Time-course of pain and salivary opiorphin release in response to oral capsaicin differ in burning mouth syndrome patients, temporomandibular disorders patients and control subjects.

OBJECTIVES: Opiorphin is an analgesic peptide released by salivary glands and capsaicin an agonist of TRPV1 receptors eliciting burning sensations. The primary objective of this study was to assess opiorphin release after stimulation of the tongue by capsaicin (STC). The secondary objectives were to compare opiorphin release after STC in 3 groups of subjects [healthy (CTRL), Burning Mouth Syndrome (BMS), painful Temporomandibular disorders (TMDp)] and pain evoked by STC in these 3 groups. MATERIALS AND METHODS: Salivary opiorphin was assessed with high-performance liquid chromatography at 3 different time points (baseline, after 5 min and 20 min of STC). Pain was self-reported on a (0-10) numeric rating scale. RESULTS: Three groups (N = 16) of adults were recruited at the Clinical Hospital Centre and School of Dental Medicine in Zagreb. Opiorphin levels were higher (1) in TMDp compared to CTRL in 1st (2.23 ± 1.72 pg/ul vs. 0.67 ± 0.44 pg/ul, p = 0.002) and 3rd sampling (2.44 ± 2.01 pg/ul vs. 0.74 ± 0.52 pg/ul, p = 0.020) and (2) within BMS group at 3rd sampling vs. baseline (p < 0.025). Pain scores were higher in BMS compared to TMDp (p < 0.025) and CTRL (p < 0.025). CONCLUSION: This study evidenced (1) a differential basal amount of opiorphin in two pain conditions and control subjects (2) a differential kinetic of release of opiorphin after STC in CTRL, BMS and TMDp (3) a differential pain perception after STC in BMS and TMDp vs. CTRL, which can provide a readout for animal models. CLINICAL RELEVANCE: The specific regulation of opiorphin release in patients with orofacial painful conditions provides valuable insights for clinicians and researchers in physiology and pathology and encourages further research in this area. TRIAL REGISTRATION: ClinicalTrials.gov NCT04694274. Registered on 01/05/2021.

Spontaneous and Masticatory Post-endodontic Pain After Using Endomethasone N vs SP Root Canal Sealers: A Randomised Controlled Clinical Trial.

OBJECTIVE: Post-endodontic pain (PEP) after endodontic treatment (ET) might be reduced by adding cortisone to the composition of root canal sealer (RCS). This study aimed to test this hypothesis using grade A methodology. METHODS: A multicentric prospective randomised controlled clinical trial was performed in general practice. Adult patients with an indication of ET in a molar or premolar performed in one session were included be-tween 2021 and 2022 in 15 centres. The main objective was to demonstrate the superiority of Endomethasone N RCS (EndoN), compared to its hydrocortisone-free equivalent Endomethasone SP RCS (EndoSP), regarding the reduction of the maximum spontaneous PEP pain during the 7 days following the ET, self-estimated on a 0���100 mm Visual Analogic Scale (VAS). The secondary objectives were to assess 1) spontaneous PEP, 2) pro-voked (masticatory) PEP, 3) intake of analgesics, 4) quality of life and anxiety before and after ET, and 5) safety. RESULTS: The final sample consisted of 286 patients with a mean age of 47.7 years, including 51% men and 49% women. Before ET, 49.7% of the teeth were asymptomatic; provoked pain occurred in 29.4% and sponta-neous pain in 21.0%. The study evidenced a lower maximum spontaneous PEP intensity during the 7 days fol-lowing ET in EndoN compared to the EndoSP group (13.5+-17.9 vs 23.9+-26.6, IC 95% 10.5 [5.2���15.8], p=0.0001 Wilcoxon test). Maximal masticatory PEP was also lower in the EndoN group (12.3+-19.1 vs 24.0+-27.8, IC 95% 11.7 [5.8���17.6], p<0.0001 Wilcoxon test). At every evaluation time, the masticatory PEP in the EndoSP group was higher than in the EndoN group. In addition, no serious adverse events occurred during the study. CONCLUSION: This RCT demonstrated EndoN's superiority over EndoSP in reducing spontaneous and mastica-tory PEP during the 7 days following ET. This study was funded by the Septodont company (Saint Maur des Foss��s, France) and registered at ClinicalTrials.gov # NCT04885686.

Chemical painful post-traumatic trigeminal neuropathy induced by dental bleaching: A case report.

Background: Teeth whitening is a frequent request in clinical practice. The most widely used whitening agent on vital teeth is carbamide peroxide. This article reports a rare adverse effect following a whitening procedure. Case description: A 29-year-old patient was referred to the dental emergency department for severe pain that exhibited the characteristics of neuropathic pain. In the absence of any visible lesion or traumatic event, this pain was linked to the recent application of carbamide peroxide (10%) during a bleaching procedure. The diagnosis of painful post-traumatic trigeminal neuropathy (PTTN) of chemical origin was made. Treatment with the anticonvulsant gabapentin (900mg per day) gradually reduced the pain until its complete disappearance. After presenting the clinical characteristics of the case, the pathophysiological hypotheses are discussed. Practical implications: Carbamide peroxide application may elicit nerve damage through a cascade of cellular and biological reactions, resulting in neuropathic pain. The successful management of this clinical case may provide useful information for similar situations. Key words:Case report, carbamide peroxide, painful neuropathy, pain, gingiva.

[Specificities of orofacial neuropathic pain]. / Spécificités de la douleur neuropathique oro-faciale.

Head pain and notably orofacial pain differs from spinal pain on pathophysiological, clinical, therapeutic and prognostic levels. Its high prevalence, important impact on quality of life and significant socio-economical burden justify specific study of such type of pain. Among them, neuropathic orofacial pain resulting from disease or trauma of the trigeminal nervous system is among the most difficult types of pain to diagnose and to treat. Deciphering of underlying peripheral and central mechanisms has allowed numerous conceptual, clinical and therapeutic advances, notably the role of neural and non neural cell types, such as glia, immunocytes, vascular endothelial cells or the role of trigeminal sensory complex neural circuitry reconfiguration in the development of post-traumatic trigeminal neuropathic pain. Cellular interactions within the trigeminal ganglion, allowing a better understanding of several painful dental, ocular or cephalalgic comorbidities, are also described.

Title: Spécificités de la douleur neuropathique oro-faciale. Abstract: Les douleurs de la région céphalique ­ et notamment les douleurs oro-faciales ­ diffèrent des douleurs spinales sur les plans physiopathologique, clinique, thérapeutique et pronostique. Leur prévalence élevée, leur fort retentissement sur la qualité de vie individuelle et leur impact économique et sociétal important justifient une étude spécifique. Parmi ces douleurs, les douleurs neuropathiques, résultant d'une maladie ou d'un traumatisme du système nerveux trigéminal, sont parmi les plus difficiles à diagnostiquer et à soigner. L'étude des mécanismes neurobiologiques, périphériques et centraux les sous-tendant a permis de nombreuses avancées conceptuelles, cliniques et thérapeutiques, avec, par exemple, la mise en évidence du rôle des cellules nerveuses et non nerveuses, telles que la glie, les immunocytes, les cellules endothéliales vasculaires ou le rôle de la reconfiguration de la circuiterie nerveuse au niveau du complexe sensitif trigéminal, dans la genèse des douleurs neuropathiques post-lésionnelles. Les interactions cellulaires au sein du ganglion trigéminal, susceptibles d'éclairer la compréhension de certaines comorbidités douloureuses dentaires, oculaires ou céphalalgiques, sont également décrites.

Opiorphin as a biomarker of orofacial conditions: a meta-analysis.

The aim of this meta-analysis was to answer the following question: "Are there any differences in opiorphin biomarker concentrations between different orofacial conditions and controls?". Two reviewers searched for observational studies that evaluated the levels of opiorphin in orofacial conditions, annotated in seven main databases and three that compile gray literature. Of the 443 articles obtained initially, 8 met the inclusion criteria for quantitative analyses. Relative percentages showed a mean 24.1% higher opiorphin concentration in chronic conditions (Burning Mouth Syndrome, Oral Potentially Malignant Diseases and Temporomandibular Disorder) compared to controls; 33.2% higher opiorphin in sustained pain (Symptomatic Irreversible Pulpitis, Symptomatic Apical Periodontitis, Painful Oral Soft-tissue conditions); and 21.7% higher opiorphin after stimuli (Corneal Foreign Body, Capsaicin). Meta-analysis revealed a standardized mean difference of 0.62 [0.02, 1.22] in the absolute concentration of opiorphin in saliva for the chronic group compared to the control. The analogous values for the sustained group and the stimulated group were 2.24 [0.34, 4.14] and 0.43 [0.00, 0.85], respectively. No differences in opiorphin levels were found for 'after Local Anesthesia before Tooth Extraction' or for apicoectomy. Based on the available evidence, in general, a statistically higher level of opiorphin is found in orofacial conditions. Salivary opiorphin levels are elevated in chronic, persisted and acute pain conditions, presumably reflecting a physiological homeostatic adaptative response to different conditions such as stress or pain. Salivary opiorphin might therefore be used as a valuable biomarker in several oral disorders.

Is burning mouth syndrome associated with stress? A meta-analysis.

BACKGROUND: Some studies have shown burning mouth syndrome (BMS) as comorbid psychosocial and psychiatric disorders, and as well, pointed at stress as a major risk factor. OBJECTIVE: The aim of this meta-analysis was to answer the following question: 'Is there an association between BMS and stress, compared to healthy controls?' METHODS: Two reviewers searched for the effect of stress in BMS and published on five main databases and three from the grey literature. Various questionnaires and biomarkers were analysed. Of the 2489 selected articles, 30 met the inclusion criteria. Studies englobed questionnaires, such as Perceived Stress Questionnaire, Lipp Stress Symptoms Inventory, Holmes-Rahe scale, Depression, Anxiety, and Stress Scale (DASS-21), Recent Experience Test; and various biomarkers, such as cortisol, opiorphin, IgA, α-amylase and interleukins. RESULTS: In all studies with questionnaires, stress was significantly increased in the BMS group vs. control. Patients with BMS presented 25.73% higher cortisol levels, 28.17% higher IgA levels and 40.62% higher α-amylase levels than controls. Meta-analysis found that BMS subjects presented 3.01 nmoL/L [0.53; 5.50] higher cortisol levels, 84.35 kU/L [15.00; 153.71] higher α-amylase levels, 29.25 mg/mL [9.86; 48.64] higher IgA levels and 258.59 pg/mL [59.24; 457.94] higher IL-8 levels than control. No differences were found for opiorphin concentration in ng/mL [-0.96; 2.53]. For interleukins, no differences were founded for IL-1 ß, IL-2, IL-4, IL-6, IL-8, IL-10 and TNF-α. CONCLUSION: Based on the available evidence, this meta-analysis suggests more stress factors in questionnaire-based studies, and higher levels of cortisol, α-amylase, IgA and IL-8 biomarkers in BMS subjects than controls.

Addition of Losartan to FOLFIRINOX and Chemoradiation Reduces Immunosuppression-Associated Genes, Tregs, and FOXP3+ Cancer Cells in Locally Advanced Pancreatic Cancer.

PURPOSE: Adding losartan (LOS) to FOLFIRINOX (FFX) chemotherapy followed by chemoradiation (CRT) resulted in 61% R0 surgical resection in our phase II trial in patients with locally advanced pancreatic cancer (LAPC). Here we identify potential mechanisms of benefit by assessing the effects of neoadjuvant LOS on the tumor microenvironment. EXPERIMENTAL DESIGN: We performed a gene expression and immunofluorescence (IF) analysis using archived surgical samples from patients treated with LOS+FFX+CRT (NCT01821729), FFX+CRT (NCT01591733), or surgery upfront, without any neoadjuvant therapy. We also conducted a longitudinal analysis of multiple biomarkers in the plasma of treated patients. RESULTS: In comparison with FFX+CRT, LOS+FFX+CRT downregulated immunosuppression and pro-invasion genes. Overall survival (OS) was associated with dendritic cell (DC) and antigen presentation genes for patients treated with FFX+CRT, and with immunosuppression and invasion genes or DC- and blood vessel-related genes for those treated with LOS+FFX+CRT. Furthermore, LOS induced specific changes in circulating levels of IL-8, sTie2, and TGF-ß. IF revealed significantly less residual disease in lesions treated with LOS+FFX+CRT. Finally, patients with a complete/near complete pathologic response in the LOS+FFX+CRT-treated group had reduced CD4+FOXP3+ regulatory T cells (Tregs), fewer immunosuppressive FOXP3+ cancer cells (C-FOXP3), and increased CD8+ T cells in pancreatic ductal adenocarcinoma lesions. CONCLUSIONS: Adding LOS to FFX+CRT reduced pro-invasion and immunosuppression-related genes, which were associated with improved OS in patients with LAPC. Lesions from responders in the LOS+FFX+CRT-treated group had reduced Tregs, decreased C-FOXP3 and increased CD8+ T cells. These findings suggest that LOS may potentiate the benefit of FFX+CRT by reducing immunosuppression.

Expression of salivary immunoglobulins and their association with analgesic neuropeptide opiorphin in anorexia nervosa during adolescence.

BACKGROUND: Patients who suffer from anorexia nervosa (AN) are characterized by exceedingly lower body weight, micro- and macro-nutrient deficiencies, and hyposalivation as compared to healthy subjects. In addition, AN may predispose to difficulties in oral health maintenance. However, little is known about the relationship between stress-dependent salivary neuro/immunopeptidergic biomarkers such as opiorphin and immunoglobulins (Ig) and AN.The aim of this case-control study was to evaluate salivary opiorphin and immunoglobulins in female children and adolescents diagnosed with AN compared to healthy controls. METHODS: Adolescent patients with clinically-confirmed severe restrictive subtype AN (Body Mass Index BMI < 15 kg/m2, mean age 15.0 ± 1.8, n = 83) were examined in the first week of hospital admission and compared to healthy matched controls (n = 79). Measurements of salivary opiorphin, IgA, IgG, IgM (ELISA technique), and oral hygiene levels (Plaque Control Record index-PCR) were performed. RESULTS: In the AN group, a significantly higher concentration of opiorphin was evidenced (3.1 ± 4.1 ng/ml) compared to the control group (1.1 ± 1.2 ng/ml), (p < 0.001), contrary to IgM, which was significantly lower (311.0 ± 185.3 ng/ml) than in the control group (421.2 ± 168.1 ng/ml), (p < 0.001). There were no significant differences in the levels of IgA and IgG, despite a higher concentration of IgA in the AN group vs. controls (p = 0.14). Spearman analysis revealed a correlation between opiorphin and age (p < 0.05), but also with all immunoglobulins IgA, IgG, IgM (p = 0.006, p < 0.001, p < 0.001). Similarly a correlation was found between PCR index and immunoglobulins IgG, IgM (respectively p = 0.028, p < 0.001), and between body mass, BMI, IBW% and IgA, IgM (all p < 0.05). CONCLUSIONS: In the acute phase of AN, salivary changes in opiorphin and immunoglobulins related to dental plaque suggest an essential role in oral health balance. Changes related to AN may affect the anti-inflammatory and analgesic components of saliva and suggest their use as neurobiological markers in severe malnutrition.

The orofacial region is affected by various inflammatory and autoimmune conditions, which might translate into general and regional changes. Saliva is one of the biological fluids where biomarkers of the aforementioned conditions, including sensitivity to pain, could be detected. It is also noteworthy that anorexia nervosa (AN) and malnutrition may change the saliva's analgesic or immune content, but this scientific area is still not satisfactorily explored. The present work related to analgesic (opiorphin peptide) and anti-infectious agents (immunoglobulins Ig A, IgG, IgM) in said body fluid among 83 adolescent patients with severe AN compared to 79 healthy controls. In addition, oral hygiene levels were assessed in the oral cavity via the Plaque Control Record index (PCR). In the AN group, the concentration of opiorphin was significantly higher as compared to the control group, in contrast to IgM, which was significantly lower than in the control group. There were no notable differences in the levels of IgA and IgG between groups, despite a slightly higher concentrations of IgA in the AN group. A correlation was found between opiorphin and all immunoglobulins. A similar correlation was found between PCR index and all immunoglobulins.The present work shows how analgesic opiorphin depends on the oral inflammatory status. This might be a direction for further investigating the immune alterations in patients with AN-related malnutrition. Inclusion of AN patients in intensive oral hygiene care may also be considered.

Effectiveness and patient satisfaction of dental emergencies in Pitié Salpêtrière Hospital, Paris, during the COVID 19 pandemic.

Background: A previous study reported the effectiveness and patient satisfaction in the dental emergency unit (DEU) of the Pitie Salpetrière Hospital in Paris before coronavirus disease 2019 (COVID-19). The same methodology was used during the COVID-19 pandemic to compare pain, anxiety, and patient satisfaction during the two periods. Methods: This prospective study was conducted in 2020 (NCT04354272) on adult patients. Data were collected on day zero (D0) on site and then by phone during the daytime on day one (D1), day three (D3), and day seven (D7). The primary objective was to assess the pain intensity at D1. Secondary objectives were to assess pain intensity at D3 and D7, anxiety intensity at D1, D3, and D7, and patient satisfaction. Patients were evaluated on a 0-10 numeric scale on D1, D3, and D7; mean scores were compared with non-parametric statistics (ANOVA, Dunn's). Results: A total of 445 patients were given the opportunity to participate in the study, and 370 patients consented. Seventy-one were lost during follow-up. Ultimately, 299 patients completed all the questionnaires and were included in the analysis. In the final sample (60% men, 40% women, aged 39 ± 14 years), 94% had health insurance. The mean pain scores were: D0, 6.1 ± 0.14; D1, 3.29 ± 0.16; D3, 2.08 ± 0.16; and D7, 1.07 ± 0.35. This indicates a significant decrease of 46%, 67%, and 82% at D1, D3, and D7, respectively, when compared to D0 (P < 0.0001). The mean anxiety scores were D0, 4.7 ± 0.19; D1, 2.6 ± 0.16; D3, 1.9 ± 0.61; and D7, 1.4 ± 0.15. This decrease was significant between D0 and D7 (ANOVA, P < 0.001). Perception of general health improved between D1 and D7. The overall satisfaction was 9.3 ± 0.06. Conclusion: DEU enabled a significant reduction in pain and anxiety with high overall satisfaction during COVID-19, which was very similar to levels observed pre-COVID-19 pandemic.

Chronic oropharyngeal pain and medical nomadism in an Eagle's syndrome patient: a case report.

BACKGROUND: Elongation of the styloid process associated with oropharyngeal pain and dysphagia is known as Eagle's syndrome, a condition whose pathophysiology is still a matter of debate. Given its low prevalence and complex symptomatology, this syndrome is often misdiagnosed, leading to chronic pain and medical nomadism. A 51-year-old woman of African origin with 3-year history of left-side oropharyngeal pain and worsening dysphagia consulted several health professionals. Medical and surgical treatments, including a sinus surgery and the extraction of three healthy teeth, did not improve her symptoms. Evaluation in an orofacial pain clinic revealed an asymmetrically elongated styloid process. Surgical shortening of the elongated styloid process provided complete pain relief and recovery of normal swallowing function. CONCLUSION: Based on this case report, the pathophysiology of Eagle's syndrome is discussed, and the need for specific follow-up in a subpopulation of patients with asymptomatic styloid process elongation is highlighted.

Effectiveness of and Patient's Satisfaction with Dental Emergency Unit in Pitié Salpêtrière Hospital (Paris), Focusing on Pain and Anxiety.

Background: The Dental Emergency Unit (DEU) of the Pitié Salpêtrière Hospital receives mainly painful emergencies. This study aimed at evaluating the suppression of pain and anxiety as well as the patient's satisfaction after a visit to the DEU. Patients and Methods. A prospective study was carried out in 2019 (NCT03819036) in adult patients. Data was collected on D0 on site and then on D1, D3, and D7 by phone, during daytime. The main objective and secondary objectives were, respectively, to assess the intensity of pain on D1; the intensity of pain on D3 and D7; the evolution of anxiety on D1, D3, and D7; and the patients' satisfaction. They were evaluated with a 0-10 numeric scale (NS) on D1, D3 and D7; mean scores were compared with nonparametric statistics (ANOVA, Dunn's test). Results: 814 patients were contacted and 581 patients included; 87 were lost to follow-up. 376 patients completed all the questionnaires. In the final sample (59% men, 40 ± 16 y.o.), 86% had health insurance. The mean pain scores were as follows: D0: 6.36 ± 0.12; D1: 3.49 ± 0.13; D3: 2.23 ± 0.13; D7: 1.07 ± 0.11-indicating a significant decrease of 45%, 65%, and 93% on D1, D3, and D7, respectively, compared to D0 (p < 0.0001) between D0 and D1, D3, D7. The mean NS anxiety scores were as follows: D0: 3.32 ± 0.15; D1: 3.69 ± 0.16; D3: 2.75 ± 0.16; D7: 1.98 ± 0.15. The decrease was significant between D0 and D7 (p < 0.0001). The perception of general heath improved between D1 and D7. The overall score of satisfaction was 8.64 ± 0.06. Conclusion: DEU enabled a significant reduction in pain and anxiety with high overall satisfaction.

Persistent, neuropathic-like trigeminal pain after dental implant loading.

BACKGROUND: Painful post-traumatic trigeminal neuropathy (PTTN) is a known complication of dental implant therapy. Besides cases resulting of nerve damage during surgery or implant placement, some patients report delayed neuropathic-like symptoms only after implant loading i.e. crown placement. The present retrospective study aimed at describing the clinical features of pain experienced by these patients. MATERIAL AND METHODS: The cohort of patients consulting for chronic orofacial pain at the Groupe Hospitalier Pitié-Salpêtrière (Paris, France) between 2015 and 2020 (ABCD study, IRB # TPS 1106180), was screened for patients with history of dental implant placement and persistent pain. Patients with no pain after surgery for 6 months and pain resulting from the loading of the implant, were included. RESULTS: Among 675 files of patients screened, 5 fulfilled inclusion criteria. All patients were women, mean age 62.4 ± 9.8 y.o, and reported trigeminal neuropathic-like persistent pain. Intensity of pain was described as moderate to severe, with pin and needles, burning and tingling, and electric shocks as main symptoms. CONCLUSIONS: These results suggest that implant loading can trigger trigeminal neuropathy, in a previously sensitized nerve. Putative neurophysiological basis of the phenomenon is discussed. Key words:Neuropathic pain, trigeminal nerve, lesion, dental implant, implant loading, allodynia.

Pulpitis in a dens invaginatus presenting as a Trigeminal Neuralgia: A case report.

INTRODUCTION: Orofacial pain diagnosis is a difficult process. This article reports the case of a 38 y.o. patient experiencing severe acute facial pain of dental origin initially diagnosed as non odontogenic. CASE REPORT: The patient consulted at the dental emergency department for severe and frequent neuropathic-like paroxysmal pain attacks located in the anterior right maxilla. The pain fulfilled the ICHD3 criteria for Trigeminal Neuralgia (TN) of the right maxillary branch (V2) and responses to sensitivity tests were ambiguous due to severe allodynia. After one week of carbamazepine treatment (600mg/day), the patient was pain free except for a slight mechanical allodynia on tooth #12. Sensitivity tests revealed pulp necrosis and tomodensitometry revealed a rare developmental abnormality, dens invaginatus. Root canal treatment was performed. RESULTS: No recurrence of the pain was noted after 18 months without any medication. CONCLUSIONS: Inflammatory pulpal pain may mimic TN, misleading experienced clinicians. Key words:Dens in dente, neuropathic pain, necrosis, diagnosis, atypical pain, endodontics.

The Role of TRP Channels in Nicotinic Provoked Pain and Irritation from the Oral Cavity and Throat: Translating Animal Data to Humans.

Tobacco smoking-related diseases are estimated to kill more than 8 million people/year and most smokers are willing to stop smoking. The pharmacological approach to aid smoking cessation comprises nicotine replacement therapy (NRT) and inhibitors of the nicotinic acetylcholine receptor, which is activated by nicotine. Common side effects of oral NRT products include hiccoughs, gastrointestinal disturbances and, most notably, irritation, burning and pain in the mouth and throat, which are the most common reasons for premature discontinuation of NRT and termination of cessation efforts. Attempts to reduce the unwanted sensory side effects are warranted, and research discovering the most optimal masking procedures is urgently needed. This requires a firm mechanistic understanding of the neurobiology behind the activation of sensory nerves and their receptors by nicotine. The sensory nerves in the oral cavity and throat express the so-called transient receptor potential (TRP) channels, which are responsible for mediating the nicotine-evoked irritation, burning and pain sensations. Targeting the TRP channels is one way to modulate the unwanted sensory side effects. A variety of natural (Generally Recognized As Safe [GRAS]) compounds interact with the TRP channels, thus making them interesting candidates as safe additives to oral NRT products. The present narrative review will discuss (1) current evidence on how nicotine contributes to irritation, burning and pain in the oral cavity and throat, and (2) options to modulate these unwanted side-effects with the purpose of increasing adherence to NRT. Nicotine provokes irritation, burning and pain in the oral cavity and throat. Managing these side effects will ensure better compliance to oral NRT products and hence increase the success of smoking cessation. A specific class of sensory receptors (TRP channels) are involved in mediating nicotine's sensory side effects, making them to potential treatment targets. Many natural (Generally Recognized As Safe [GRAS]) compounds are potentially beneficial modulators of TRP channels.

Bevacizumab improves tumor infiltration of mature dendritic cells and effector T-cells in triple-negative breast cancer patients.

A single dose of bevacizumab reduced the density of angiopoietin-2-positive vessels while improving the infiltration of CD4+ T and CD8+ T cells, and mature dendritic cells in patients with primary triple-negative breast cancer. Our findings provide a rationale for including bevacizumab during neoadjuvant treatment to enhance the efficacy of immune checkpoint blockers in this disease.

Salivary Biomarkers (Opiorphin, Cortisol, Amylase, and IgA) Related to Age, Sex, and Stress Perception in a Prospective Cohort of Healthy Schoolchildren.

BACKGROUND: The use of easily accessible biomarkers for assessing young patients' health is weighty. This cohort study is aimed at measuring stress/immune biomarkers in the saliva of healthy school-age children and comparing subgroups according to age, sex, and stress perception. Material and Methods. 503 children under 12 years old (8.7 ± 1.3) were included with anthropometric evaluation (height, waist, hip circumference, body weight, and body mass index (BMI)). Levels of opiorphin (OPI), free cortisol, alpha-amylase (sAA), and secreted immunoglobulin (sIgA) were determined by quantitative assays (ELISA) in unstimulated saliva. Unpaired t-test, Welch test, and Mann-Whitney U test were applied for appropriate group comparisons, and the correlation between variables was analyzed with Spearman's rank coefficient. Results were considered significant at p < 0.05. RESULTS: sIgA and sAA exhibited significant differences depending on age and sex: IgA (ng/mL): 86 ± 68.6 vs. 104.9 ± 72.1 for (6-7 y.o.) and (8-11 y.o.), respectively, and 108.1 ± 80.1 vs. 94.6 ± 62.2 for male and females, respectively; sAA (U/mL): 78.9 ± 54.4 vs. 100.5 ± 81.2 for (6-7 y.o.) and (8-11 y.o.). No difference related to age or sex between groups was observed for cortisol and OPI. However, OPI levels were higher and correlated to prior stress exposure in children (0.31 ± 0.4 vs. 0.26 ± 0.5 ng/mL, p = 0.031). sAA was negatively correlated to low mood self-declaration in children in the last two weeks (r = -0.10, p = 0.045). CONCLUSIONS: sIgA and sAA can be used as sex- and age-related biomarkers in children 6-12 y.o., which is not the case for free cortisol and opiorphin. However, OPI reflected previous exposure to stress, suggesting its use for evaluating stress-related changes in children.

Hedging against Neuropathic Pain: Role of Hedgehog Signaling in Pathological Nerve Healing.

The peripheral nervous system has important regenerative capacities that regulate and restore peripheral nerve homeostasis. Following peripheral nerve injury, the nerve undergoes a highly regulated degeneration and regeneration process called Wallerian degeneration, where numerous cell populations interact to allow proper nerve healing. Recent studies have evidenced the prominent role of morphogenetic Hedgehog signaling pathway and its main effectors, Sonic Hedgehog (SHH) and Desert Hedgehog (DHH) in the regenerative drive following nerve injury. Furthermore, dysfunctional regeneration and/or dysfunctional Hedgehog signaling participate in the development of chronic neuropathic pain that sometimes accompanies nerve healing in the clinical context. Understanding the implications of this key signaling pathway could provide exciting new perspectives for future research on peripheral nerve healing.

Taste disorder's management: a systematic review.

BACKGROUND: Taste disorder is a frequent drug-induced or disease-related oral trouble. Various pharmacological, surgical, or physical treatments have previously been proposed for taste function recovery. OBJECTIVES: The aim of the present systematic review was to assess the effects of palliative and curative interventions on taste recovery in light of recent literature. MATERIALS AND METHODS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, a search of the literature published up to June 2019 was conducted using MEDLINE via PubMed, EMBASE, and The US National Institutes of Health Trials Register (PROSPERO registration reference: CRD 42019139315). The methodological quality of the included trials was rated with the "Delphi list For Quality Assessment of Randomized Clinical Trials" and the Newcastle-Ottawa scale. RESULTS: From the 1842 titles first identified, 28 articles met the inclusion criteria. Interventions included zinc (aspartate, sulfate, gluconate, acetate, picolinate, and Polaprezinc®), esomeprazole, L-thyroxin, bethanechol, oral glutamine, delta-9-tetrahydrocannabinol, alpha-lipoic acid, Ginkgo biloba, artificial saliva, pilocarpine, local anesthesia, and improved oral hygiene. The quality of evidence ranged from poor to high. CONCLUSION: Improving oral hygiene may promote taste ability. Zinc may prevent and alleviate taste disorder in patients undergoing head and neck radiotherapy. CLINICAL RELEVANCE: The systematic review provided evidence about the clinical efficacy of oral procedures, zinc supplementation, and palliative cares in dysgeusic patients. Further research is needed to find effective treatments with low adverse effects.

Intra-oral trigeminal-mediated sensations influencing taste perception: A systematic review.

Food perception is a multimodal sensation which implies cross-modal interplays. Tactile, thermal, painful and kinaesthetic stimuli arising from food intake may impact on flavour perception, especially taste perception. The influence of oral somatosensory signals on food taste perception remains unclear. The aim of the present systematic review was to appraise the effects of oral mechanical, thermal, chemical and pain sensations on taste perception. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, a search of the literature from 1968 to 2018 was conducted using MEDLINE via PubMed, EMBASE and clinical trials (PROSPERO registration reference: CRD42018100176). A total of 105 articles were included for analysis. The results from this review suggest that taste abilities and taste perception are frequently modified by food textural and chemical properties. Furthermore, saliva features, dental and prosthetic status and oral pain can also modulate taste perception. Biological and physiological phenomena underlying these results may be involved such as tastant release, tastant detection, taste transduction and central trigemino-gustatory interplays.

Salivary opiorphin levels in anorexia nervosa: A case-control study.

Objectives: Opiorphin is a physiological inhibitor of peptidases inactivating endogenous opioids displaying strong analgesic properties without undesirable side effects, antidepressant properties or hormonal dependency. It might therefore play an important role in patients with painful diseases related to neuro-hormonal dysregulation of the nervous system, affecting saliva secretion and composition such as anorexia nervosa (AN). The main objective aim of this study was to compare the level of opiorphin in saliva of patients with AN to matched subjects free of eating disorders.Methods: A case-control clinical trial was conducted in 68 AN patients and 43 healthy matched control subjects. Depression symptoms were assessed with the self-scored questionnaire Beck Depression Inventory (BDI) and salivary samples were taken during the acute stage of AN (BMI <15 kg/m2) for measuring opiorphin. Opiorphin levels were measured with a quantitative assay using a commercial immunoenzymatic Elisa kit (cat no. EH1927, Wuchan, Hubei, China).Results: No statistically significant difference was found in salivary opiorphin levels between the AN and control groups, (P = 0.499, Mann-Whitney U-test). Positive correlations to duration of the disease, BDI and bodyweight in AN patients were evidenced.Conclusions: Measurement of salivary opiorphin levels cannot be used as a marker of AN but may allow new perspectives in monitoring AN in its early stages.