug that may proactively activate hERG1 channels reducing cardiovascular risks. Small molecules-activators have a great potential for co-therapies where the risk of hERG-related QT prolongation is significant and rehabilitation of the drug is impractical. Although a number of hERG1 activators have been identified in the last decade, their binding sites, functional moieties responsible for channel activation and thus mechanism of action, have yet to be established. Here, we present a proof-of-principle study that combines de-novo drug design, molecular modeling, chemical synthesis with whole cell electrophysiology and Action Potential (AP) recordings in fetal mouse ventricular myocytes to establish basic chemical principles required for efficient activator of hERG1 channel. In order to minimize the likelihood that these molecules would also block the hERG1 channel they were computationally engineered to minimize interactions with known intra-cavitary drug binding sites. The combination of experimental and theoretical studies led to identification of functional elements (functional groups, flexibility) underlying efficiency of hERG1 activators targeting binding pocket located in the S4-S5 linker, as well as identified potential side-effects in this promising line of drugs, which was associated with multi-channel targeting of the developed drugs.

Introduction Effective root canal disinfection is a fundamental component of successful root canal treatment. Photodynamic therapy (PDT) has been proposed as a new adjunctive method for additional disinfection of the root canal system with the possibility of improved treatment outcomes. The aim of this systematic review was to investigate the effect of PDT on bacterial load reduction during root canal disinfection. Methods Two reviewers independently conducted a comprehensive literature search using a combination of medical subject heading terms and key words to identify studies relevant to the Population Intervention Control Outcome question. The selection of articles for inclusion was performed in 2 phases based on predetermined eligibility criteria according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Inter-reviewer agreement for each phase was recorded. The effect of PDT on bacterial load reduction during root canal disinfection was evaluated as the primary outcome variable during data extraction. Results The literature search provided 57 titles and abstracts. Three articles met the inclusion criteria and were selected for this systematic review. The reasons for study exclusion in each phase were recorded. Because of the heterogeneity in clinical indications and PDT protocols among the included studies, a meta-analysis could not be performed. All included studies showed a positive effect of PDT in the reduction of microbial load in root canal treatment ranging from 91.3%–100%. Conclusions Limited clinical information is currently available on the use of PDT in root canal disinfection. If supported by future clinical research, PDT may have efficacy for additional root canal disinfection, especially in the presence of multi–drug-resistant bacteria.

Estimation of the effort required for a software project is difficult. Various means are used, but most rely on some expert assessment of the individual requirements and their implications. A method of supporting this assessment for object-oriented developments is described. Lexical analysis of a draft requirements specification can be used to identify individual objects which will translate directly into the final implementation. These object counts can then be used to provide ‘first-cut’ effort estimates, using historical information from previous projects. Experiments were conducted on a problem implemented by student project teams. The results show that the untrained domain-independent automated noun and technical term finding programs used were no worse than the typical student group in deriving problem-space objects, and that these object counts provided a reasonable indicator to the effort required. Further work in this area is discussed.

Musculoskeletal pain is one of the most frequent symptoms for which medical assistance is sought. Yet, the majority of our knowledge regarding pain physiology is based on studies of cutaneous tissue. Comparatively little is known about activation of visceral, joint and perhaps least of all, musculoskeletal nociceptors although clinically-treated pain originates principally in these structures. Studies elucidating the mechanisms of muscle hyperalgesia have been hampered by the lack of an animal model that permits the evaluation of hypotheses using behavioral, biochemical, pharmacological, anatomical and molecular experimental approaches. Here we describe an animal model of muscle hyperalgesia we recently developed that permits such multidisciplinary investigation. This model employs the intramuscular injection of carrageenan, a chemical stimulus which evokes a well recognized model of cutaneous inflammation and is reported to activate muscle nociceptors. Intramuscular carrageenan evokes a time- and dose-dependent reduction in forelimb grip force that is anatomically specific. The carrageenan-evoked reduction in grip force is blocked by the mu-opioid agonist levorphanol in a dose-dependent, stereoselective and naltrexone-reversible manner. This behavioral dependent measure is also significantly reversed by agents used clinically to treat muscle pain, indomethacin and dexamethasone, as well as the non-competitive N-methyl-D-aspartate receptor antagonist MK801. Finally, evidence that reduction in grip force is in part mediated by small, unmyelinated afferents is provided by the demonstration that neonatal capsaicin treatment significantly reduced carrageenan-evoked behavioral hyperalgesia ( approximately 45% reduction) and reduced muscle content of immunoreactive CGRP ( approximately 60% reduction) relative to control levels. Collectively, these findings provide converging lines of evidence for the validity of this animal model to investigate mechanisms involved in the development of muscle hyperalgesia.

Dental pulp is richly innervated with neurons containing calcitonin gene-related peptide (CGRP) or substance P (SP). Prior studies have demonstrated that inflammation alters these pulpal neuropeptides. In this study, we used a radioimmunoassay to evaluate the specificity of this response and the contribution of axonal transport. Rat mandibular molars were exposed and immunoreactive CGRP (iCGRP) and immunoreactive SP were measured. At 7 to 14 days after exposure, both pulpal iCGRP (73%) and immunoreactive SP (135%) displayed peak increases above control levels. This response was somatotopically restricted, with no changes observed in contralateral (intact) molars, or in ipsilateral mandibular molars after exposure of maxillary molars. Transection of the inferior alveolar nerve on day 13 significantly reduced pulpal levels of iCGRP on day 14. Collectively, these studies indicate that pulpal inflammation evokes a selective alteration in neuropeptide levels, due at least in part to alterations in transport or synthesis of neuropeptides in the trigeminal ganglion.

Pain due to tissue injury is often characterized by the presence of hyperalgesia and allodynia. It is hypothesized that these perceptual states are mediated by sensitization of peripheral terminals of primary afferent neurons together with several changes in the central nervous system. This provides a rationale for preemptive analgesia, whereby the blockade of primary afferent input prior to injury may result in a reduction of post-injury pain. One approach for prolonged blockade of primary afferent input is the use of bioerodible polymer systems providing regulated release of local anesthetics. Bioerodible polymer systems offer the theoretical advantage of controlled drug delivery maintained over prolonged periods. Local application of this system to the inflamed tissue compartment permits the use of smaller total drug doses. This may minimize systemic side effects, while maintaining prolonged peripherally-mediated antinociception. In the present study, we evaluated the effects of a bioerodible polymer/bupivacaine system (PLGA/bupivacaine) on several indices of inflammation and on hindpaw levels of the inflammatory mediators, substance P and bradykinin in the complete Freund's adjuvant model. We observed that PLGA/bupivacaine reduces inflammatory hyperalgesia, edema and hyperthermia in a temporal and dose-related fashion in awake animals. Moreover, we demonstrated that PLGA/bupivacaine has a prolonged inhibitory effect on the tissue levels of substance P and bradykinin in the inflamed hindpaws. The results of these studies clearly indicate the potential therapeutic utility of the PLGA bupivacaine system, with the single dose administration producing a prolonged suppression of hyperalgesia, edema and biochemical indices of inflammation.

The P2X3 receptor subunit, a member of the P2X family of ATP-gated ion channels, is almost exclusively localized in sensory neurons. In the present study, we sought to gain insight into the role of P2X3 and P2X3-containing neurons in sensory transmission, using immunohistochemical approaches. In rat dorsal root ganglia (DRG), P2X3-immunoreactivity (-ir) was observed in small- and medium-sized neurons. Approximately 40% of DRG neuronal profiles in normal rats contained P2X3-ir. In rats that had received neonatal capsaicin treatment, the number of P2X3-positive neurons was decreased by approximately 70%. Analysis of the colocalization of P2X3-ir with cytochemical markers of DRG neurons indicated that approximately 94% of the P2X3-positive neuronal profiles were labelled by isolectin B4 from Bandeiraea simplicifolia, while only 3% contained substance P-ir, and 7% contained somatostatin-ir. In dorsal horn of rat spinal cord, P2X3-ir was observed in the inner portion of lamina II and was reduced subsequent to dorsal rhizotomy, as well as subsequent to neonatal capsaicin treatment. Finally, P2X3-ir accumulated proximal to the site of sciatic nerve ligation, and was seen in nerve fibres in skin and corneal epithelium. In summary, our results suggest that P2X3 is expressed by a functionally heterogeneous population of BSI-B4-binding sensory neurons, and is transported into both central and peripheral processes of these neurons.

We report an enhanced prospective survey of invasive Haemophilus influenzae infections that has defined the pattern of invasive disease in five English regions for 2 years before and 4 years after the introduction of the H. influenzae type b (Hib) vaccination program. During the prevaccination period the majority of cases of invasive H. influenzae were caused by type b; most (89%) of these infections occurred in children

Chronic nicotine exposure in the rat produces a characteristic increase in neuronal nicotinic binding sites in many brain regions. The conventional method for inducing such increases utilizes twice daily subcutaneous injections of a near maximal, sub-convulsive dose of nicotine. Alternatively, nicotine may be chronically infused via an osmotic mini-pump. However, little is known about how administration of nicotine by chronic infusion compares to multiple injections in producing nicotinic receptor upregulation. This study used [3H]-epibatidine, a high potency neuronal nicotinic agonist radioligand, to compare the increases in receptor levels in rat brain, spinal cord and trigeminal ganglion tissues following chronic nicotine administration via either twice daily injections (2 mg/kg s.c.) or an osmotic mini-pump (1 mg/kg/hr) for 10 days. All central and peripheral nervous system tissues examined demonstrated significant neuronal nicotinic receptor up-regulation following chronic infusion of nicotine. Only the cerebral cortex and hippocampus displayed significant up-regulation following nicotine administration by injections. Moreover, in all tissues studied, the receptor levels measured were significantly higher in the animals that received nicotine by chronic infusion compared with multiple injections. These data indicate that chronic infusion of nicotine is a convenient and efficacious alternative to multiple injections for producing neuronal nicotinic receptor up-regulation in both central and peripheral nervous tissues.