eLIFEwithIBD: study protocol for a randomized controlled trial of an online acceptance and commitment therapy and compassion-based intervention in inflammatory bowel disease.

Background: Inflammatory bowel disease (IBD) entails physical, psychological, and social burden and holds a significant impact on quality of life. Experiential avoidance, cognitive fusion, shame, and self-criticism have been identified as possible therapeutic targets for improving mental health in people with IBD. Traditional face-to-face psychological therapy continues to provide obstacles for patients seeking assistance. Online psychological therapies centered on acceptance, mindfulness, and compassion have been shown to improve psychological distress in other populations. Objective: This paper presents the study protocol of a two-arm Randomized Controlled Trial (RCT) of an ACT and compassion-based, online intervention - eLIFEwithIBD - on the improvement of psychological distress, quality of life, work and social functioning, IBD symptom perception, illness-related shame, psychological flexibility, and self-compassion. Methods: The eLIFEwithIBD intervention is an adaptation of the LIFEwithIBD programme (delivered through an in-person group format) and entails an ACT, mindfulness, and compassion-based intervention designed to be delivered as an e-health tool for people with IBD. This protocol outlines the structure and contents of the eLIFEwithIBD intervention. Participants were recruited by an advertisement on the social media platforms of Portuguese Associations for IBD in January 2022. A psychologist conducted a brief interview with 80 patients who were interested in participating. Fifty-five participants were selected and randomly assigned to one of two conditions [experimental group (eLIFEwithIBD + medical TAU; n = 37) or control group (medical TAU; n = 18)]. Outcome measurement took place at baseline, post-intervention, and 4-month follow-up. All analyses are planned as intent-to-treat (ITT). Results: The eLIFEwithIBD intervention is expected to empower people with IBD by fostering psychological strategies that promote illness adjustment and well-being and prevent subsequent distress. The eLIFEwithIBD aims to gain a novel and better understanding of the role of online contextual behavioral interventions on improving the quality of life and mental health of people with IBD. Clinical Trial Registration: https://classic.clinicaltrials.gov/ct2/show/NCT05405855, NCT05405855.

Debridement ability of the WaveOne Gold and TruNatomy systems in the apical third of root canals: ex vivo assessment.

Cleaning and shaping the root canal system are essential steps for performing successful endodontic therapy, and are challenging procedures in the apical region. This study aimed to conduct an ex vivo assessment of the debridement ability of the WaveOne Gold (Medium 35/.06) and TruNatomy (Medium 36/.03) systems in the apical third of round root canals of mandibular premolars. Forty-eight teeth, extracted for orthodontic or periodontal reasons, were divided into three groups (n=16), as follows: Group C, control (without instrumentation or irrigation); Group WOG, instrumentation with WaveOne Gold; Group TN, instrumentation with TruNatomy. A total of 40 mL of 2.5% sodium hypochlorite and 5 mL of 17% ethylenediamine tetraacetic acid were used per root canal in all the groups. Ten 0.5-µm serial cross-sections per specimen were obtained every 0.2 mm from a 2-mm segment of the apical region, extending from 1 to 3 mm short of the root apex. The sections were stained with hematoxylin-eosin and analyzed under a digital microscope (100x). The percentages of unprepared walls and remaining debris were quantified using ImageJ software. Generalized linear models were used to analyze the results (α=5%). Groups WOG and TN had significantly lower percentages of unprepared walls and remaining debris than Group C (p<0.05). There was no significant difference between groups WOG and TN for either of the variables studied (p>0.05). Instrumentation with the WaveOne Gold Medium and TruNatomy Medium instruments was associated with equivalent percentages of unprepared walls and remaining debris in the apical third of round canals of mandibular premolars.

Topical diosmetin attenuates nociception and inflammation in a ultraviolet B radiation-induced sunburn model in mice.

Burns are a global health problem and can be caused by several factors, including ultraviolet (UV) radiation. Exposure to UVB radiation can cause sunburn and a consequent inflammatory response characterised by pain, oedema, inflammatory cell infiltration, and erythema. Pharmacological treatments available to treat burns and the pain caused by them include nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, antimicrobials and glucocorticoids, which are associated with adverse effects. Therefore, the search for new therapeutic alternatives is needed. Diosmetin, an aglycone of the flavonoid diosmin, has antinociceptive, antioxidant and anti-inflammatory properties. Thus, we evaluated the antinociceptive and anti-inflammatory effects of topical diosmetin (0.01, 0.1 and 1%) in a UVB radiation-induced sunburn model in mice. The right hind paw of the anaesthetised mice was exposed only once to UVB radiation (0.75 J/cm2) and immediately treated with diosmetin once a day for 5 days. The diosmetin antinociceptive effect was evaluated by mechanical allodynia and pain affective-motivational behaviour, while its anti-inflammatory activity was assessed by measuring paw oedema and polymorphonuclear cell infiltration. Mice exposed to UVB radiation presented mechanical allodynia, increased pain affective-motivational behaviour, paw oedema and polymorphonuclear cell infiltration into the paw tissue. Topical Pemulen® TR2 1% diosmetin reduced the mechanical allodynia, the pain affective-motivational behaviour, the paw oedema and the number of polymorphonuclear cells in the mice's paw tissue similar to that presented by Pemulen® TR2 0.1% dexamethasone. These findings indicate that diosmetin has therapeutic potential and may be a promising strategy for treating patients experiencing inflammatory pain, especially those associated with sunburn.

Effects of association between resveratrol and ketamine on behavioral and biochemical analysis in mice.

Resveratrol (3,5,4'-trihydroxy-trans-stilbene), a phenol commonly found in grapes and wine, has been associated as protective in experimental models involving alterations in different neurotransmitter systems. However, studies are reporting that resveratrol could have adverse effects. This study evaluated if the association of a low dose of ketamine and resveratrol could induce behavioral manifestations associated with biochemical alterations. Moreover, the effects of treatment with resveratrol and/or ketamine on monoamine oxidase (MAO) activity, oxidative stress markers, and IL-6 levels in the brain were also investigated. Male Swiss mice received a low dose of ketamine (20 mg/kg) for 14 consecutive days, and resveratrol (10, 30, or 100 mg/kg) from day 8 up to day 14 of the experimental period, intraperitoneally. Locomotor, stereotyped behavior, Y-maze, novel recognition object test (NORT), and social interaction were quantified as well as ex vivo analysis of MAO activity, IL-6 levels, and oxidative stress markers (TBARS and total thiol levels) in brain tissues. Ketamine per se reduced the number of bouts of stereotyped behavior on day 8 of the experimental period. Resveratrol per se reduced the locomotor and exploratory activity in the open field, the time of exploration of new objects in the NORT, MAO-A activity in the striatum and increased the IL-6 levels in the cortex. These effects were attenuated when the mice were co-treated with ketamine and resveratrol. There was a decrease in MAO-A activity in the cortex of mice treated with ketamine + resveratrol 100 mg/kg. No significant alterations were found in oxidative stress markers. Resveratrol does not appear to cause summative effects with ketamine on behavioral alterations. However, the effect of resveratrol per se, mainly on locomotor and exploratory activity, should be better investigated.

Schwann cell TRPA1 elicits reserpine-induced fibromyalgia pain in mice.

BACKGROUND AND PURPOSE: Fibromyalgia is a complex clinical disorder with an unknown aetiology, characterized by generalized pain and co-morbid symptoms such as anxiety and depression. An imbalance of oxidants and antioxidants is proposed to play a pivotal role in the pathogenesis of fibromyalgia symptoms. However, the precise mechanisms by which oxidative stress contributes to fibromyalgia-induced pain remain unclear. The transient receptor potential ankyrin 1 (TRPA1) channel, known as both a pain sensor and an oxidative stress sensor, has been implicated in various painful conditions. EXPERIMENTAL APPROACH: The feed-forward mechanism that implicates reactive oxygen species (ROS) driven by TRPA1 was investigated in a reserpine-induced fibromyalgia model in C57BL/6J mice employing pharmacological interventions and genetic approaches. KEY RESULTS: Reserpine-treated mice developed pain-like behaviours (mechanical/cold hypersensitivity) and early anxiety-depressive-like disorders, accompanied by increased levels of oxidative stress markers in the sciatic nerve tissues. These effects were not observed upon pharmacological blockade or global genetic deletion of the TRPA1 channel and macrophage depletion. Furthermore, we demonstrated that selective silencing of TRPA1 in Schwann cells reduced reserpine-induced neuroinflammation (NADPH oxidase 1-dependent ROS generation and macrophage increase in the sciatic nerve) and attenuated fibromyalgia-like behaviours. CONCLUSION AND IMPLICATIONS: Activated Schwann cells expressing TRPA1 promote an intracellular pathway culminating in the release of ROS and recruitment of macrophages in the mouse sciatic nerve. These cellular and molecular events sustain mechanical and cold hypersensitivity in the reserpine-evoked fibromyalgia model. Targeting TRPA1 channels on Schwann cells could offer a novel therapeutic approach for managing fibromyalgia-related behaviours.

IgG4-related disease: Case report and 6-year follow-up of an elusive diagnosis mimicking malignancy.

Key Clinical Message: IgG4-related disease is a rare and emerging pathology, characterized by the appearance of pseudotumors. Due to the ability to mimic other pathologies, it is essential to consider it as a differential diagnosis in multisystemic processes. The diagnosis is challenging, requiring a multidisciplinary approach, to minimize the associated morbidity and mortality. Abstract: IgG4-related disease (IgG4-RD) is a rare, emerging, systemic and chronic pathology, characterized by the appearance of pseudotumors resulting from tissue infiltration by IgG4-positive plasma cells that promote eosinophilic inflammation of the tissue with subsequent fibrosis. We present the case of a male, 45-year-old patient, with marked weight loss and skin pallor detected by his family doctor during a child health consultation of his daughter. When questioned, the patient referred complaints of postprandial discomfort in the left hypochondrium with a feeling of fullness, weight loss, chronic fatigue and hyperhidrosis that had lasted for a month. On physical examination, he was pale, and had pain at palpation of the left hypochondrium. Laboratory data showed increased inflammation markers, abdominal ultrasound and CT demonstrated numerous enlarged lymph nodes in the upper quadrants, raising concern for a malignant lymphoproliferative process. Serological, imaging, clinical and laparoscopic excisional biopsy revealed features of IgG4-related disease and excluded malignant lymphoproliferative disease. The immediate response to treatment with oral prednisolone 30 mg/day also contributed for diagnosis confirmation. Due to refractory disease after gradual prednisolone reduction, second-line therapy with rituximab was initiated. Over the 6 years of follow-up, the patient presented multiple exacerbations characterized by the emergence of systemic symptoms, being maintained under close clinical and imaging follow-up by reumathology, infectious diseases, and family medicine specialists.

Randomized controlled trial of an Acceptance and Commitment Therapy and compassion-based group intervention for persons with inflammatory bowel disease: the LIFEwithIBD intervention.

Objectives: This study tested the acceptability and efficacy of an Acceptance and Commitment Therapy and compassion-based intervention (LIFEwithIBD) in people with IBD through a two-arm RCT. Methods: Participants were recruited at the Gastroenterology Department of the Coimbra University Hospital between June and September 2019. Of the 355 patients screened, those who accepted to participate were randomly assigned to one of two conditions: experimental group (LIFEwithIBD; n = 25) or control group (waitlist; n = 29). Participants completed self-report measures at baseline (T0), post-intervention (T1), and 3-month (T2) and 12-month (T3) follow-ups. Intervention acceptability was assessed. Efficacy was examined using intent-to-treat ANCOVA at post-intervention after adjusting for baseline values of depressive, anxiety, and stress symptoms (primary outcomes). Linear mixed models for all longitudinal outcomes were also analysed. Inflammatory and disease biomarkers were determined at T0 and T3. Results: Acceptability results revealed a high level of satisfaction and perceived usefulness regarding the intervention. Both groups experienced a significant decrease in stress symptoms and IBD symptom perception at T1. No significant differences were observed at follow-up for the primary outcomes. The experimental group reported significantly lower Crohn's disease Symptom severity at T2 than the control group. Post-hoc analyses designed to mitigate floor effects revealed substantial treatment effects for the experimental group regarding anxiety symptoms. No significant differences were observed in clinical biomarkers from T0 to T3. Conclusion: The LIFEwithIBD intervention shows promising, although preliminary, benefits for managing disease activity and reducing anxiety symptoms in IBD patients with high severity of psychological distress.Clinical trial registration: https://www.clinicaltrials.gov/ct2/show/NCT03840707, identifier NCT03840707.

Diosmetin attenuates fibromyalgia-like symptoms in a reserpine-induced model in mice.

Fibromyalgia is a potentially disabling idiopathic disease characterized by widespread chronic pain associated with comorbidities such as fatigue, anxiety, and depression. Current therapeutic approaches present adverse effects that limit adherence to therapy. Diosmetin, an aglycone of the flavonoid glycoside diosmin found in citrus fruits and the leaves of Olea europaea L., has antinociceptive, anti-inflammatory, and antioxidant properties. Here, we investigated the effect of diosmetin on nociceptive behaviors and comorbidities in an experimental fibromyalgia model induced by reserpine in mice. To induce the experimental fibromyalgia model, a protocol of subcutaneous injections of reserpine (1 mg/kg) was used once a day for three consecutive days in adult male Swiss mice. Mice received oral diosmetin on the fourth day after the first reserpine injection. Nociceptive (mechanical allodynia, muscle strength, and thermal hyperalgesia) and comorbid (depressive-like and anxiety behavior) parameters were evaluated. Potential adverse effects associated with diosmetin plus reserpine (locomotor alteration, cataleptic behavior, and body weight and temperature changes) were also evaluated. Oral diosmetin (0.015-1.5 mg/kg) reduced the mechanical allodynia, thermal hyperalgesia, and loss of muscle strength induced by reserpine. Diosmetin (0.15 mg/kg) also attenuated depressive-like and anxiety behaviors without causing locomotor alteration, cataleptic behavior, and alteration in weight and body temperature of mice. Overall, diosmetin can be an effective and safe therapeutic alternative to treat fibromyalgia symptoms, such as pain, depression and anxiety.

Assessing the environmental impacts of three different types of accommodations in Portugal and Spain by using an LCA approach.

The tourism industry, affected by COVID-19, must reduce greenhouse gas emissions. This study evaluated the environmental impact of three hotels in coastal and mountainous regions of Spain and Portugal using Life Cycle Assessment (LCA). Data was gathered via surveys in the Greentour tool. Results indicate that the 2-star hotel (focused on cultural-urban tourism) has the highest impacts in most categories, except for CC, FRD, and POF indicators. The 3-star hotel (beach tourism) contributes the most to CC and FRD indicators, while the hostel (nature-religious tourism) has the highest value in the POF indicator. LCA findings reveal that diesel consumption in the hostel and electricity usage in both the 2-star and 3-star hotels are major contributors to environmental impacts across various categories. Overall, evidence suggests that fossil fuel and electricity usage significantly affect tourism activities environmentally. Interestingly, this study highlights that a 2-star hotel can have a higher carbon footprint (CC indicator) compared to a 3-star hotel, challenging the notion that higher star ratings imply lower environmental impact.

Sleep Disorders and Subjective Well-Being in Portuguese Adults: Evidence from a Representative Study.

Objective The quality and quantity of sleep affect people's well-being, as chronic sleep disorders are associated with social, physical, and psychological problems, as well as low self-reported life satisfaction. The present cross-sectional study examined the associations of sleep disorders with self-reported life satisfaction in Portuguese adults. Materials and Methods Data from a representative sample of the Portuguese population (14,341 participants, aged ≥ 18 years) extracted from the Sixth Portuguese National Health Survey was analyzed. Data on subjective well-being and sleep disorders was collected through a questionnaire, and multivariable regression models were performed to examine the associations between these variables, adjusted for potential confounders such as age, gender, level of schooling, degree of urbanization, and family income. Results Sleep disorders were negatively associated with self-reported life satisfaction. Having at least one sleep disturbance in the last two weeks was significantly associated with a 3-point decrease in life satisfaction: ß = -3.0 (95% confidence interval = -3.2--2.7). Discussion Among Portuguese adults, sleep disorders were associated with a decline in life satisfaction. The present study provides new evidence from a representative sample to support the promotion of good sleep hygiene intervention programs.

An interpretable machine learning system for colorectal cancer diagnosis from pathology slides.

Considering the profound transformation affecting pathology practice, we aimed to develop a scalable artificial intelligence (AI) system to diagnose colorectal cancer from whole-slide images (WSI). For this, we propose a deep learning (DL) system that learns from weak labels, a sampling strategy that reduces the number of training samples by a factor of six without compromising performance, an approach to leverage a small subset of fully annotated samples, and a prototype with explainable predictions, active learning features and parallelisation. Noting some problems in the literature, this study is conducted with one of the largest WSI colorectal samples dataset with approximately 10,500 WSIs. Of these samples, 900 are testing samples. Furthermore, the robustness of the proposed method is assessed with two additional external datasets (TCGA and PAIP) and a dataset of samples collected directly from the proposed prototype. Our proposed method predicts, for the patch-based tiles, a class based on the severity of the dysplasia and uses that information to classify the whole slide. It is trained with an interpretable mixed-supervision scheme to leverage the domain knowledge introduced by pathologists through spatial annotations. The mixed-supervision scheme allowed for an intelligent sampling strategy effectively evaluated in several different scenarios without compromising the performance. On the internal dataset, the method shows an accuracy of 93.44% and a sensitivity between positive (low-grade and high-grade dysplasia) and non-neoplastic samples of 0.996. On the external test samples varied with TCGA being the most challenging dataset with an overall accuracy of 84.91% and a sensitivity of 0.996.

Increased levels of advanced oxidation protein products (AOPPs) were associated with nociceptive behavior and clinical scores in an experimental progressive autoimmune encephalomyelitis model (PMS-EAE).

Multiple sclerosis (MS) is a neurodegenerative disease that affects the central nervous system (CNS) generating neuropathic pain and anxiety. Primary progressive MS (PPMS) is the most disabling clinical form, and the patients present an intense neurodegenerative process. In this context, the advanced oxidation protein products (AOPPs) are oxidized compounds and their accumulation in plasma has been related to clinical disability in MS patients. However, the involvement of AOPPs in neuropathic pain- and anxiety-like symptoms was not previously evaluated. To assess this, female mice C57BL/6J were used to induce progressive experimental autoimmune encephalomyelitis (PMS-EAE). Clinical score, weight, strength of plantar pressure, rotarod test, mechanical allodynia, and cold hypersensitivity were evaluated before induction (baseline) and on days 7th, 10th, and 14th post-immunization. We assessed nest building, open field, and elevated plus-maze tests 13 days post-immunization. Animals were killed at 14 days post-immunization; then, AOPPs levels, NADPH oxidase, and myeloperoxidase (MPO) activity were measured in the prefrontal cortex, hippocampus, and spinal cord samples. The clinical score increased 14th post-immunization without changes in weight and mobility. Reduced paw strength, mechanical allodynia, and cold allodynia increased in the PMS-EAE animals. PMS-EAE mice showed spontaneous nociception and anxiety-like behavior. AOPPs concentration, NADPH oxidase, and MPO activity increase in CNS structures. Multivariate analyses indicated that the rise of AOPPs levels, NADPH oxidase, and MPO activity influenced the clinical score and cold allodynia. Thus, we indicated the association between non-stimuli painful perception, anxiety-like, and CNS oxidative damage in the PMS-EAE model.

The Association of Oleic Acid and Dexamethasone Acetate into Nanocapsules Enables a Reduction in the Effective Corticosteroid Dose in a UVB Radiation-Induced Sunburn Model in Mice.

Dexamethasone has a high anti-inflammatory efficacy in treating skin inflammation. However, its use is related to the rebound effect, rosacea, purple, and increased blood glucose levels. Nanotechnology approaches have emerged as strategies for drug delivery due to their advantages in improving therapeutic effects. To reduce dexamethasone-related adverse effects and improve the anti-inflammatory efficacy of treatments, we developed nanocarriers containing this corticosteroid and oleic acid. Nanocapsules and nanoemulsion presented dexamethasone content close to the theoretical value and controlled dexamethasone release in an in vitro assay. Gellan gum-based hydrogels were successfully prepared to employ the nanostructured systems. A permeation study employing porcine skin showed that hydrogels containing non-nanoencapsulated dexamethasone (0.025%) plus oleic acid (3%) or oleic acid (3%) plus dexamethasone (0.025%)-loaded nanocapsules provided a higher amount of dexamethasone in the epidermis compared to non-nanoencapsulated dexamethasone (0.5%). Hydrogels containing oleic acid plus dexamethasone-loaded nanocapsules effectively inhibited mice ear edema (with inhibitions of 89.26 ± 3.77% and 85.11 ± 2.88%, respectively) and inflammatory cell infiltration (with inhibitions of 49.58 ± 4.29% and 27.60 ± 11.70%, respectively). Importantly, the dexamethasone dose employed in hydrogels containing the nanocapsules that effectively inhibited ear edema and cell infiltration was 20-fold lower (0.025%) than that of non-nanoencapsulated dexamethasone (0.5%). Additionally, no adverse effects were observed in preliminary toxicity tests. Our study suggests that nanostructured hydrogel containing a reduced effective dose of dexamethasone could be a promising therapeutic alternative to treat inflammatory disorders with reduced or absent adverse effects. Additionally, testing our formulation in a clinical study on patients with skin inflammatory diseases would be very important to validate our study.

Melanoxetin: A Hydroxylated Flavonoid Attenuates Oxidative Stress and Modulates Insulin Resistance and Glycation Pathways in an Animal Model of Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (DM) continues to escalate, necessitating innovative therapeutic approaches that target distinct pathways and address DM complications. Flavonoids have been shown to possess several pharmacological activities that are important for DM. This study aimed to evaluate the in vivo effects of the flavonoid melanoxetin using Goto-Kakizaki rats. Over a period of 14 days, melanoxetin was administered subcutaneously to investigate its antioxidant, anti-inflammatory, and antidiabetic properties. The results show that melanoxetin reduced insulin resistance in adipose tissue by targeting protein tyrosine phosphatase 1B. Additionally, melanoxetin counteracted oxidative stress by reducing nitrotyrosine levels and modulating superoxide dismutase 1 and hemeoxygenase in adipose tissue and decreasing methylglyoxal-derived hydroimidazolone (MG-H1), a key advanced glycation end product (AGE) implicated in DM-related complications. Moreover, the glyoxalase 1 expression decreased in both the liver and the heart, correlating with reduced AGE levels, particularly MG-H1 in the heart. Melanoxetin also demonstrated anti-inflammatory effects by reducing serum prostaglandin E2 levels, and increasing the antioxidant status of the aorta wall through enhanced acetylcholine-dependent relaxation in the presence of ascorbic acid. These findings provide valuable insights into melanoxetin's therapeutic potential in targeting multiple pathways involved in type 2 DM, particularly in mitigating oxidative stress and glycation.

G Protein-Coupled Receptors and Ion Channels Involvement in Cisplatin-Induced Peripheral Neuropathy: A Review of Preclinical Studies.

Cisplatin is a platinum-based chemotherapy drug widely used to treat various solid tumours. Although it is effective in anti-cancer therapy, many patients develop peripheral neuropathy during and after cisplatin treatment. Peripheral neuropathy results from lesions or diseases in the peripheral somatosensory nervous system and is a significant cause of debilitation and suffering in patients. In recent years, preclinical studies have been conducted to elucidate the mechanisms involved in chemotherapy-induced peripheral neuropathic pain, as well as to promote new therapeutic targets since current treatments are ineffective and are associated with adverse effects. G-protein coupled receptors and ion channels play a significant role in pain processing and may represent promising targets for improving the management of cisplatin-induced neuropathic pain. This review describes the role of G protein-coupled receptors and ion channels in cisplatin-induced pain, analysing preclinical experimental studies that investigated the role of each receptor subtype in the modulation of cisplatin-induced pain.

Involvement of peripheral mast cells in a fibromyalgia model in mice.

Fibromyalgia is a painful disorder of unknown aetiology that presents activation and recruitment of innate immune cells, including mast cells. Efforts have been made to understand its pathogenesis to manage it better. Thus, we explored the involvement of peripheral mast cells in an experimental model of fibromyalgia induced by reserpine. Reserpine (1 mg/kg) was subcutaneously (s.c.) injected once daily in the back of male Swiss mice for three consecutive days. We analysed mechanical and cold allodynia, muscle fatigue and number of mast cell in plantar tissue. The fibromyalgia induction produced mast cell infiltration (i.e., mastocytosis) in the mice's plantar tissue. The depletion of mast cell mediators with the compound 48/80 (0.5-4 mg/kg, intraperitoneal (i.p.)) or the mast cell membrane stabilizer ketotifen fumarate (10 mg/kg, oral route (p.o.) widely (80-90 %) and extensively (from 1 up to 10 days) prevented reserpine-induced mechanical and cold allodynia and muscle fatigue. Compound 48/80 also prevented the reserpine-induced mastocytosis. Finally, we demonstrated that PAR-2, 5-HT2A, 5-HT3, H1, NK1 and MrgprB2 receptors, expressed in neuronal or mast cells, seem crucial to mediate fibromyalgia-related cardinal symptoms since antagonists or inhibitors of these receptors (gabexate (10 mg/kg, s.c.), ENMD-1068 (10 mg/kg, i.p.), ketanserin (1 mg/kg, i.p.), ondansetron (1 mg/kg, p.o.), promethazine (1 mg/kg, i.p.), and L733,060 (5 mg/kg, s.c.), respectively) transiently reversed the reserpine-induced allodynia and fatigue. The results indicate that mast cells mediate painful and fatigue behaviours in this fibromyalgia model, representing potential therapy targets to treat fibromyalgia syndrome.

TRPV4 Activation and its Intracellular Modulation Mediated by Kinin Receptors Contribute to Painful Symptoms Induced by Anastrozole.

Anastrozole, an aromatase inhibitor, induces painful musculoskeletal symptoms, which affect patients' quality of life and lead to therapy discontinuation. Efforts have been made to understand the mechanisms involved in these painful symptoms to manage them better. In this context, we explored the role of the Transient Receptor Potential Vanilloid 4 (TRPV4), a potential transducer of several nociceptive mechanisms, in anastrozole-induced musculoskeletal pain in mice. Besides, we evaluated the possible sensibilization of TRPV4 by signalling pathways downstream, PLC, PKC and PKCε from kinin B2 (B2R) and B1 (B1R) receptors activation in anastrozole-induced pain. Anastrozole caused mechanical allodynia and muscle strength loss in mice. HC067047, TRPV4 antagonist, reduced the anastrozole-induced mechanical allodynia and muscle strength loss. In animals previously treated with anastrozole, the local administration of sub-nociceptive doses of the TRPV4 (4α-PDD or hypotonic solution), B2R (Bradykinin) or B1R (DABk) agonists enhanced the anastrozole-induced pain behaviours. The sensitizing effects induced by local injection of the TRPV4, B2R and B1R agonists in animals previously treated with anastrozole were reduced by pre-treatment with TRPV4 antagonist. Furthermore, inhibition of PLC, PKC or PKCε attenuated the mechanical allodynia and muscle strength loss induced by TRPV4, B2R and B1R agonists. The generation of painful conditions caused by anastrozole depends on direct TRPV4 activation or indirect, e.g., PLC, PKC and PKCε pathways downstream from B2R and B1R activation. Thus, the TRPV4 channels act as sensors of extracellular and intracellular changes, making them potential therapeutic targets for alleviating pain related to aromatase inhibitors use, such as anastrozole.

Debridement ability of the WaveOne Gold and TruNatomy systems in the apical third of root canals: ex vivo assessment

Abstract Cleaning and shaping the root canal system are essential steps for performing successful endodontic therapy, and are challenging procedures in the apical region. This study aimed to conduct an ex vivo assessment of the debridement ability of the WaveOne Gold (Medium 35/.06) and TruNatomy (Medium 36/.03) systems in the apical third of round root canals of mandibular premolars. Forty-eight teeth, extracted for orthodontic or periodontal reasons, were divided into three groups (n=16), as follows: Group C, control (without instrumentation or irrigation); Group WOG, instrumentation with WaveOne Gold; Group TN, instrumentation with TruNatomy. A total of 40 mL of 2.5% sodium hypochlorite and 5 mL of 17% ethylenediamine tetraacetic acid were used per root canal in all the groups. Ten 0.5-μm serial cross-sections per specimen were obtained every 0.2 mm from a 2-mm segment of the apical region, extending from 1 to 3 mm short of the root apex. The sections were stained with hematoxylin-eosin and analyzed under a digital microscope (100x). The percentages of unprepared walls and remaining debris were quantified using ImageJ software. Generalized linear models were used to analyze the results (α=5%). Groups WOG and TN had significantly lower percentages of unprepared walls and remaining debris than Group C (p<0.05). There was no significant difference between groups WOG and TN for either of the variables studied (p>0.05). Instrumentation with the WaveOne Gold Medium and TruNatomy Medium instruments was associated with equivalent percentages of unprepared walls and remaining debris in the apical third of round canals of mandibular premolars.

Resumo A limpeza e modelagem do sistema de canais radiculares são etapas fundamentais para o sucesso da terapia endodôntica e são procedimentos desafiadores na região apical. O objetivo deste trabalho foi realizar uma avaliação ex vivo da capacidade de debridamento dos sistemas WaveOne Gold (Medium 35/.06) e TruNatomy (Medium 36/.03) no terço apical de canais radiculares circulares de pré-molares inferiores. Quarenta e oito dentes que haviam sido extraídos por razões ortodônticas ou periodontais foram divididos em três grupos (n=16),da seguinte forma: Grupo C, Controle (sem instrumentação nem irrigação); Grupo WOG, instrumentação com WaveOne Gold; Grupo TN, instrumentação com TruNatomy. Um total de 40 mL de hipoclorito de sódio a 2,5% e 5 mL de ácido etilenodiamino tetraacético a 17% foi utilizado por canal radicular em todos os grupos. Dez secções transversais em série de 0,5 μm por espécime foram obtidas a cada 0,2 mm de um segmento de 2 mm da região apical, estendendo-se desde 1 até 3 mm aquém do ápice radicular. As seções foram coradas com hematoxilina-eosina e analisadas sob um microscópio digital (100x). As porcentagens de paredes não tocadas e detritos remanescentes foram quantificadas utilizando-se o software ImageJ. Modelos lineares generalizados foram utilizados para analisar os resultados (α=5%). Os grupos WOG e TN apresentaram porcentagens significativamente menores de paredes intocadas e detritos remanescentes do que o grupo C (p<0,05). Não houve diferença significativa entre os grupos WOG e TN quanto a nenhuma das variáveis estudadas (p>0,05). A instrumentação com os instrumentos WaveOne Gold Medium e TruNatomy Medium foi associada a porcentagens equivalentes de paredes intocadas e detritos remanescentes no terço apical de canais circulares de pré-molares inferiores.

What Feedback Content Do Clinical Teachers Address During OSTEs?

Purpose: How to give feedback is widely taught and assessed during Faculty Development programs. As part of such programs, clinical teachers can attend objective structured teaching sessions (OSTEs), during which they are asked to give feedback to simulated residents on different tasks. Study aimed at: -analysing the feedback content provided during these OSTEs; -evaluating the impact of the training phase, medical discipline, or observed task; -assessing the alignment between feedback content addressed by clinical teachers and content identified as essential by experts. Methods: We conducted a multimethod study. Clinical teachers (N=89) from five departments were trained to give feedback to residents in a six-month training program. Before and after training, they completed three OSTE stations which focused on tasks involving communication, interprofessional, physical exam or procedural skills. We analysed feedback content descriptively. ANOVA test was applied to evaluate feedback contents' influencing factors (ie participants' training phase, medical discipline, type of task addressed). For each OSTE, we analysed the percentage of items identified as essential by 3 experts that were addressed by clinical teachers during the feedback. Results: We analysed 317 feedback sessions and coded 5388 occurrences. Feedback content distribution was: targeted content (73%), other clinical content (20%), learning strategies (4%), and self-management/other (3%). Feedback was often negative (73%). The training phase did not influence the content addressed while the topic of the observed task and clinical teachers' specialization slightly did. Alignment between content identified by experts and addressed by clinical teachers during OSTEs was low (3-38%). Conclusion: Clinical teachers give mostly negative and targeted feedback according to the task. The poor alignment in selecting key content to be addressed is striking and should be further explored since clinical teachers may address elements of competence more according to their personal preferences than to residents' needs and context priorities.