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cGAS is a sensor of cytosolic DNA and responds equally to exogenous and endogenous DNA. After recognition of cytosolic dsDNA or ssDNA, cGAS synthesizes the second messenger 2′3′-cGAMP, which then binds to and activates stimulator of interferon genes (STING). STING plays an essential role in responding to pathogenic DNA and self-DNA in the context of autoimmunity. In pathologic conditions, such as stroke or hypoxia-ischemia (HI), DNA can gain access into the cytoplasm of the cell and leak from the dying cells into the extracellular environment, which potentially activates cGAS/STING. Recent in vivo studies of myocardial ischemia, traumatic brain injury, and liver damage models suggest that activation of cGAS/STING is not only a side-effect of the injury, but it can also actively contribute to cell death and apoptosis. We found, for the first time, that cGAS/STING pathway becomes activated between 24 and 48 h after HI in a 10-day-old rat model. Silencing STING with siRNA resulted in decreased infarction area, reduced cortical neurodegeneration, and improved neurobehavior at 48 h, suggesting that STING can contribute to injury progression after HI. STING colocalized with lysosomal marker LAMP-1 and blocking STING reduced the expression of cathepsin B and decreased the expression of Bax and caspase 3 cleavage. We observed similar protective effects after intranasal treatment with cGAS inhibitor RU.521, which were reversed by administration of STING agonist 2′3′-cGAMP. Additionally, we showed that long interspersed element 1 (LINE-1) retrotransposon, a potential upstream activator of cGAS/STING pathway was induced at 48 h after HI, which was evidenced by increased expression of ORF1p and ORF2p proteins and increased LINE-1 DNA content in the cytosol. Blocking LINE-1 with the nucleoside analog reverse-transcriptase inhibitor (NRTI) stavudine reduced infarction area, neuronal degeneration in the cerebral cortex, and reduced the expression of Bax and cleaved caspase 3. Thus, our results identify the cGAS/STING pathway as a potential therapeutic target to inhibit delayed neuronal death after HI.

Introduction and hypothesisPregnancy and delivery are well-established risk factors for pelvic floor dysfunction (PFD), but the physiopathology, such as the delivery route, is not well understood. This study evaluated the impact of delivery route on the pelvic floor muscles via 3D ultrasound.MethodsThis review is registered in the PROSPERO database. The criteria for inclusion were prospective studies with 3D translabial ultrasound assessment in primigravida women during pregnancy and postpartum published in English, Spanish or Portuguese between 1980 and 2016. We excluded studies that did not include the topic of urogenital hiatus measurement and literature reviews. The MeSH terms were obstetric delivery, postpartum period, labor, parturition, three-dimensional images, ultrasonography, pelvic floor, and pelvic floor disorders.ResultsThe search retrieved 155 articles. After analysis, 6 articles were included. Four studies showed that vaginal delivery (VD) was associated with a larger hiatal area. One study associated the hiatal area with levator ani muscle (LAM) defects in VD. Four articles evaluated the bladder neck, 3 of which showed a significant increase in bladder neck mobility associated with VD and 1 showed decreased bladder neck elevation, not associated with the delivery mode; the first 3 articles all evaluated LAM injuries and showed an association between VD and LAM injury. Women who underwent VD presented defects of the puborectalis muscle.ConclusionsVaginal delivery was associated with a higher number of LAM injuries, puborectalis defects, increased bladder neck mobility, and enlargement of the hiatal area.

Although most melanoma cases may be treated by surgical intervention upon early diagnosis, a significant portion of patients can still be refractory, presenting low survival rates within 5 years after the discovery of the illness. As a hallmark, melanomas are highly prone to evolve into metastatic sites. Moreover, melanoma tumors are highly resistant to most available drug therapies and their incidence have increased over the years, therefore leading to public health concerns about the development of novel therapies. Therefore, researches are getting deeper in unveiling the mechanisms by which melanoma initiation can be triggered and sustained. In this context, important progress has been achieved regarding the roles and the impact of cellular signaling pathways in melanoma. This knowledge has provided tools for the development of therapies based on the intervention of signal(s) promoted by these cascades. In this review, we summarize the importance of major signaling pathways (mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)-Akt, Wnt, nuclear factor κ-light-chain-enhancer of activated B cell (NF-κB), Janus kinase (JAK)-signal transducer and activator of transcription (STAT), transforming growth factor β (TGF-β) and Notch) in skin homeostasis and melanoma progression. Available and developing melanoma therapies interfering with these signaling cascades are further discussed.

To assess a comparative analysis of the ROX index, Wood-Downes-Ferrés score (WDF), p-ROXI, and the SpO2/FiO2 ratio as predictors of high-flow nasal cannula (HFNC) failure in children hospitalized for bronchiolitis. Data were extracted from the clinical trial \"Comparison between HFNC and NIV in children with acute respiratory failure caused by bronchiolitis\" conducted at a tertiary Brazilian hospital (Emergency Department and PICU). The inclusion criteria were children under 2 years of age admitted for bronchiolitis who developed mild to moderate respiratory distress and were eligible for HFNC therapy. Performance was determined by ROC and AUC metrics to define the best sensitivity and specificity for each variable. Children were evaluated at 0 h, 2 h, 6 h, 12 h, 24 h, 48 h, 72 h and 96 h after HFNC therapy initiation. A total of 126 patients were recruited for this analysis. The median age was 3 months. Ninety-one percent of the patients had an identified viral agent, with RSV being the most common (65%). Twenty-three percent (29/126) of patients experienced failed HFNC therapy and required mechanical ventilation. The best cutoff points at 12 hours were 4.5 for WDF (AUC = 0.83, 0.74-0.92), 8.8 for ROX (AUC = 0.7, 0.54-0.84), 1.45 for p-ROXI (AUC = 0.56, 0.38-0-74), and 269 for SpO2/FiO2 (AUC = 0.64, 0.48-0.74). The scores and indices were also correlated with the PICU and hospital LOS. The ROX index and WDF were the most accurate scores for assessing HFNC failure considering 12-hour cutoff points. U1111-1262-1740; RBR-104z966s. Date of registration: 03/01/2023.

Past studies revealed the prognosis differed between aneurysmal subarachnoid hemorrhage (aSAH) patients with surgical clipping and endovascular coiling. We retrospectively reviewed aSAH patients in our institution to investigate the effectiveness of grading scores between two groups. In the surgical clipping group (n = 349), VASOGRADE had a favorable performance for predicting delayed cerebral ischemia (DCI) (area under curve (AUC) > 0.750), and had better results than clinical (World Federation of Neurosurgical Societies (WFNS), Hunt & Hess (HH) and radiological scores (modified Fisher Scale (mFS), Subarachnoid Hemorrhage Early Brain Edema Score) ( P  < 0.05). Clinical and combined scores (VASOGRADE, HAIR) had favorable performance for predicting poor outcome (AUC > 0.750), and had better results than radiological scores ( P  < 0.05). In the coiling group (n = 320), none of the grading scores demonstrated favorable predictive accuracy for DCI (AUC < 0.750). Only WFNS and VASOGRADE had AUC > 0.700, with better performance than mFS ( P  < 0.05). The clinical and combined scores showed favorable performance for predicting a poor outcome (AUC > 0.750), and were better than the radiological scores ( P  < 0.05). Radiological scores appeared inferior to the clinical and combined scores in clipping and coiling groups. VASOGRADE can be an effective grading score in patients with clipping or coiling for predicting DCI and poor outcome.

Background Gastric cancer is the third leading cause of cancer-related deaths worldwide and has been associated with infections that may promote tumour progression. Accordingly, we analysed the presence of Mollicutes, Mycoplasma hyorhinis , Fusobacterium nucleatum and Helicobacter pylori in gastric cancer tissues and evaluated their correlation with clinicopathological factors. Methods Using a commercial kit, DNA were extracted from 120 gastric samples embedded in paraffin: 80 from patients with gastric cancer and 40 from cancer free patients, dating from 2006 to 2016. Mollicutes and H. pylori were detected by PCR; F. nucleatum and M. hyorhinis were detected by qPCR, together with immunohistochemistry for the latter bacteria. Results Mollicutes were detected in the case and control groups (12% and 2.5%) and correlated with the papillary histologic pattern ( P  = 0.003), likely due to cell transformation promoted by Mollicutes. M. hyorhinis was detected in the case and control group but was not considered a cancer risk factor. H. pylori was detected at higher loads in the case compared to the control group (8% and 22%, P  = 0.008) and correlated with metastasis ( P  = 0.024), lymphatic invasion ( P  = 0.033), tumour of diffused type ( P  = 0.028), and histopathological grading G1/G2 ( P  = 0.008). F. nucleatum was the most abundant bacteria in the case group, but was also detected in the control group (26% and 2.5%). It increased the cancer risk factor ( P  = 0.045, OR = 10.562, CI95% = 1.057–105.521), and correlated with old age ( P  = 0.030) and tumour size ( P  = 0.053). Bacterial abundance was significantly different between groups ( P  = 0.001). Conclusion Our findings could improve the control and promote our understanding of opportunistic bacteria and their relevance to malignant phenotypes.

Background Denture-related stomatitis (DS) is chronic multifactorial inflammation, strongly related to the presence of the biofilm that is the complex structure formed by microorganisms held together by a mucus-like matrix of carbohydrate that adheres to different surfaces, including the denture surface. DS has recently been correlated with deleterious cardiovascular alterations. The potential effect of hygiene protocols in the control of DS and randomized clinical trials that address this oral condition with cardiovascular complications are important in clinical decision-making. Material/design A clinical trial, randomized, double-blind, and with parallel groups, will be conducted in Brazil The sample will consist of 100 patients without teeth in both arches, users of at least maxillary complete dentures, and diagnosed with DS, who will be allocated to groups ( n  = 25 per group) according to the different hygiene protocols: (1) brushing of the palate and immersion of the prosthesis in 0.25% sodium hypochlorite solution (positive control); (2) brushing of the palate and immersion of the prosthesis in 0.15% triclosan solution; (3) brushing of the palate and immersion of the prosthesis in lactose monohydrate; or (4) brushing the palate with citric acid and immersing the prosthesis in lactose monohydrate. The response variables will be heart rate variability and alteration of blood pressure (systemic level), remission of DS, removal of biofilm, reduction of microbial load (colony-forming units (CFU)), mouth and prosthesis odor level, expression of MUC1, proinflammatory cytokines, C-reactive protein (CRP), viscosity, pH and salivary flow (locally); patient-centred qualitative analysis will also be undertaken. Measurements will be performed at baseline and 10 days after the interventions. The results obtained will be statistically analyzed as pertinent, with a level of significance of 0.05. Discussion This study will provide a guideline for clinical practice regarding the use of hygiene protocols in the treatment of oral diseases (DS) mediated by biofilm. Also, it may provide evidence of correlation of oral manifestation with cardiac risk. Trial registration Brazilian Registry of Clinical Trials, RBR-4hhwjb . Registered on 9 November 2018.

Introduction and hypothesis This study was aimed at evaluating the impact of a mobile app-guided pelvic floor muscle training (PFMT) program on urinary symptoms and quality of life in women suffering from urinary incontinence. Methods The study included women with stress urinary incontinence (SUI), who underwent a structured interview and completed validated questionnaires, including the Questionnaire for Urinary Incontinence Diagnosis (QUID), the International Consultation on Incontinence Questionnaire – Short Form (ICIQ-SF), and the Incontinence Quality of Life Questionnaire (I-QOL). These women were randomly assigned to one of two groups: the app group, which received a visual depiction on the expected contraction pattern through a mobile app to support their PFMT exercises, and the control (paper) group. Both groups were instructed to perform PFMT exercises twice daily for 30 days. Data were collected at baseline and at 30, 60, 90, and 120 days after completing the exercises. Results A total of 154 women participated, with 76 in the app group and 78 in the paper group. The mean ages were 61 (± 6.1) and 60.6 (± 6.8) in the app and paper groups respectively ( p  = 0.644). Both groups showed significant improvements in QUID SUI scores ( p  < 0.001), overactive bladder (OAB; p  < 0.001), ICIQ-SF scores ( p  < 0.001), and quality-of-life scores ( p  < 0.001). When comparing the two groups, the app group exhibited a more substantial reduction in OAB ( p  = 0.017) as assessed by QUID and total ( p  = 0.042), psychosocial ( p  = 0.032) and social embarrassment ( p  = 0.006) I-QOL scores. Conclusions The study findings suggest that PFMT guided by a mobile app with visual guidance leads to greater improvements in storage symptoms and quality of life than the home-based PFMT guidance.

The bentfin devil ray (Mobula thurstoni) is a migratory elasmobranch species with a wide distribution range. Despite the recent increase in mobulid research, critical habitats and home ranges are still being identified for these threatened species. In the present study, photo and video records opportunistically gathered by SCUBA diving effort were used to identify individuals and habitat usage by M. thurstoni in a marine protected area in the western equatorial Atlantic Ocean, Fernando de Noronha Archipelago (FNA). The bentfin devil ray was identified in five distinct records, in different years and sites around the archipelago. All the males showed developed claspers, suggesting mature individuals using the area. The UNESCO heritage site of FNA is considered an area of high biological importance, containing essential habitats for several species of fish, turtles and marine mammals. However, habitat usage by devil ray species is poorly reported in the region; therefore, the present study presents the first report of M. thurstoni at FNA, which adds the fifth mobulid ray species recorded in the region. Additionally, these results correspond to the second record of living specimens of M. thurstoni in Brazilian jurisdictional waters, highlighting new information on the species’ distribution and the home range of mobulids in Brazil.

Uncertainty remains about how long the protective immune responses against severe acute respiratory syndrome coronavirus 2 persists, and suspected reinfection in recovered patients has been reported. We describe a case of reinfection from distinct virus lineages in Brazil harboring the E484K mutation, a variant associated with escape from neutralizing antibodies.