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Dental pain from apical periodontitis is an infection induced-orofacial pain condition that presents with diversity in pain phenotypes among patients. While 60% of patients with a full-blown disease present with the hallmark symptom of mechanical allodynia, nearly 40% of patients experience no pain. Furthermore, a sexual dichotomy exists, with females exhibiting lower mechanical thresholds under basal and diseased states. Finally, the prevalence of post-treatment pain refractory to commonly used analgesics ranges from 7-19% (~2 million patients), which warrants a thorough investigation of the cellular changes occurring in different patient cohorts. We, therefore, conducted a transcriptomic assessment of periapical biopsies (peripheral diseased tissue) from patients with persistent apical periodontitis. Surgical biopsies from symptomatic male (SM), asymptomatic male (AM), symptomatic female (SF), and asymptomatic female (AF) patients were collected and processed for bulk RNA sequencing. Using strict selection criteria, our study found several unique differentially regulated genes (DEGs) between symptomatic and asymptomatic patients, as well as novel candidate genes between sexes within the same pain group. Specifically, we found the role of cells of the innate and adaptive immune system in mediating nociception in symptomatic patients and the role of genes involved in tissue homeostasis in potentially inhibiting nociception in asymptomatic patients. Furthermore, sex-related differences appear to be tightly regulated by macrophage activity, its secretome, and/or migration. Collectively, we present, for the first time, a comprehensive assessment of peripherally diseased human tissue after a microbial insult and shed important insights into the regulation of the trigeminal system in female and male patients.SummaryClinical diversity paves the way for translational research. We conducted a comprehensive transcriptomic assessment of peripherally diseased human tissue from patients with apical periodontitis to understand better clinical diversity observed in pain phenotypes between patients as well as perform in-depth analyses of sex-related dimorphism in patients with apical periodontitis.

National audience; Background: Atrial fibrillation is the most common arrhythmia in post-industrialized populations. Older age, hypertension, obesity, chronic inflammation, and diabetes are significant atrial fibrillation risk factors, suggesting that modern urban environments may promote atrial fibrillation.Objective: Here we assess atrial fibrillation prevalence and incidence among tropical horticulturalists of the Bolivian Amazon with high levels of physical activity, a lean diet, and minimal coronary atherosclerosis, but also high infectious disease burden and associated inflammation.Methods: Between 2005–2019, 1314 Tsimane aged 40–94 years (52% female) and 534 Moseten Amerindians aged 40–89 years (50% female) underwent resting 12-lead electrocardiograms to assess atrial fibrillation prevalence. For atrial fibrillation incidence assessment, 1059 (81% of original sample) Tsimane and 310 Moseten (58%) underwent additional ECGs (mean time to follow up 7.0, 1.8 years, respectively).Findings:Only one (male) of 1314 Tsimane (0.076%) and one (male) of 534 Moseten (0.187%) demonstrated atrial fibrillation at baseline. There was one new (female) Tsimane case in 7395 risk years for the 1059 participants with >1 ECG (incidence rate = 0.14 per 1,000 risk years). No new cases were detected among Moseten, based on 542 risk years.Conclusion: Tsimane and Moseten show the lowest levels of atrial fibrillation ever reported, 1/20 to ~1/6 of rates in high-income countries. These findings provide additional evidence that a subsistence lifestyle with high levels of physical activity, and a diet low in processed carbohydrates and fat is cardioprotective, despite frequent infection-induced inflammation. Findings suggest that atrial fibrillation is a modifiable lifestyle disease rather than an inevitable feature of cardiovascular aging.

Introduction Dental professionals are at high risk of contracting coronavirus disease 2019 (COVID-19) infection because of their scope of practice with aerosol-generating procedures. Recommendation by the Centers for Disease Control and Prevention to suspend elective dental procedures and avoid aerosol-generating procedures posed significant challenges in the management of patients presenting with endodontic emergencies and uncertainty of outcomes for endodontic procedures initiated, but not completed, before shutdown. The purpose of this study was to evaluate the success of palliative care on endodontic emergencies during the COVID-19 pandemic and to evaluate the stability of teeth with long-term Ca(OH)2 placement because of delays in treatment completion. Methods Patients presenting for endodontic emergencies during COVID-19 Shelter-in-Place orders received palliative care, including pharmacologic therapy and/or non–aerosol-generating procedural interventions. Part I of the study evaluated the effectiveness of palliative care, and need for aerosol-generating procedures or extractions was quantified. Part II of the study evaluated survivability and rate of adverse events for teeth that received partial or full root canal debridement and placement of calcium hydroxide before shutdown. Results Part I: Twenty-one patients presented with endodontic emergencies in 25 teeth during statewide shutdown. At a follow-up rate of 96%, 83% of endodontic emergencies required no further treatment or intervention after palliative care. Part II: Thirty-one teeth had received partial or full root canal debridement before statewide shutdown. Mean time to complete treatment was 13 weeks. At a recall rate of 100%, 77% of teeth did not experience any adverse events due to delays in treatment completion. The most common adverse event was a fractured provisional restoration (13%), followed by painful and/or infectious flare-up (6.4%), which were managed appropriately and therefore seemed successful. Only 1 tooth was fractured and nonrestorable (3%), leading to a failed outcome of tooth extraction. The remaining 4 outcome failures (13%) were due to patient unwillingness to undergo school-mandated COVID testing or patient unwillingness to continue treatment because of perceived risk of COVID infection. Conclusions Palliative care for management of endodontic emergencies is a successful option when aerosol-generating procedures are restricted. This treatment approach may be considered in an effort to reduce risk of transmission of COVID-19 infection during subsequent shutdowns. Prolonged Ca(OH)2 medicament because of COVID-19 related delays in treatment completion appeared to have minimal effect on survival of teeth.

Tissue engineering protocols, such as regenerative endodontic procedures (REPs), comprise biologically based procedures designed to restore normal physiologic function. For REPs, the goal is reconstitution of the pulp-dentin complex by delivering mesenchymal stem cells (MSCs), including the stem cells of the apical papilla (SCAP) into a root canal system. Many patients regain cold sensitivity after REPs, but the mechanism is not understood. We hypothesized that SCAP modulate nociceptive function through a paracrine mechanism that activates cold-sensitive ion channels in neurons. We established a coculture system with human SCAP and rat trigeminal (TG) sensory neurons in order to determine the effect of SCAP co-culture on neuronal responses using whole-cell patch-clamp electrophysiology. TG neurons co-cultured with SCAP demonstrated increased TRPA1-mediated (p < 0.01) and TRPM8-mediated inward current densities (p < 0.01) at 24 h in co-culture. Cold stimulation to SCAP significantly increased ATP release (p < 0.01), and supernatant collected after cold stimulation to SCAP was able to activate cultured TG neurons. Co-culture with SCAP significantly increased sustained ATP-evoked inward current density (p < 0.05). These data suggest that SCAP release trophic factors that act on afferent neurons to enhance cold-sensitive ion channel activity.

Heart failure is a clinical diagnosis that is supported by various laboratory, imaging, and invasive hemodynamic measures. There is no single diagnostic test. A variety of structural and/or functional myocardial abnormalities can lead to the inability of the heart to fill or eject blood. Despite ejection fraction being the most commonly assessed measure of systolic function in clinical practice, it is a poor measure of contractility because it is susceptible to loading conditions and chamber size. Invasive hemodynamic assessment remains of great importance in the evaluation of patients with myocardial disease or hypertrophic cardiomyopathy.

Endogenous TRPV1 agonists such as oxidized linoleic acid metabolites (OLAMs) and the enzymes releasing them [eg, cytochrome P450 (CYP)] are up-regulated after inflammation in the rat. However, it is not known whether such agonists are elevated in human inflammatory pain conditions. Because TRPV1 is expressed in human dental pulp nociceptors, we hypothesized that OLAM-CYP machinery is active in this tissue type and is increased under painful inflammatory conditions such as irreversible pulpitis (IP). The aim of this study was to compare CYP expression and linoleic acid (LA) metabolism in normal vs inflamed human dental pulp. Our data showed that exogenous LA metabolism was significantly increased in IP tissues compared to normal tissues and that pretreatment with a CYP inhibitor, ketoconazole, significantly inhibited LA metabolism. Additionally, extracts obtained from LA-treated inflamed tissues evoked significant inward currents in trigeminal ganglia neurons and were blocked by pretreatment with the TRPV1 antagonist IRTX. Moreover, extracts obtained from ketoconazole-pretreated inflamed tissues significantly reduced inward currents in trigeminal ganglia neurons. These data suggest that LA metabolites produced in human inflamed tissues act as TRPV1 agonists and that the metabolite production can be targeted by CYP inhibition. In addition, immunohistochemical analysis of 2 CYP isoforms, CYP2J and CYP3A1, were shown to be predominately expressed in immune cells infiltrating the inflamed dental pulp, emphasizing the paracrine role of CYP enzymes in OLAM regulation. Collectively, our data indicate that the machinery responsible for OLAM production is up-regulated during inflammation and can be targeted to develop potential analgesics for inflammatory-induced dental pain.

Patients with normal myocardial perfusion imaging (MPI) have a good prognosis. However, pre-clinical coronary and extracoronary atherosclerosis may exist in the absence of myocardial ischemia. 154 Egyptian patients (mean age 53 years) underwent whole-body non-contrast CT following normal MPI. Atherosclerosis in the form of calcification was observed in ≥1 vascular bed in 115 of 154 (75%) patients. This included the iliofemoral (62%), abdominal aorta (53%), thoracic aorta (47%), coronary (47%), and carotid (25%) vascular beds. Mean total body calcium score was 3172 ± 530 AU. Extracoronary atherosclerosis in patients with a zero coronary artery calcium (CAC) score was common, occurring in the above-listed beds 42%, 36%, 29%, and 7% of the time, respectively. CAC was rarely present without iliofemoral or abdominal aortic calcification. Quantitative assessment of calcification in different vascular beds demonstrates that extracoronary atherosclerosis is common in patients who have normal MPI. Atherosclerotic calcifications are most common in the iliofemoral arteries and abdominal aorta, which typically predate coronary calcifications. An imaging strategy to detect extracoronary atherosclerosis could lead to greater understanding of the natural history of atherosclerosis in its long pre-clinical phase and possibly to earlier preventive strategies.

Nerve growth factor (NGF) is elevated in certain chronic pain conditions and is a sufficient stimulus to cause lasting pain in humans, but the actual mechanisms underlying the persistent effects of NGF remain incompletely understood. We developed a rat model of NGF-induced persistent thermal hyperalgesia and mechanical allodynia to determine the role of transient receptor potential vanilloid 1 (TRPV1) and oxidative mechanisms in the persistent effects of NGF. Persistent thermal hypersensitivity and mechanical allodynia requirede novoprotein translation and are mediated by TRPV1 and oxidative mechanisms. By comparing effects after systemic (subcutaneous), spinal (intrathecal) or hindpaw (intraplantar) injections of test compounds, we determined that TRPV1 and oxidation mediate persistent thermal hypersensitivity via peripheral and spinal sites of action and mechanical allodynia via only a spinal site of action. Therefore, NGF-evoked thermal and mechanical allodynia are mediated by spatially distinct mechanisms. NGF treatment evoked sustained increases in peripheral and central TRPV1 activity, as demonstrated by increased capsaicin-evoked nocifensive responses, increased calcitonin gene-related peptide release from hindpaw skin biopsies, and increased capsaicin-evoked inward current and membrane expression of TRPV1 protein in dorsal root ganglia neurons. Finally, we showed that NGF treatment increased concentrations of linoleic and arachidonic-acid-derived oxidized TRPV1 agonists in spinal cord and skin biopsies. Furthermore, increases in oxidized TRPV1-active lipids were reduced by peripheral and spinal injections of compounds that completely blocked persistent nociception. Collectively, these data indicate that NGF evokes a persistent nociceptive state mediated by increased TRPV1 activity and oxidative mechanisms, including increased production of oxidized lipid TRPV1 agonists.

The transient receptor potential family V1 channel (TRPV1) is activated by multiple stimuli, including capsaicin, acid, endovanilloids, and heat (>42C). Post-translational modifications to TRPV1 result in dynamic changes to the sensitivity of receptor activation. We have previously demonstrated that β-arrestin2 actively participates in a scaffolding mechanism to inhibit TRPV1 phosphorylation, thereby reducing TRPV1 sensitivity. In this study, we evaluated the effect of β-arrestin2 sequestration by G-protein coupled receptors (GPCRs) on thermal and chemical activation of TRPV1. Here we report that activation of mu opioid receptor by either morphine or DAMGO results in β-arrestin2 recruitment to mu opioid receptor in sensory neurons, while activation by herkinorin does not. Furthermore, treatment of sensory neurons with morphine or DAMGO stimulates β-arrestin2 dissociation from TRPV1 and increased sensitivity of the receptor. Conversely, herkinorin treatment has no effect on TRPV1 sensitivity. Additional behavioral studies indicate that GPCR-driven β-arrestin2 sequestration plays an important peripheral role in the development of thermal sensitivity. Taken together, the reported data identify a novel cross-talk mechanism between GPCRs and TRPV1 that may contribute to multiple clinical conditions.