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Abstract Background Endothelial dysfunction contributes to increased cardiovascular (CV) disease in rheumatoid arthritis (RA). Angiogenic T cells (Tang) are a key regulator of vascular function via their interaction with endothelial progenitor cells (EPCs). Methotrexate (MTX) has been associated to reduced CV disease risk, but its effects on endothelial homeostasis have been poorly explored. We investigated MTX effects on endothelial homeostasis in early, treatment-naïve RA patients. Methods Fifteen untreated, early RA patients and matched healthy controls (HC) were enrolled. RA patients with long-standing disease in remission or low disease activity treated with MTX for at least 6 months were selected as controls. Circulating CD28+ and CD28null Tang cell, endothelial microparticle (EMP), EPC and soluble vascular cell adhesion molecule (sVCAM)-1 levels were measured. Results Tang percentage was higher in early RA than in HCs and significantly increased after 3-month MTX treatment. Tang cells in RA were characterized by higher percentage of CD28null and lower CD28-positive cells than HCs. MTX restored a Tang cell phenotype similar to HCs. Altered sVCAM-1, EMP and EPC were restored to levels similar to HCs after a 3-month MTX. Biomarker levels after 3 months of MTX were not different to those of patients with long-standing treatment. Conclusions MTX has a positive effect on Tang, sVCAM-1, EPCs and EMPs in RA. Restoration of imbalance between CD28 + and CD28null Tang by MTX may be one of the mechanisms underlying its favourable effects on endothelial dysfunction. These effects seem to be long-lasting and independent from systemic inflammation reduction, suggesting a direct effect of MTX on the endothelium.

Purpose: The most used neurosurgical approach to reach cerebellar-pontine angle is the retrosigmoid route. This article describes the presigmoid approach which requires excellent knowledge of the labyrinthine block together with quantitative analysis of temporal bone CT., Methods: CT-based quantitative measurements were obtained in patients undergoing vestibular neurectomy with a presigmoid approach. Eighteen patients were enrolled, and five measures were taken: Trautmann's area, the petro-clival angle, presigmoid dura length and its angle. The relationship between these measurements and hospitalization days, operating times, and complications was explored., Results: The posterior semicircilar canal (PSC)-sigmoid sinus (SS) distance, presigmoid dura- internal auditory canal (IAC)-PSC angle, and duration of surgery are predictors of complications. Specifically, a PSC-sigmoid sinus distance <11 mm, a dura presig-IAC-PSC angle <14 are associated with the highest risk of complications., Conclusion: Preoperative temporal bone CT scan can guide the surgeon through the narrowest areas of the surgical approach. Trautmann's triangle area and petro-clival angle reduction are challenging and can be faced with combined microscopic-endoscopic technique, and with optics angulation-rotation. The retrolabyrinthine approach can enable hearing preservation and minimal cerebellar retraction., (Copyright © 2024. Published by Elsevier España, S.L.U.)

Pain is often one of the initial indicators of a viral infection, yet our understanding of how viruses induce pain is limited. Immune cells typically recognize viral nucleic acids, which activate viral receptors and signaling, leading to immunity. Interestingly, these viral receptors and signals are also present in nociceptors and are associated with pain. Here, we investigate the response of nociceptors to nucleic acids during viral infections, specifically focusing on the role of the viral signal, Stimulator of Interferon Genes (STING). Our research shows that cytosolic double-stranded DNA (dsDNA) from viruses, like herpes simplex virus 1 (HSV-1), triggers pain responses through STING expression in nociceptors. In addition, STING agonists alone can elicit pain responses. Notably, these responses involve the direct activation of STING in nociceptors through TRPV1. We also provided a proof-of-concept showing that STING and TRPV1 significantly contribute to the mechanical hypersensitivity induced by HSV-1 infection. These findings suggest that STING could be a potential therapeutic target for relieving pain during viral infections., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Meniere's disease (MD) is a disabling disease, especially in patients who are refractory to medical therapy. Moreover, selective vestibular neurectomy (VN), in these selected cases, can be considered a surgical alternative which preserves hearing function and facial nerve., Methods: We retrospectively studied 23 patients with MD diagnosis and history of failed extradural endolymphatic sac surgery (ELSS) who underwent combined micro-endoscopic selective VN, between January 2019 and August 2023, via a presigmoid retrolabyrinthine approach. All patients were stratified according to clinical features, assessing preoperative and postoperative hearing levels and quality of life., Results: At the maximum present follow-up of 2 years, this procedure is characterized by a low rate of complications and about 90% vertigo control after surgery. No definitive facial palsy or hearing loss was described in this series. One patient required reintervention for a CSF fistula. Statistically significant ( p = 0.001) difference was found between the preoperative and the postoperative performance in terms of physical, functional, and emotive scales assessed via the DHI questionnaire., Conclusions: Selective VN via a presigmoid retrolabyrinthine approach is a safe procedure for intractable vertigo associated with MD, when residual hearing function still exists. The use of the endoscope and intraoperative neuromonitoring guaranteed a precise result, saving the cochlear fibers and facial nerve. The approach for VN is a familiar procedure to the otolaryngologist, as is lateral skull base anatomy to the neurosurgeon; therefore, the best results are obtained with multidisciplinary teamwork.

Background: Ménière's disease is an inner ear disorder causing recurrent vertigo, hearing loss, and tinnitus. Diagnosis is based on the variability of the symptoms over time and absence of radiological abnormalities. Medical therapy is effective only in a small percentage of patients. Surgical strategies remain controversial. In this article, we revisit a surgical technique neglected over the years: endolymphatic sac surgery., Methods: Fifty-four patients affected by Ménière's disease underwent endolymphatic duct and sac decompression. According to the American Academy of Otolaryngology-Head and Neck Surgery criteria, vertigo control was evaluated with follow-up at 6 months, 1 year, and 2 years from the intervention. Hearing results were evaluated before the surgery and at 2 years of follow-up using the pure tone average. The results were compared with similar techniques of endolymphatic sac surgery described in the literature., Results: According to the American Academy of Otolaryngology-Head and Neck Surgery criteria classification, 2 years after surgery, 87% patients achieved complete control of vertigo (class A). The hearing remained stable in 93.5% of patients. The results appear compatible with other publications data regarding endolymphatic sac surgeries., Conclusion: The duct and endolymphatic sac decompression allows the control of vertigo and preserves hearing from the pathological effects of Ménière's disease. The revised technique allows the functional restoration of endolymphatic homeostasis.

Objective: High-pressure physiological saline isotonic solution (HPpSIS) delivery into the nasal cavity was found to modulate the local expression of immune cells, increase NGF protein, and enhance the NGF receptors' expression. Since the nasal cavity directly communicates with the eye and as NGF was previously found to ameliorate the symptoms of dry eye when topically delivered, the aim of this study was to establish whether the HPpSIS might ameliorate ocular dryness and tear film composition., Subjects and Methods: This is an observational self-controlled case study carried out on 16 patients with dry-eye diagnosis, concerning 3-month self-administration of HPpSIS and two serial assessments of the ocular surface and tear film. OSDI questionnaire was used for ocular symptoms of dryness. BUT and Schirmer tests were used for qualitative and quantitative tear film analysis. The lipid composition was also examined. R-studio was employed for the detection of the difference between the pre- and post-analysis., Results: On the basis of the OSDI questionnaire, the study population was divided into severe (61.1%), moderate (5.5%), and mild (16.6%) dry-eye symptoms. OSDI score was significantly reduced after HPpSIS (p<0.05). BUT and TMH values also ameliorated after HPpSIS (p>0.05), although not significantly. The lipid layer improved statistically (p<0.05) and correlated positively with OSDI grading. The variability of presentation in the numerical distribution before and after therapy suggests poor test sensitivity., Conclusions: HPpSIS showed a positive effect in reducing OSDI scores and ameliorating tear film quality. The possibility of an endogenous HPpSIS-induced NGF should be taken into account in dry-eye therapy.

Objective: In a previous study, we reported an increase of nasal nerve growth factor (NGF) in patients treated with high-pressure administration of sterile saline isotonic solution (HPpSIS). Herein we characterized the nasal mucosa in terms of innate immune response and cytokine signature, including antiviral properties. Potential NGF and antiviral benefits of HPpSIS were also discussed., Patients and Methods: Twenty (20) patients (11 males, 9 females; age range 30-75 years old) underwent HPpSIS and nasal samples were collected before and after treatment. Nasal scraping was used for morphological (smears and Quick May-Grunwald Giemsa staining, MGG), biochemical (Histamine, Serotonin; ELISA) and molecular (messenger RNA, mRNA) analyses. Amplification of transcripts specific for Toll-like receptor (TLR) 3 (TLR3), TLR7, TLR9, Interleukin-(IL) 18 (IL18), IL13, IL12, eosinophil-derived neurotoxin (EDN), Eosinophil Cationic Protein (ECP), γ Interferon (γIFN), tryptase and serotonin was performed using the 2-step real-time Reverse Transcription Polymerase Chain Reaction (RT-PCR). Clinical and laboratory data were analyzed and compared., Results: The clinical evaluation showed a protective effect of our therapy. Smears showed the presence of leucocytes, eosinophils (EOs) and mast cells (MCs), and increased immunoreactivity for ECP/RNase3 and EDN after HPpSIS. ELISA showed increased levels of Serotonin and EDN associated with unchanged levels of substance P(SP) and histamine. Increased eosinophil-derived neurotoxin eosinophil-derived neurotoxin (EDN) levels were confirmed by in situ fluorescent analysis. HPpSIS induced the upregulation of TLR3, TLR7 and TLR9 transcripts, while no changes were observed for Intercellular Adhesion Molecule 1 (ICAM1), IL18, Interleukin-15 (IL15) and IL12 transcripts nor for Interleukin-6 (IL6) and IL13. No changes were also observed for γIFN and EDN/RNase2 transcripts, while ECP/RNase3 transcripts were significantly upregulated after HPpSIS. Finally, tryptase transcripts were unchanged while serotonin transcripts were significantly increased after HPpSIS., Conclusions: The clinical and biomolecular changes observed at the nasal mucosa due to HpSS treatment suggest the activation of an innate surveillance, by means of TLR transcription, and a possible anti-viral response due to EDN upregulation. It remains to be verified if NGF, known to be released locally upon HpSIS treatment, might in part be responsible for this local activation.

Introduction: In this article, the bi-fenestral surgical chemical labyrinthectomy is introduced as a surgical demolition technique for treating resisting incurable forms of Meniere's disease in patients aged over 70 and/or with low hearing residues refractory to medical treatment., Materials and Methods: The results on participants fitting the inclusion criteria (n = 16) were reported using anamnesis (frequency of the crisis), Dizziness Handicap Inventory (DHI) and Functional Level Scale (FLS) before and after the intervention., Results: Vertigo control was achieved in all patients of this case series. A difference of 57 and 3.67 in mean DHI (from 68 (SD 16.7) to 11 (SD 14)) and FLS (from 4.68 (SD 0.7) to 0.1 (SD 0.3)) scores respectively were seen after an average of 16.28 months. Contextually tinnitus was reported to improve in seven patients (43.75%), aggravate in three (18.75%) and remain unchanged in the remaining six (37.5%)., Conclusion: Bi-fenestral surgical chemical labyrinthectomy appears a safe, immediate, and effective demolition treatment for vertigo control in a restricted class of patients affected by intractable Meniere disease., (Copyright © 2022. Published by Elsevier España, S.L.U.)

Sharks and rays are key functional components of coral reef ecosystems, yet many populations of a few species exhibit signs of depletion and local extinctions. The question is whether these declines forewarn of a global extinction crisis. We use IUCN Red List to quantify the status, trajectory, and threats to all coral reef sharks and rays worldwide. Here, we show that nearly two-thirds (59%) of the 134 coral-reef associated shark and ray species are threatened with extinction. Alongside marine mammals, sharks and rays are among the most threatened groups found on coral reefs. Overfishing is the main cause of elevated extinction risk, compounded by climate change and habitat degradation. Risk is greatest for species that are larger-bodied (less resilient and higher trophic level), widely distributed across several national jurisdictions (subject to a patchwork of management), and in nations with greater fishing pressure and weaker governance. Population declines have occurred over more than half a century, with greatest declines prior to 2005. Immediate action through local protections, combined with broad-scale fisheries management and Marine Protected Areas, is required to avoid extinctions and the loss of critical ecosystem function condemning reefs to a loss of shark and ray biodiversity and ecosystem services, limiting livelihoods and food security., (© 2023. The Author(s).)

Background: The present article aims to introduce the endolymphatic duct and sac decompression technique (DASD) and to give a spotlight on its benefits in Ménière's disease (MD) treatment., Methods: Eighty-two patients with intractable MD which met the inclusion criteria were recruited and underwent DASD. This technique allows a meningeal decompression of the duct and the sac from the posterior cranial fossa to the labyrinthine block. The authors considered as main outcomes, the change of the dizziness handicap inventory (DHI) results, with the evaluations of the three sub-scales (Functional scale, Physical scale, and Emotional scale); ear fullness and tinnitus change on the perceptions of the patient; and hearing stage with four-Pure Tone Average (500 hz-1000 hz-2000 hz-4000 hz). The differences between the preoperative and the postoperative score were evaluated. A comparison with the literature was conducted., Results: After a 14-month follow-up, patients that underwent DASD reported a remarkable improvement of the symptoms in all three functional scales, confirmed by the total DHI. The difference between preoperative and postoperative scores is statistically significant. The data describe an ear fullness and tinnitus improvement. The multi-frequency tonal average before and after the surgery does not suggest a worsening of the value for any of 82 patients., Conclusion: The modification of sac surgery includes the endolymphatic duct in the decompression area allowing inner ear functional improvement, vertigo control, ear fullness improvement with minimal risk of facial nerve paralysis, and hearing loss. DASD is an improved old surgical technique., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Surgical Neurology International.)

The superior semicircular canal dehiscence is a vestibular disease recognized condition in recent years, and surgical therapy has been modeling itself over the years to ensure the control of vestibular symptoms and auditory symptoms. In this case series, the authors have experienced an intervention aimed at closing the superior semicircular canal dehiscence through the insertion of bone paté between the meninx and the residual middle cranial fossa bone wall. Seven patients underwent this intervention, they reported an improvement in all vestibular and auditory symptoms, and hearing threshold remained stable. Despite the small sample size, the difference was significant in the control of dizziness and the reduction of pulsatile tinnitus. The technique described in this article allows the control of symptoms in superior semicircular canal dehiscence, and it is a type of surgery familiar to the otosurgeon and easily replicable as it involves a modified mastoidectomy. More data are needed., (Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2022.)

Objective: Serotonin, which is a vasoactive amine, is an important neurotransmitter and is involved in many behavioral and psychological phenomena, such as pain, appetite, mood, and sleep. The primary purpose of our study was to investigate the effect of high-pressure administration of sterile physiological saline isotonic solution (HpPSIS) into nasal cavity and to determine the expression of the serotonin., Patients and Methods: The study was made in two branches, the previous with 14 volunteers, the subsequent study with 40 patients with mild anxiety disorder. The middle third of the inferior turbinate epithelial cells on the right nostril was scraped using a sterile curette and indicated as (pre), then, a spray of sterilized isotonic solution at high pressure on the left nostril was delivered, and 5 minutes later a similar stimulation was delivered on the same nostril. The stimulation was made with a specific spray dispenser. The middle third of the inferior turbinate epithelial cells on the left nostril was scraped using a sterile curette and indicated as (post). Then, based on the first part of our study, we started the second part and gave a treatment on forty new patients with anxiety disorder., Results: The results of these studies highlight the possibility of endogenous enhancement of serotonin by stimulation of mast cells. In the first part of the study, Serotonin significantly increased in protein extracts after treatment (64.35±5.33 vs. 10.97±2.17; unpaired two tailed t-test, t=9.8, df=24, p≤0.0001; F=6.035; DFn=12; DFd=12). In the second part of the study, in patients treated with HpPSIS, we observed improvement of mood, after one, two and three months, with a statistically significant reduction of DASS-21, while no reduction was observed in control patients, treated with normal pressure commercial spray., Conclusions: This pilot study showed that the topical treatment of HpPHIS increases serotonin levels in nasal cavity. The observation reported in this study opens the way to a new valid strategy to enhance the level of endogenous serotonin. We observed a significant improvement of ASI on patients during HpPHIS therapy.

Anadenanthera (Fabaceae) is endemic to the Neotropics and consists of two tree species: A. colubrina (Vell.) Brenan and A. peregrina (L.) Speg. This study examined the mating system and contemporary gene flow of A. colubrina (Acol) and A. peregrina (Aper) in a highly fragmented area of the Atlantic Forest to provide valuable information that informs conservation strategies. Reproductive adults from forest remnants [n A. colubrina = 30 (2.7 ha), n A. peregrina = 55 (4.0 ha)] and progeny-arrays (n A. colubrina = 322, n A. peregrina = 300) were genotyped for seven nuclear microsatellite markers. Mating system analyses revealed that A. colubrina is a mixed mating species ( t m = 0.619) while A. peregrina is a predominantly outcrossing species ( t m = 0.905). For both Anadenanthera species, high indices of biparental inbreeding were observed (Acol = 0.159, Aper = 0.216), resulting in low effective pollination neighborhood sizes. Categorical paternity analysis revealed different scales of pollen dispersal distance: the majority of crossings occurring locally (i.e., between nearby trees within the same population), with moderate pollen dispersal coming from outside the forest fragments boundaries (Acol mp = 30%, Aper mp = 35%). Nevertheless, pollen immigration from trees outside the populations for both species suggests that the populations are not reproductively isolated. This study highlights the importance of evaluating both mating system and contemporary gene flow for a better understanding of the biology of Anadenanthera species. This information should be considered to ensure the effective conservation and management practices of these plant species., Competing Interests: Alison G. Nazareno is an Academic Editor for PeerJ., (© 2021 Feres et al.)