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Diabetic retinopathy (DR), one of the most common complications of diabetes mellitus, is characterized by degeneration of retinal neurons and neoangiogenesis. Until today, the pharmacological approaches for DR are limited and focused on counteracting the end-stage of this neurodegenerative disease, therefore efforts should be carried out to discover novel pharmacological targets useful to prevent DR development. Hyperglycemia is a major risk factor for endothelial dysfunction and vascular complication, which subsequently may trigger neurodegeneration. We previously demonstrated that, in the rat retina, hyperglycemia activates a new molecular cascade implicating, up-stream, protein kinase C βII (PKC βII), which in turn leads to a higher expression of vascular endothelial growth factor (VEGF), via the mRNA-binding Hu-antigen R (HuR) protein. VEGF is a pivotal mediator of neovascularization and a well-known vasopermeability factor. Blocking the increase of VEGF via modulation of this cascade can thus represent a new pharmacological option to prevent DR progression. To this aim, proper in vitro models are crucial for drug discovery, as they allow to better identify promising effective molecules. Considering that endothelial cells are key elements in DR and that hyperglycemia triggers the PKCβII/HuR/VEGF pathway, we set up two distinct in vitro models applying two different stimuli. Namely, human umbilical vein endothelial cells were exposed to phorbol 12-myristate 13-acetate, which mimics diacylglycerol whose synthesis is triggered by diabetic hyperglycemia, while human retinal endothelial cells were treated with high glucose for different times. After selecting the optimal experimental conditions able to determine an increased VEGF production, in search of molecules useful to prevent DR development, we investigated the capability of troxerutin, an antioxidant flavonoid, to counteract not only the rise of VEGF but also the activation of the PKCβII/HuR cascade in both in vitro models. The results show the capability of troxerutin to hinder the hyperglycemia-induced increase in VEGF in both models through PKCβII/HuR pathway modulation. Further, these data confirm the key engagement of this cascade as an early event triggered by hyperglycemia to promote VEGF expression. Finally, the present findings also suggest the potential use of troxerutin as a preventive treatment during the early phases of DR.

Objectives: To evaluate the effect of recombinant human TSH (rhTSH) on endothelial function, aortic and carotid stiffness, and wave reflection in a population living in the Chernobyl area at the time of 1986 blast, treated with thyroidectomy for thyroid cancer. Methods: 23 subjects (age 26±3 years, 10 men) underwent evaluations at baseline and after rhTSH administration, 0.9mg daily on 2 consecutive days. A real time contour tracking algorithm was applied to B-mode scans for assessing brachial artery endothelium-dependent (flow-mediated dilation, FMD), and -independent dilation (glycerol trinitrate, GTN, 25 μg sublingual) and carotid stiffness (CS) by Bramwell-Hill equation. Carotid blood pressure (BP) waveform, augmentation index (AIx), and carotid-femoral PWV were assessed by applanation tonometry. Results: RhTSH decreased diastolic BP (from 79±11 to 72±9 mmHg, p

Both endothelial dysfunction and arterial stiffness are considered as independent predictors of cardiovascular mortality, but their interrelationship has been poorly explored. Therefore we evaluated the relationship between endothelial function and pulse wave velocity (PWV) in essential hypertensive patients with (DM+) or without (DM-) diabetes mellitus, on chronic pharmacological treatment. 51 DM+ patients and 51 DM- patients matched for age, gender and BP were included. Applanation tonometry (Sphygmocor®) was used to determine aortic (carotid to femoral) PWV. Brachial artery endothelium-dependent flow-mediated dilation (FMD), and endothelium-independent dilation by 25 μg sublingual glycerol trinitrate (GTN) were assessed by high resolution ultrasound and computerized edge detection system. In DM+ PWV was higher (9.9±1.8 vs 8.4±1.4m/s, p=0.0001) and FMD was lower (3.1±1.7 vs 6.3±3.5, p

This paper presents a novel method to objectively select electroencephalographic (EEG) cortical sources estimated by independent component analysis (ICA) in event-related potential (ERP) studies. A proximity measure based on mutual information is employed to estimate residual dependences of the components that are then hierarchically clustered based on these residual dependences. Next, the properties of each group of components are evaluated at each level of the hierarchical tree by two indices that aim to assess both cluster tightness and physiological reliability through a template matching process. These two indices are combined in three different approaches to bring to light the hierarchical structure of the cluster organizations. Our method is tested on a set of experiments with the purpose of enhancing late positive ERPs elicited by emotional picture stimuli. Results suggest that the best way to look for physiologically plausible late positive potential (LPP) sources is to explore in depth the tightness of those clusters that, taken together, best resemble the template. According to our results, after brain sources clustering, LPPs are always identified more accurately than from ensemble-averaged raw data. Since the late components of an ERP involve the same associative areas, regardless of the modality of stimulation or specific tasks administered, the proposed method can be simply adapted to other ERP studies, and extended from psychophysiological studies to pathological or sport training evaluation support. [ABSTRACT FROM AUTHOR]

Fibromyalgia (FM) is a complex and multifaceted condition characterized by a range of clinical symptoms, including widespread pain and a strong association with migraine headaches. Recent findings have underscored the role of oxidative stress and transient receptor potential ankyrin 1 (TRPA1) channel in migraine and FM. However, the precise mechanisms underlying the comorbidity between migraine and FM are unclear. Periorbital mechanical allodynia (PMA), which recapitulates one of the major symptoms of migraine, and the feed-forward mechanism driven by reactive oxygen species and TRPA1, were investigated in a reserpine-induced FM model in C57BL/6J mice, employing pharmacological interventions and genetic approaches. Reserpine-treated mice developed PMA (which was alleviated by antimigraine drugs) and increased endoneurial macrophages and oxidative stress markers in the trigeminal nerve tissues (neuroinflammation). These responses were absent upon macrophage depletion and by pharmacological inhibition or global genetic deletion of the TRPA1 channel. Furthermore, selective silencing of TRPA1 in Schwann cells attenuated both reserpine-induced PMA and neuroinflammation, while selective silencing of TRPA1 in sensory neurons reduced PMA but not neuroinflammation. In reserpine-treated mice, Schwann cell TRPA1 promoted NADPH oxidase 1-mediated reactive oxygen species generation and macrophage density increase in the mouse trigeminal nerve, which sustains PMA. Targeting TRPA1 channels in Schwann cells could offer a novel therapeutic strategy for FM-related headaches., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Purpose: To present a case of autosomal recessive bestrophinopathy (ARB) complicated by intraretinal fluid and subretinal fluid, successfully managed with navigated subthreshold micropulse laser (SML) treatment., Obervations: A 25-year-old female was referred to our clinic by her ophthalmologist due to a diagnosis of reduced vision in both eyes. The patient presented with a visual acuity of 0.9 logMAR in both eyes. Structural optical coherence tomography (OCT) revealed bilateral intraretinal fluid (IRF) and subretinal fluid (SRF), while OCT angiography (OCT-A) demonstrated bilateral macular neovascularization (MNV). Following the initiation of intravitreal therapy with anti-VEGF agents, administered via monthly injections for one year, we observed no improvement in visual acuity or resolution of IRF and SRF. SML treatment was administered to both eyes in the macular region. At the 3-month follow-up visit, OCT revealed complete resolution of IRF in the right eye and partial resolution of IRF in the left eye, and best-corrected visual acuity (BCVA) improved from 0.9 logMAR to 0.7 logMAR., Conclusions and Importance: In our case, SML emerges as a promising treatment modality for patients with ARB complicated by MNV who exhibit poor response to anti-VEGF therapy. However, further prospective studies with longer follow-up periods and larger cohorts are warranted to confirm the optimal treatment strategy in ARB., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Purpose: The oxidant sensor transient receptor potential ankyrin 1 (TRPA1) channel expressed by Schwann cells (SCs) has recently been implicated in several models of neuropathic pain in rodents. Here we investigate whether the pro-algesic function of Schwann cell TRPA1 is not limited to mammals by exploring the role of TRPA1 in a model of chemotherapy-induced peripheral neuropathy (CIPN) in zebrafish larvae., Experimental Approach: We used zebrafish larvae and a mouse model to test oxaliplatin-evoked nociceptive behaviours. We also performed a TRPA1 selective silencing in Schwann cells both in zebrafish larvae and mice to study their contribution in oxaliplatin-induced CIPN model., Key Results: We found that zebrafish larvae and zebrafish TRPA1 (zTRPA1)-transfected HEK293T cells respond to reactive oxygen species (ROS) with nociceptive behaviours and intracellular calcium increases, respectively. TRPA1 was found to be co-expressed with the Schwann cell marker, SOX10, in zebrafish larvae. Oxaliplatin caused nociceptive behaviours in zebrafish larvae that were attenuated by a TRPA1 antagonist and a ROS scavenger. Oxaliplatin failed to produce mechanical allodynia in mice with Schwann cell TRPA1 selective silencing (Plp1 + -Trpa1 mice). Comparable results were observed in zebrafish larvae where TRPA1 selective silencing in Schwann cells, using the specific Schwann cell promoter myelin basic protein (MBP), attenuated oxaliplatin-evoked nociceptive behaviours., Conclusion and Implications: These results indicate that the contribution of the oxidative stress/Schwann cell/TRPA1 pro-allodynic pathway to neuropathic pain models seems to be conserved across the animal kingdom., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

The smaller-incision new-generation implantable miniature telescope (SING IMT) represents an advancement over the previous model, WA-IMT, serving as a unilateral prosthetic device for patients with late-stage age-related macular degeneration (AMD). Purpose: This study aims to report changes in multifocal electroretinography (mfERG) 6 months post-SING IMT implantation. Methods: In this case series, we prospectively evaluated a cohort of phakic patients with late-stage AMD who underwent SING IMT implantation at the Ophthalmology Unit, University of Bari Aldo Moro, Italy. We assessed best-corrected distance visual acuity (BCDVA) and best-corrected near visual acuity (BCNVA) preoperatively and at 6 months postoperatively. Additionally, mfERGs were conducted using Retimax (CSO, Florence, Italy). Results: All four treated patients showed an increase in both BCDVA and BCNVA at the 6-month follow-up. Additionally, all eyes demonstrated increased P1 density at this time point, with the greatest augmentation observed at the central fixation point, gradually diminishing across the five concentric rings. While all patients displayed a general increase in P1 amplitude, the third patient exhibited a slight decrease in the foveal region. Conclusions: In this case series with four cases, the new generation implantable miniature telescope, SING IMT, demonstrates promising results in enhancing mfERG parameters in patients with late-stage AMD. Six months post-surgery, we observed an augmentation in both P1 density and amplitude, predominantly at the fixation point and gradually tapering in the surrounding concentric rings.

Over 60% of women with endometriosis experience abdominopelvic pain and broader pain manifestations, including chronic back pain, fibromyalgia, chronic fatigue, vulvodynia, and migraine. Although the imbalance of proinflammatory mediators, including the complement component C5a, is associated with endometriosis-related pain, the mechanisms causing widespread pain and the C5a role remain unclear. Female mice and women with endometriosis exhibit increased plasma C5a levels and pain. We hypothesize the Schwann cells involvement in endometriotic pain. Here, we show that silencing the C5a receptor (C5aR1) in Schwann cells blocks the C5a-induced activation of the NLRP1 inflammasome and subsequent release of interleukin-1β (IL-1β). Macrophages, recruited to sciatic/trigeminal nerves by IL-1β from Schwann cells, increase oxidative stress, which activates the proalgesic TRPA1 pathway, resulting in widespread pain. These findings reveal a pathway involving Schwann cell C5aR1, NLRP1/IL-1β activation, macrophage recruitment, oxidative stress, and TRPA1 engagement, contributing to pain in a mouse model of endometriosis., Competing Interests: Competing interests: R.N., F.D.L. and P.G. are founding scientists of FloNext Srl. G.B. is fully employed at FloNext Srl, Italy. Other authors declare no competing interests., (© 2024. The Author(s).)

Introduction: Despite an improved understanding of its pathogenesis, dry eye disease (DED) remains relatively underestimated and its treatment challenging. A better alignment between the clinical evaluation and the patient self-assessment also requires capturing the whole patient experience of DED. This project aimed to unveil this experience through narrative medicine (NM)., Methods: The project involved 38 expert centres in Italy and one in San Marino, targeting adult patients with DED, their informal caregivers and their treating ophthalmologists. Written narratives and sociodemographic and quality of life (QoL)-related data were anonymously collected through the project's webpage. Narratives were analysed through MAXQDA (VERBI Software, Berlin, Germany), NM classifications and content analysis., Results: A total of 171 patients with DED, 37 informal caregivers and 81 ophthalmologists participated in the research. DED was defined as a disabling condition by 19% of patients and 35% of caregivers; 70% of patients reported that a therapeutic alliance is an integral part of DED treatment and 32% hope for more effective therapies. Forty-four per cent of patients assessed their own QoL as good; however, DED emerged as importantly impacting work performance and social events. DED physical, emotional and economic burden and the cruciality of a trusting care relationship represent the main themes that emerged across all narratives, while empathy and effective treatment are among the factors favouring coping with DED., Conclusion: This project marked a pioneering initiative investigating the lived experience of patients with DED through NM, simultaneously involving all viewpoints involved in the care pathway. NM enabled the unveiling of factors favouring the ability to cope with DED and its associated QoL implications and provided valuable insights to improve the therapeutic alliance., (© 2024. The Author(s).)

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., (© 2024 British Pharmacological Society.)

Purpose: To explore the long-term effect of diabetic retinopathy on response to anti-vascular endothelial growth factor (VEGF) treatment in age-related macular degeneration-associated type 1 macular neovascularization (MNV) using optical coherence tomography angiography (OCTA)., Methods: A total of 45 eyes with exudative neovascular age-related macular degeneration (nAMD) with type 1 MNV were included in the analysis. Among them, 24 eyes of 24 patients had no history of diabetes mellitus (DM) in their anamnesis and were assigned to the Not Diabetic group; 21 eyes of 21 patients had mild diabetic retinopathy and were included in the Diabetic group. We considered the following outcome measures: (1) best-corrected visual acuity changes; (2) central macular thickness; (3) MNV lesion area; and (4) MNV flow area. The OCTA acquisitions were performed at the following time points: (1) baseline visit, which corresponded to the day before the first injection; (2) post-loading phase (LP), which was scheduled at 1 month after the last LP injection; and (3) 12-month follow-up visit., Results: All morphofunctional parameters showed a significant improvement after the LP and at the 12-month follow-up visit. Specifically, both the Diabetic group and the Not Diabetic group displayed a significant reduction of MNV lesion areas at both the post-LP assessment (P = 0.026 and P = 0.016, respectively) and the 12-month follow-up (P = 0.039 and P = 0.025, respectively). Similarly, the MNV flow area was significantly decreased in both the Diabetic group and the Not Diabetic group at the post-LP assessment (P < 0.001 and P = 0.012, respectively) and at the 12-month follow-up (P = 0.01 and P = 0.035, respectively) compared to baseline. A smaller reduction in the MNV lesion area was observed in the Diabetic group at both the post-LP evaluation (P = 0.015) and the 12-month follow-up (P = 0.032). No other significant differences were found between the groups for the other parameters (P > 0.05)., Conclusions: Our results indicated that the Diabetic group exhibited a smaller reduction in MNV lesion area after 12 months of anti-VEGF treatment. This highlights the importance of considering diabetic retinopathy as a potential modifier of treatment outcomes in nAMD management, with DM serving as a crucial risk factor during anti-angiogenic treatment.

Purpose: This study was designed to investigate retinal nerve fiber layer (RNFL) and radial peripapillary capillaries (RPC) changes on optical coherence tomography (OCT) angiography and OCT thickness alterations associated with acutely increased intraocular pressure after intravitreal injections., Methods: This observational clinical study was conducted on 35 eyes (35 patients) with treatment-naïve age-related macular degeneration (AMD) and type 1 or type 2 MNV were enrolled. All patients underwent anti-vascular endothelial grow factor (VEGF) intravitreal injections with 0.05-mL aflibercept (2 mg) between January 2022 and October 2022. Peripapillary OCT angiography perfusion density, retinal nerve fiber layer thickness, and intraocular pressure (IOP) were measured before and immediately after intravitreal injections. In particular, the analysis was performed at the following visits: (T0) 5 to 15 min before the injection of aflibercept; (T1) 2 to 5 min after the injection of aflibercept. Paired t-test was used to compare pre-injection and post-injection values., Results: The mean baseline IOP (T0) value was 17.26 ± 2.4 mmHg and the immediate post-injection IOP (T1) mean value was 34.7 ± 11.50 mmHg (P < 0.01). The mean global RNFL thickness before and immediately after the injection was 100.9 ± 18.8 m and 98.6 ± 17.4 m (P = 0.001). Furthermore, the topographical RNFL analysis showed significant thickness reduction of the nasal and inferior sectors after the procedure when compared to T0 (P = 0.046 and P = 0.001). On the contrary, the mean RCP density changes at T1 did not reach statistically significant (P = 0.636). Furthermore, we found a significant negative correlation between the retinal nerve fiber layer global thickness and the IOP changes (Pearson's correlation = -0.126; P = 0.031). In particular, the nasal RNFL region showed a significant negative correlations with IOP values (Pearson's correlation = -0.198, P = 0,046)., Conclusions: We reported acute IOP changes that are associated with reduced RNFL thickness in a group of patients undergoing intravitreal injections of anti-VEGF drugs for neovascular age-related macular degeneration. Moreover, topographical sub-analysis revealed that the nasal RNFL region is most prone to IOP fluctuations. This finding may explain the sudden visual acuity change in patients immediately after injection and may sustain injuries to optic nerve head structures producing glaucomatous damage., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Deaths due to dog attacks are a worldwide issue. Fatal dog attacks may occur in various environments, including the dog owner's property. A lot of difficulties emerge when the attack involves a pack of dogs, of different species and sizes. In this case, it becomes much more difficult for forensic investigators to evaluate the event, especially regarding the identification of the dog or dogs that caused the death as well as the identification of the owner and the reconstruction of the dynamics for forensic purposes. In this paper, we analyze a specific case of an attack by a herd of Maremma sheepdogs. A crime scene investigation has been carried out. In the first phase of this case, the victim interacted with dogs that had non-aggressive attitudes. Then, after an escape attempt, she was assaulted by about 20 Maremma dogs of different sizes, leading to multiple injuries all over her body. The greatest difficulty was precisely that of reconstructing the dynamics due to the numerous injuries and dogs involved in the attack. The dynamics were divided into several stages following the analysis of the injuries found on the victim. This case study highlights how the forensic multidisciplinary approach has made it possible to precisely reconstruct the event. The analysis of the dogs' state of malnutrition and their suddenly aggressive attitude towards the victim revealed profiles of responsibility of the owner attributable to improper management and training of the animals to defend their property., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Sacco et al.)

Background: Anterior Chamber bleeding without vitreous hemorrhage had been described after the removal of 23G vitrectomy cannulas. We report the case of an anterior chamber bleeding after an intravitreal Dexamethasone implant., Case Report: One patient with macular edema due to central retinal vein occlusion in a vitrectomized eye underwent an intravitreal Dexamethasone implant. After the injection the patient suffered from anterior chamber bleeding without signs of vitreous hemorrhage. The complication resolved with a conservative treatment., Conclusion: Anterior Chamber bleeding is a possible complication of dexamethasone implant, that can be treated in a conservative way., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Anorexia nervosa (AN) is characterised by the restriction of energy intake in relation to energy needs and a significantly lowered body weight than normally expected, coupled with an intense fear of gaining weight. Treatment of AN is currently based on psychological and refeeding approaches, but their efficacy remains limited since 40% of patients after 10 years of medical care still present symptoms of AN. The intestine hosts a large community of microorganisms, called the "microbiota", which live in symbiosis with the human host. The gut microbiota of a healthy human is dominated by bacteria from two phyla: Firmicutes and, majorly, Bacteroidetes . However, the proportion in their representation differs on an individual basis and depends on many external factors including medical treatment, geographical location and hereditary, immunological and lifestyle factors. Drastic changes in dietary intake may profoundly impact the composition of the gut microbiota, and the resulting dysbiosis may play a part in the onset and/or maintenance of comorbidities associated with AN, such as gastrointestinal disorders, anxiety and depression, as well as appetite dysregulation. Furthermore, studies have reported the presence of atypical intestinal microbial composition in patients with AN compared with healthy normal-weight controls. This review addresses the current knowledge about the role of the gut microbiota in the pathogenesis and treatment of AN. The review also focuses on the bidirectional interaction between the gastrointestinal tract and the central nervous system (microbiota-gut-brain axis), considering the potential use of the gut microbiota manipulation in the prevention and treatment of AN.

Introduction: Inverted Internal Limiting Membrane (ILM)-flap technique demonstrated its effectiveness, in terms of anatomical closure rate and visual acuity recovery for high myopic macular holes. We evaluated macular function after a successful inverted ILM-flap for macular holes in high myopic eyes (hMMH) using microperimetry to predict visual prognosis., Methods: A retrospective study on 23 eyes of 23 patients after surgical closure of hMMH, was performed. All patients underwent inverted ILM-flap and gas tamponade. Cataract surgery was performed in phakic eyes. Study outcomes including best-corrected visual acuity (BCVA), retinal sensitivity (RS) at central 12°, central retinal sensitivity (CRS) at central 4° and mean deviation (MD), and fixation behavior as bivariate contour ellipse area (BCEA, degrees2) measured by microperimetry, were evaluated over 6 months. A mixed-effects model was used to evaluate and compare the repeated measurements of outcomes between phakic and pseudophakic eyes. A regression model was performed to assess the relationship between BCVA at 6 months and independent variables., Results: Overall mean BCVA improved from 0.98 ± 0.21 logMAR at baseline to 0.47 ± 0.31 logMAR at the last follow-up ( p  < 0.001). Over 6 months, overall sensitivity measurements improved (RS, p  = 0.001; CRS, p  < 0.0001; MD, p  = 0.03), and the BCEA decreased in dimension, although not significantly ( p  ≥ 0.05). The mixed model revealed a significantly better effect of inverted ILM-flap combined with cataract surgery on BCVA and CRS in phakic eyes than inverted ILM-flap alone in pseudophakic ones. The regression model revealed a relationship of 6-month BCVA with pre-operative BCVA ( β  = 0.60, p  = 0.02) and RS ( β  = -0.03, p  = 0.01)., Conclusion: The inverted ILM-flap technique significantly improved visual acuity and retinal sensitivity after the hMMH closure, particularly when combined with cataract extraction. Pre-operative visual acuity and retinal sensitivity at central 12° may predict post-surgical visual acuity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sborgia, Boscia, Niro, Landini, Pastore, Albano, Piepoli, Donghia, Dore, Viggiano, Buonamassa, Di Pardo, Molfetta, Eye Clinic Research Group, Coassin, Dell’Omo, Boscia, Alessio and Sborgia.)

Background/purpose: Inverted Inner Limiting Membrane (ILM)-flap approach can fail in the treatment of Optic disc pit maculopathy (ODPM). We report a surgical technique involving human amniotic membrane (hAM) patch implant to treat unresolved ODPM after inverted (ILM)-flap technique., Case Report: One patient with decreased visual acuity (1 LogMar) after unsuccessful inverted ILM-flap technique to treat ODPM, underwent hAM patch implant and was evaluated. A surgical approach including a 2 mm size graft patch of hAM implantation over the optic disc pit followed by fluid-air exchange was performed. A gas endotamponade was finally used. The patient was instructed to maintain face-down position for the first three days after surgery. The hAM patch remained detectable over the pit for the entire 6-months follow-up. The ODPM gradually resolved and visual acuity partially recovered to 0.17 LogMar during follow-up. No postoperative complications or recurrence were reported., Conclusion: hAM patch implant may be effective to manage ODPM after unsuccessful inverted ILM-flap., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The purpose of this study was to investigate the effect of diabetic retinopathy (DR) on longitudinal morphological changes in AMD-associated type 1 macular neovascularization using optical coherence tomography angiography (OCTA). We enrolled fifty treatment-naïve eyes with a diagnosis of exudative AMD and type 1 MNV. Twenty of 50 eyes were affected by mild DR. En face OCT angiography were examined for the MNV lesion area (mm 2 ), the MNV flow area (mm 2 ), the central macular thickness (CMT) and the BCVA. The OCTA acquisition was performed at the following visits: (i) before the loading phase (LP) of intravitreal injection of aflibercept (T1), and (ii) 1 month after the last intravitreal injection of loading phase comprising 3 monthly injections (T2). All morpho-functional parameters showed a significantly change at T2 compared to T1 values in both groups. Furthermore, we found a greater MNV area reduction after LP in eyes without DR (P = 0.023). With regard to the remaining parameters, no significant changes were found between two groups (P > 0.05). Our analysis revealed a less MNV area reduction after loading dose of anti-VEGF therapy in eyes affected by diabetic retinopathy., (© 2023. Springer Nature Limited.)

The present study was conducted to investigate the potential of radiomics to develop an explainable AI-based system to be applied to ultra-widefield fundus retinographies (UWF-FRTs) with the objective of predicting the presence of the early signs of Age-related Macular Degeneration (AMD) and stratifying subjects with low- versus high-risk of AMD. The ultimate aim was to provide clinicians with an automatic classifier and a signature of objective quantitative image biomarkers of AMD. The use of Machine Learning (ML) and radiomics was based on intensity and texture analysis in the macular region, detected by a Deep Learning (DL)-based macular detector. Two-hundred and twenty six UWF-FRTs were retrospectively collected from two centres and manually annotated to train and test the algorithms. Notably, the combination of the ML-based radiomics model and the DL-based macular detector reported 93% sensitivity and 74% specificity when applied to the data of the centre used for external testing, capturing explainable features associated with drusen or pigmentary abnormalities. In comparison to the human operator's annotations, the system yielded a 0.79 Cohen κ , demonstrating substantial concordance. To our knowledge, these results are the first provided by a radiomic approach for AMD supporting the suitability of an explainable feature extraction method combined with ML for UWF-FRT.

Background: Microperimetric biofeedback training improved visual acuity and fixation stability in patients who previously underwent macular surgery. We aimed to compare the functional results of biofeedback training with the standard of care in patients who underwent successful inverted Internal Limiting Membrane (ILM)-flap technique for high myopic macular holes (hMMH)., Methods: This was a retrospective, comparative, cohort study. Patients with hMMH after surgical hole closure underwent microperimetric biofeedback using structured light stimulus plus acoustic tone (n = 12; Biofeedback) or standard of care with scheduled visits (n = 11; Control). Best-corrected visual acuity, retinal sensitivity at central 12° (RS) and 4° (CRS) with a mean deviation at central 12° (MD), and fixation stability as bivariate contour ellipse area (BCEA 68%, 95%, and 99%) were assessed at baseline and month 1, 3, 6, and 12. The Mann-Whitney test was used to test the difference between the groups., Results: Baseline functional parameters were not significantly different among the groups. BCVA significantly improved in each group (Biofeedback, p = 0.002; Control, p ≤ 0.02) at all follow-up visits. CRS significantly improved at 6 ( p = 0.03) and 12 ( p = 0.01) months in the Biofeedback group and at month 12 ( p = 0.01) in the Control group. RS ( p = 0.001) and MD ( p = 0.005) improved at the last follow-up only in the trained group. After training, BCEA 68% and 95% significantly improved (6 and 12 months, p < 0.05). The Biofeedback group had better results in RS ( p ≤ 0.02), CRS ( p ≤ 0.02), and BCEA 68%, 95%, and 99% ( p ≤ 0.01) compared to the Control at all follow-ups. BCVA and MD were better in the Biofeedback group at month 3 ( p = 0.01), and month 3 ( p = 0.01) and 12 ( p = 0.003), respectively., Conclusions: Microperimetric biofeedback can increase retinal sensitivity and stabilize fixation better than the standard care over months after a successful inverted ILM-flap for hMMH.

Background : Transient receptor potential ankyrin 1 (TRPA1) activation is implicated in neuropathic pain-like symptoms. However, whether TRPA1 is solely implicated in pain-signaling or contributes to neuroinflammation in multiple sclerosis (MS) is unknown. Here, we evaluated the TRPA1 role in neuroinflammation underlying pain-like symptoms using two different models of MS. Methods : Using a myelin antigen, Trpa1 + / + or Trpa1 - / - female mice developed relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE) (Quil A as adjuvant) or progressive experimental autoimmune encephalomyelitis (PMS)-EAE (complete Freund's adjuvant). The locomotor performance, clinical scores, mechanical/cold allodynia, and neuroinflammatory MS markers were evaluated. Results : Mechanical and cold allodynia detected in RR-EAE, or PMS-EAE Trpa1 + / + mice, were not observed in Trpa1 - / - mice. The increased number of cells labeled for ionized calcium-binding adapter molecule 1 (Iba1) or glial fibrillary acidic protein (GFAP), two neuroinflammatory markers in the spinal cord observed in both RR-EAE or PMS-EAE Trpa1 + / + mice, was reduced in Trpa1 - / - mice. By Olig2 marker and luxol fast blue staining, prevention of the demyelinating process in Trpa1 - / - induced mice was also detected. Conclusions : Present results indicate that the proalgesic role of TRPA1 in EAE mouse models is primarily mediated by its ability to promote spinal neuroinflammation and further strengthen the channel inhibition to treat neuropathic pain in MS.

Insulin growth factor-1 (IGF-1), an osteoclast-dependent osteolysis biomarker, contributes to metastatic bone cancer pain (MBCP), but the underlying mechanism is poorly understood. In mice, the femur metastasis caused by intramammary inoculation of breast cancer cells resulted in IGF-1 increase in femur and sciatic nerve, and IGF-1-dependent stimulus/non-stimulus-evoked pain-like behaviors. Adeno-associated virus-based shRNA selective silencing of IGF-1 receptor (IGF-1R) in Schwann cells, but not in dorsal root ganglion (DRG) neurons, attenuated pain-like behaviors. Intraplantar IGF-1 evoked acute nociception and mechanical/cold allodynia, which were reduced by selective IGF-1R silencing in DRG neurons and Schwann cells, respectively. Schwann cell IGF-1R signaling promoted an endothelial nitric oxide synthase-mediated transient receptor potential ankyrin 1 (TRPA1) activation and release of reactive oxygen species that, via macrophage-colony stimulating factor-dependent endoneurial macrophage expansion, sustained pain-like behaviors. Osteoclast derived IGF-1 initiates a Schwann cell-dependent neuroinflammatory response that sustains a proalgesic pathway that provides new options for MBCP treatment., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: FDL, PG, and RN are the founding scientists of FloNext Srl. PG has been in advisory boards and/or received fees for lectures from Novartis, Amgen, TEVA, AbbVie, Eli-Lilly, Lundbeck. The other authors have no conflicts of interest to declare., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Purpose: The pro-algesic transient receptor potential ankyrin 1 (TRPA1) channel, expressed by a subpopulation of primary sensory neurons, has been implicated in various pain models in mice. However, evidence in rats indicates that TRPA1 conveys nociceptive signals elicited by channel activators, but not those associated with tissue inflammation or nerve injury. Here, in rats, we explored the TRPA1 role in mechanical allodynia associated with stimulation of peptidergic primary sensory neurons (neurogenic inflammation) and moderate (partial sciatic nerve ligation, pSNL) or severe (chronic constriction injury, CCI) sciatic nerve injury., Experimental Approach: Acute nociception and mechanical hypersensitivity associated with neurogenic inflammation and sciatic nerve injury (pSNL and CCI) were investigated in rats with TRPA1 pharmacological antagonism or genetic silencing. TRPA1 presence and function were analysed in cultured rat Schwann cells., Key Results: Hind paw mechanical allodynia (HPMA), but not acute nociception, evoked by local injection of capsaicin or allyl isothiocyanate, the TRP vanilloid 1 (TRPV1) or the TRPA1 activators was mediated by CGRP released from peripheral sensory nerve terminals. CGRP-evoked HPMA was sustained by a ROS-dependent TRPA1 activation, probably in Schwann cells. HPMA evoked by pSNL, but not that evoked by CCI, was mediated by ROS and TRPA1 without the involvement of CGRP., Conclusions and Implications: As found in mice, TRPA1 mediates mechanical allodynia associated with neurogenic inflammation and moderate nerve injury in rats. The channel contribution to mechanical hypersensitivity is a common feature in rodents and might be explored in humans., (© 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Ingestion of alcoholic beverages is a known trigger of migraine attacks. However, whether and how ethanol exerts its pro-migraine action remains poorly known. Ethanol stimulates the transient receptor potential vanilloid 1 (TRPV1) channel, and its dehydrogenized metabolite, acetaldehyde, is a known TRP ankyrin 1 (TRPA1) agonist., Methods: Periorbital mechanical allodynia following systemic ethanol and acetaldehyde was investigated in mice after TRPA1 and TRPV1 pharmacological antagonism and global genetic deletion. Mice with selective silencing of the receptor activated modifying protein 1 (RAMP1), a component of the calcitonin gene-related peptide (CGRP) receptor, in Schwann cells or TRPA1 in dorsal root ganglion (DRG) neurons or Schwann cells, were used after systemic ethanol and acetaldehyde., Results: We show in mice that intragastric ethanol administration evokes a sustained periorbital mechanical allodynia that is attenuated by systemic or local alcohol dehydrogenase inhibition, and TRPA1, but not TRPV1, global deletion, thus indicating the implication of acetaldehyde. Systemic (intraperitoneal) acetaldehyde administration also evokes periorbital mechanical allodynia. Importantly, periorbital mechanical allodynia by both ethanol and acetaldehyde is abrogated by pretreatment with the CGRP receptor antagonist, olcegepant, and a selective silencing of RAMP1 in Schwann cells. Periorbital mechanical allodynia by ethanol and acetaldehyde is also attenuated by cyclic AMP, protein kinase A, and nitric oxide inhibition and pretreatment with an antioxidant. Moreover, selective genetic silencing of TRPA1 in Schwann cells or DRG neurons attenuated periorbital mechanical allodynia by ethanol or acetaldehyde., Conclusions: Results suggest that, in mice, periorbital mechanical allodynia, a response that mimics cutaneous allodynia reported during migraine attacks, is elicited by ethanol via the systemic production of acetaldehyde that, by releasing CGRP, engages the CGRP receptor in Schwann cells. The ensuing cascade of intracellular events results in a Schwann cell TRPA1-dependent oxidative stress generation that eventually targets neuronal TRPA1 to signal allodynia from the periorbital area., (© 2023. The Author(s).)

Biomedical applications of molecules that are able to modulate β-adrenergic signaling have become increasingly attractive over the last decade, revealing that β-adrenergic receptors (β-ARs) are key targets for a plethora of therapeutic interventions, including cancer. Despite successes in β-AR drug discovery, identification of β-AR ligands that are useful as selective chemical tools in pharmacological studies of the three β-AR subtypes, or lead compounds for drug development is still a highly challenging task. This is mainly due to the intrinsic plasticity of β-ARs as G protein-coupled receptors in conjunction with the requirement for functional receptor subtype selectivity, tissue specificity and minimal off-target effects. With the aim to provide insight into structure-activity relationships for the three β-AR subtypes, we have synthesized and obtained the pharmacological profile of a series of structurally diverse compounds (named MC) that were designed based on the aryloxy-propanolamine scaffold of SR59230A. Comparative analysis of their predicted binding mode within the active and inactive states of the receptors in combination with their pharmacological profile revealed key structural elements that control their activity as agonists or antagonists, in addition to clues about substituents that mediate selectivity for one receptor subtype over the others. We anticipate that these results will facilitate selective β-AR drug development efforts., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Growing evidence indicates that transient receptor potential (TRP) channels contribute to different forms of pruritus. However, the endogenous mediators that cause itch through transient receptor potential channels signaling are poorly understood. In this study, we show that genetic deletion or pharmacological antagonism of TRPV4 attenuated itch in a mouse model of psoriasis induced by topical application of imiquimod. Human psoriatic lesions showed increased expression of several microRNAs, including the miR-203b-3p, which induced a calcium ion response in rodent dorsal root ganglion neurons and scratching behavior in mice through 5-HTR2B activation and the protein kinase C‒dependent phosphorylation of TRPV4. Computer simulation revealed that the miR-203b-3p core sequence (GUUAAGAA) that causes 5-HTR2B/TRPV4-dependent itch targets the extracellular side of 5-HTR2B by interacting with a portion of the receptor pocket consistent with its activation. Overall, we reveal the unconventional pathophysiological role of an extracellular microRNA that can behave as an itch promoter through 5-HTR2B and TRPV4., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To explore the linear association between inner retinal layers thickness and macular capillary density compared to variations of global cognition evaluated by psychometric measures in a cohort of Mediterranean subjects aged 65+ years., Materials and Methods: We performed a cross-sectional analysis of 574 participants aged 65 years+ drawn from a population-based Southern Italian study. All subjects underwent neurological evaluations, including global cognitive screening, the Mini-Mental State Examination (MMSE) and frontal assessment battery (FAB), together with an ophthalmic examination including optical coherence tomography (OCT) and OCT-Angiography. We assessed the average thickness of the ganglion cell complex (GCC) and the retinal nerve fiber layer (RNFL), the foveal avascular zone area, and vascular density (VD) of superficial (SVD) and deep (DVD) capillary plexi at the foveal and parafoveal area. Linear regression was applied to assess associations of ocular measurements with MMSE and FAB scores., Results: In the linear regression model, foveal DVD (beta = 0.01, 95% CI:0.004-0.052), whole DVD (beta = 0.04, 95% CI:0.02-0.08), and whole SVD (beta = 0.04, 95% CI:0.02-0.07) showed a positive association with MMSE. In addition, foveal SVD (beta = 0.01, 95% CI:0.003-0.05) and whole SVD (beta = 0.03, 95% CI:0.004-0.08) were positively associated with the FAB score. We found no further significant association between the MMSE score or the FAB score and the average thickness of the GCC and RNFL, and FAZ area., Conclusion: A direct linear association between the VD of the macular capillary plexi with global and frontal cognitive functions was observed in elderly subjects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Giuliani, Sborgia, Niro, Castellana, Lampignano, Puzo, Pascale, Pastore, Buonamassa, Galati, Bordinone, Cassano, Clemente, Landini, Scotti, Gaudiomonte, Guglielmi, Semeraro, Santoro, Alessio, Sardone and Boscia.)

Purpose: To evaluate the short- (within 90 min) and long-term (after 21 days of treatment) effects of an artificial tear containing carbomer, hyaluronic acid, glycerol, and medium-chain triglycerides in patients with mild-to-moderate dry eye symptoms., Methods: Subjects received the tested artificial tears in the right eye and control artificial tears in the left eye and were assessed 10, 30, 60, and 90 min after instillation in the short-term study phase. They received the study product in both eyes in the long-term phase. Non-invasive break-up time (NIBUT), tear lipid layer pattern, tear evaporation, and tear film objective optical dynamics (TFOOD) were measured in controlled environmental conditions., Results: In total, 32 patients (10 males, mean age 42 ± 11 years) were enrolled. During the short-term phase, NIBUT increased significantly in the right eyes at all time points compared with baseline (all p  < 0.05). Conversely, in the left eyes, NIBUT increased significantly at 10 and 30 min ( p  < 0.05). The tear evaporation values increased at 10 min and decreased at 30 and 60 min ( p  < 0.05) in the right eyes, while they increased only at 10 min ( p  < 0.05) in the left eyes. Compared with baseline, the TFOOD was significantly more stable at all time points in the right eyes ( p  < 0.05), while it was more stable at 10 and 30 min in the left eyes ( p  < 0.05). In the long-term phase, treated eyes showed a significant increase in NIBUT values, a significant reduction of tear evaporation, a significant improvement of tear lipid layer pattern, and a more stable TFOOD compared with baseline (all p  < 0.05). Symptoms, measured with the Ocular Surface Disease Index questionnaire, were also significantly reduced compared with baseline ( p  < 0.05)., Conclusion: The tested product increased tear film stability and reduced tear evaporation, normalizing lipid layer pattern and reducing symptoms in the short- and long-term observation.

Objective: To evaluate the feasibility of kinetic modeling-based approaches from [18F]-Flobetaben dynamic PET images as a non-invasive diagnostic method for cardiac amyloidosis (CA) and to identify the two AL- and ATTR-subtypes., Methods and Results: Twenty-one patients with diagnoses of CA (11 patients with AL-subtype and 10 patients with ATTR-subtype of CA) and 15 Control patients with no-CA conditions underwent PET/CT imaging after [18F]Florbetaben bolus injection. A two-tissue-compartment (2TC) kinetic model was fitted to time-activity curves (TAC) obtained from left ventricle wall and left atrium cavity ROIs to estimate kinetic micro- and macro-parameters. Combinations of kinetic parameters were evaluated with the purpose of distinguishing Control subjects and CA patients, and to correctly label the last ones as AL- or ATTR-subtype. Resulting sensitivity, specificity, and accuracy for Control subjects were: 0.87, 0.9, 0.89; as far as CA patients, the sensitivity, specificity, and accuracy were respectively 0.9, 1, and 0.97 for AL-CA patients and 0.9, 0.92, 0.97 for ATTR-CA patients., Conclusion: Pharmacokinetic analysis based on a 2TC model allows cardiac amyloidosis characterization from dynamic [18F]Florbetaben PET images. Estimated model parameters allows to not only distinguish between Control subjects and patients, but also between AL- and ATTR-amyloid patients., (© 2021. American Society of Nuclear Cardiology.)

Abstract: Primary headache conditions are frequently associated with multiple sclerosis (MS), but the mechanism that triggers or worsens headaches in patients with MS is poorly understood. We previously showed that the proalgesic transient receptor potential ankyrin 1 (TRPA1) mediates hind paw mechanical and cold allodynia in a relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE) model in mice. Here, we investigated the development of periorbital mechanical allodynia (PMA) in RR-EAE, a hallmark of headache, and if TRPA1 contributed to this response. RR-EAE induction by injection of the myelin oligodendrocyte peptide fragment35-55 (MOG35-55) and Quillaja A adjuvant (Quil A) in C57BL/6J female mice elicited a delayed and sustained PMA. The PMA at day 35 after induction was reduced by the calcitonin gene-related peptide receptor antagonist (olcegepant) and the serotonin 5-HT1B/D receptor agonist (sumatriptan), 2 known antimigraine agents. Genetic deletion or pharmacological blockade of TRPA1 attenuated PMA associated with RR-EAE. The levels of oxidative stress biomarkers (4-hydroxynonenal and hydrogen peroxide, known TRPA1 endogenous agonists) and superoxide dismutase and NADPH oxidase activities were increased in the trigeminal ganglion of RR-EAE mice. Besides, the treatment with antioxidants (apocynin or α-lipoic acid) attenuated PMA. Thus, the results of this study indicate that TRPA1, presumably activated by endogenous agonists, evokes PMA in a mouse model of relapsing-remitting MS., (Copyright © 2021 International Association for the Study of Pain.)

Aim: To identify clinical criteria that are easily achievable with follow-up tests and can identify subjects not suitable for driving., Patients and Methods: We recruited 194 subjects with a clear diagnosis of glaucoma, with no other conditions that could affect the visual field (VF), and who performed a reliable VF examination. All patients underwent a full ophthalmologic evaluation and a questionnaire considering driving habits. An integrated visual field (IVF) was built using both monocular VF charts; the number of missed points (NoMP) within the central 20°, the average sensitivity (AS), and the better eye mean deviation (BEMD) were evaluated., Results: A total of 128 subjects showed a valid driving license (DL); 61.7% of drivers did not show missed points within the central 20° of the IVF, 27.4% presented one to three missed points, and 10.9% had four or more missed points. Best corrected visual acuity (BCVA) was highly above the legal criteria.Stratifying drivers by their BEMD (-7, -10, and -14 dB), we confirmed that the BEMD decrease corresponds to an increased NoMP and a decreased AS., Conclusion: Better eye mean deviation can be useful in clinical practice to identify patients at increased risk of being unsuitable for driving. Nevertheless, it is important to set specific cut-offs based on on-road driving performance. IVF evaluation may also be implemented in perimeter analysis software so that the composition of IVF, the BEMD, and the AS could directly describe the patient's binocular VF, excluding recourse to the Esterman visual field test (EVFT)., Clinical Significance: This new methodology will allow every physician-not just ophthalmologists-even if not an expert in evaluating a VF test, in assessing the ability to drive of glaucomatous patients., How to Cite This Article: Landini L, Donati S, Digiuni M, et al. Glaucoma and Driving License: How to Identify Patients at Risk of Revocation. J Curr Glaucoma Pract 2022;16(2):117-123., Competing Interests: Source of support: This study was conducted with university funds for clinical and experimental research. Conflict of interest: None, (Copyright © 2022; The Author(s).)

The transient receptor potential ankyrin 1 (TRPA1), a member of the TRP superfamily of channels, is primarily localized in a subpopulation of primary sensory neurons of the trigeminal, vagal, and dorsal root ganglia, where its activation mediates neurogenic inflammatory responses. TRPA1 expression in resident tissue cells, inflammatory, and immune cells, through the indirect modulation of a large series of intracellular pathways, orchestrates a range of cellular processes, such as cytokine production, cell differentiation, and cytotoxicity. Therefore, the TRPA1 pathway has been proposed as a protective mechanism to detect and respond to harmful agents in various pathological conditions, including several inflammatory diseases. Specific attention has been paid to TRPA1 contribution to the transition of inflammation and immune responses from an early defensive response to a chronic pathological condition. In this view, TRPA1 antagonists may be regarded as beneficial tools for the treatment of inflammatory conditions.

The purpose of this study is to analyze exposure to the time-varying magnetic field caused by worker movements in a 3-T clinical magnetic resonance imaging (MRI) scanner. Measurements of the static magnetic field ( B ) in the proximity of the MRI scanner were performed to create a detailed map of the spatial gradient of B , in order to indicate the areas at high risk of exposure. Moreover, a personal exposure recording system was used in order to analyze and compare exposure to the static magnetic field during different routine procedures in MRI. We found that for all of the performed work activities, exposure was compliant with International Commission on Non-Ionizing Radiation Protection levels. However, our findings confirm that there is great variability of exposure between different workers and suggest the importance of performing personal exposure measurements and of detailed knowledge of the magnetic field spatial distribution.

Efficacy of monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor (calcitonin receptor-like receptor/receptor activity modifying protein-1, CLR/RAMP1) implicates peripherally-released CGRP in migraine pain. However, the site and mechanism of CGRP-evoked peripheral pain remain unclear. By cell-selective RAMP1 gene deletion, we reveal that CGRP released from mouse cutaneous trigeminal fibers targets CLR/RAMP1 on surrounding Schwann cells to evoke periorbital mechanical allodynia. CLR/RAMP1 activation in human and mouse Schwann cells generates long-lasting signals from endosomes that evoke cAMP-dependent formation of NO. NO, by gating Schwann cell transient receptor potential ankyrin 1 (TRPA1), releases ROS, which in a feed-forward manner sustain allodynia via nociceptor TRPA1. When encapsulated into nanoparticles that release cargo in acidified endosomes, a CLR/RAMP1 antagonist provides superior inhibition of CGRP signaling and allodynia in mice. Our data suggest that the CGRP-mediated neuronal/Schwann cell pathway mediates allodynia associated with neurogenic inflammation, contributing to the algesic action of CGRP in mice., (© 2022. The Author(s).)

Magnetic resonance imaging (MRI) is one of the most-used diagnostic imaging methods worldwide. There are ∼50,000 MRI scanners worldwide each of which involves a minimum of five workers from different disciplines who spend their working days around MRI scanners. This review analyzes the state of the art of literature about the several aspects of the occupational exposure to electromagnetic fields (EMF) in MRI: regulations, literature studies on biological effects, and health surveillance are addressed here in detail, along with a summary of the main approaches for exposure assessment. The original research papers published from 2013 to 2021 in international peer-reviewed journals, in the English language, are analyzed, together with documents published by legislative bodies. The key points for each topic are identified and described together with useful tips for precise safeguarding of MRI operators, in terms of exposure assessment, studies on biological effects, and health surveillance., (© 2021. International Federation for Medical and Biological Engineering.)

Objective: To determine one or more indexes able to detect the presence of cardiac amyloidosis (CA) from planar scintigraphy images after injection of 99mTc-HMDP tracer and to identify the earliest acquisition time able to ensure an accurate diagnosis of amyloid transthyretin CA., Methods and Results: A total of 38 patients were included: 18 subjects with a final diagnosis of ATTR-CA and 20 controls. Dynamic planar images of the anterior thorax were acquired, starting at intravenous injection of ≈ 700 MBq of 99mTc-HMDP. From time/activity curves (TAC) of regions of interest such as heart, vascular region, right ribcage, and soft tissues, several indices were considered. From the analysis, it resulted that both TAC Heart/Bone (t) and RI heart-bone (t), for t > 6 minutes, well distinguish ATTR-CA patients from controls subjects. This is confirmed by the area under curves (AUC) analysis giving AUC values =.9 at t ≅ 6 minutes and AUC ≅ 1 for t > 10 minutes., Conclusions: The method proposed allows determining the presence of ATTR-CA, in an inexpensive manner both in terms of examination costs and time spent., (© 2020. American Society of Nuclear Cardiology.)

The bioimaging of cancer cells by the specific targeting of overexpressed biomarkers is an approach that holds great promise in the identification of selective diagnostic tools. Tumor-associated human carbonic anhydrase (hCA) isoforms IX and XII have been considered so far as well-defined biomarkers, with their expression correlating with cancer progression and aggressiveness. Therefore, the availability of highly performant fluorescent tools tailored for their targeting and able to efficiently visualize such key targets is in high demand. We report here on the design and synthesis of a kind of quantum dot (QD)-based fluorescent glyconanoprobe coated with a binary mixture of ligands, which, according to the structure of the terminal domains, impart specific property sets to the fluorescent probe. Specifically, monosaccharide residues ensured the dispersibility in the biological medium, CA inhibitor residues provided specific targeting of membrane-anchored hCA IX overexpressed on bladder cancer cells, and the quantum dots imparted the optical/fluorescence properties., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Macrophages (MΦs) and reactive oxygen species (ROS) are implicated in carcinogenesis. The oxidative stress sensor, transient receptor potential ankyrin 1 (TRPA1), activated by ROS, appears to contribute to lung and breast cancer progression. Although TRPA1 expression has been reported in melanoma cell lines, and oxidative stress has been associated with melanocytic transformation, their role in melanoma remains poorly known. Here, we localized MΦs, the final end-product of oxidative stress, 4-hydroxynonenal (4-HNE), and TRPA1 in tissue samples of human common dermal melanocytic nevi, dysplastic nevi, and thin (pT1) and thick (pT4) cutaneous melanomas. The number (amount) of intratumoral and peritumoral M2 MΦs and 4-HNE staining progressively increased with tumor severity, while TRPA1 expression was similar in all samples. Hydrogen peroxide (H 2 O 2 ) evoked a TRPA1-dependent calcium response in two distinct melanoma cell lines (SK-MEL-28 and WM266-4). Furthermore, H 2 O 2 induced a TRPA1-dependent H 2 O 2 release that was prevented by the TRPA1 antagonist, A967079, or Trpa1 gene silencing (siRNA). ROS release from infiltrating M2 MΦs may target TRPA1-expressing melanoma cells to amplify the oxidative stress signal that affects tumor cell survival and proliferation.

Sarcopenia is a progressive clinical syndrome characterized by general loss of skeletal muscle mass and impaired muscle function. Due to the general progressive aging of population, sarcopenia has gradually grown into a global health problem, with great negative impact on the quality of life of the affected patients as well as an adverse societal impact. In this review, we discuss the pathophysiology, diagnosis, and determination of severity of sarcopenia. Special attention is given to the rehabilitative treatment against sarcopenia, pointing out that a thorough evaluation and intervention of nutritional deficits and exercise capacity as well as treatment with medical agents are needed in order to personalize the treatment according to the patient's needs. By targeting goals to improve musculoskeletal and functional disorders associated with chronic conditions, clinicians could apply a therapeutic plan focusing on how to prevent/delay the development of sarcopenia and improve the quality of the patients' lives.

Headaches are frequently described in progressive multiple sclerosis (PMS) patients, but their mechanism remains unknown. Transient receptor potential ankyrin 1 (TRPA1) was involved in neuropathic nociception in a model of PMS induced by experimental autoimmune encephalomyelitis (PMS-EAE), and TRPA1 activation causes periorbital and facial nociception. Thus, our purpose was to observe the development of periorbital mechanical allodynia (PMA) in a PMS-EAE model and evaluate the role of TRPA1 in periorbital nociception. Female PMS-EAE mice elicited PMA from day 7 to 14 days after induction. The antimigraine agents olcegepant and sumatriptan were able to reduce PMA. The PMA was diminished by the TRPA1 antagonists HC-030031, A-967079, metamizole and propyphenazone and was absent in TRPA1-deficient mice. Enhanced levels of TRPA1 endogenous agonists and NADPH oxidase activity were detected in the trigeminal ganglion of PMS-EAE mice. The administration of the anti-oxidants apocynin (an NADPH oxidase inhibitor) or alpha-lipoic acid (a sequestrant of reactive oxygen species), resulted in PMA reduction. These results suggest that generation of TRPA1 endogenous agonists in the PMS-EAE mouse model may sensitise TRPA1 in trigeminal nociceptors to elicit PMA. Thus, this ion channel could be a potential therapeutic target for the treatment of headache in PMS patients.

The objective of the present work was to evaluate the potential of deep learning tools for characterizing the presence of cardiac amyloidosis from early acquired PET images, i.e. 15 min after [18F]-Florbetaben tracer injection. 47 subjects were included in the study: 13 patients with transthyretin-related amyloidosis cardiac amyloidosis (ATTR-CA), 15 patients with immunoglobulin light-chain amyloidosis (AL-CA), and 19 control-patients (CTRL). [18F]-Florbetaben PET/CT images were acquired in list mode and data was sorted into a sinogram, covering a time interval of 5 min starting 15 min after the injection. The resulting sinogram was reconstructed using OSEM iterative algorithm. A deep convolutional neural network (CAclassNet) was designed and implemented, consisting of five 2D convolutional layers, three fully connected layers and a final classifier returning AL, ATTR and CTRL scores. A total of 1107 2D images (375 from AL-subtype patients, 312 from ATTR-subtype, and 420 from Controls) have been considered in the study and used to train, validate and test the proposed network. CAclassNet cross-validation resulted with train error mean ± sd of 2.001% ± 0.96%, validation error of 4.5% ± 2.26%, and net accuracy of 95.49% ± 2.26%. Network test error resulted in a mean ± sd values of 10.73% ± 0.76%. Sensitivity, specificity, and accuracy evaluated on the test dataset were respectively for AL-CA sub-type: 1, 0.912, 0.936; for ATTR-CA: 0.935, 0.897, 0.972; for control subjects: 0.809, 0.971, 0.909. In conclusion, the proposed CAclassNet model seems very promising as an aid for the clinician in the diagnosis of CA from cardiac [18F]-Florbetaben PET images acquired a few minutes after the injection., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V. part of Springer Nature.)

Although macrophages (MΦ) are known to play a central role in neuropathic pain, their contribution to cancer pain has not been established. Here we report that depletion of sciatic nerve resident MΦs (rMΦ) in mice attenuates mechanical/cold hypersensitivity and spontaneous pain evoked by intraplantar injection of melanoma or lung carcinoma cells. MΦ-colony stimulating factor (M-CSF) was upregulated in the sciatic nerve trunk and mediated cancer-evoked pain via rMΦ expansion, transient receptor potential ankyrin 1 (TRPA1) activation, and oxidative stress. Targeted deletion of Trpa1 revealed a key role for Schwann cell TRPA1 in sciatic nerve rMΦ expansion and pain-like behaviors. Depletion of rMΦs in a medial portion of the sciatic nerve prevented pain-like behaviors. Collectively, we identified a feed-forward pathway involving M-CSF, rMΦ, oxidative stress, and Schwann cell TRPA1 that operates throughout the nerve trunk to signal cancer-evoked pain. SIGNIFICANCE: Schwann cell TRPA1 sustains cancer pain through release of M-CSF and oxidative stress, which promote the expansion and the proalgesic actions of intraneural macrophages. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/12/3387/F1.large.jpg., (©2021 American Association for Cancer Research.)

Objective: This preliminary study aims at investigating the neural correlates of the stress response, intended as an emotional and cognitive response, through the description of the activation of the autonomic nervous system in a problem-solving task and central functional data; in particular, we recorded skin conductance level (SCL) and response (SCR) and observed the correlation with fMRI data., Materials and Methods: The results obtained from 6 healthy subjects, 3 males and 3 females, aged between 18 and 45 (average = 27, SD = 7.08) who voluntarily offered to participate in the study were examined. They were previously subjected to a brief clinical psychological assessment (MMPI-2) and then to a psychophysiological evaluation. The real experiment consisted in subjecting the participants to an adapted version of the Raven's Coloured Progressive Matrices 47 (CPM 47) test to evaluate some consequences on brain activity of attention, orientation, reflex and response to stress during fMRI data acquisition and SCL-SCR recording., Results: SCR changes were found to be related to the activity of different brain regions such as bilateral precentral gyrus, right inferior frontal gyrus, right medial frontal gyrus, bilateral superior frontal gyri and left anterior cingulate suggesting a specific relationship between attentive processing and autonomic arousal., Conclusion: The association of SC measurement with neuroimaging allows to highlight the interaction between emotional and cognitive processes: although preliminary, these results partially confirm what previously found in literature on the neural correlates of psychological stress and underline the interaction between cognitive function and autonomic arousal system during a stressful problem-solving task.

Lysosomal storage disorders (LSDs) are a group of clinically heterogeneous disorders affecting the function of lysosomes and are characterized by an accumulation of undigested substrates within several cell types. In recent years there have been substantial advances in supportive care and drug treatment for some LSDs, leading to improved patient survival, as seen in Gaucher, Pompe and Fabry disease and some Mucopolysaccharidoses; however, many symptoms still persist. Thus it is now even more important to improve patients' quality of life and reduce symptoms and comorbidities. One potential way of achieving this goal is through adjunct nutritional therapy, which is challenging as patients may be overweight with associated consequences, or malnourished, or underweight. Furthermore, drugs used to treat LSDs can modify the metabolic status and needs of patients. There are currently not enough data to make specific dietary recommendations for individual LSDs; however, suggestions can be made for managing clinical manifestations of the diseases, as well as treatment-associated adverse events. The metabolic and nutritional status of adult patients must be regularly assessed and individualized dietary plans may be created to cater to a patient's specific needs. Damage to the autophagic process is a common feature in LSDs that is potentially sensitive to dietary manipulation and needs to be assessed in clinical studies., Competing Interests: Declaration of competing interest Francesca Carubbi received honoraria for lectures, advisory board and meetings from Amgen, Sanofi, Shire and Amicus. Francesco Francini-Pesenti received honoraria for advisory boards and meetings from Sanofi. Elena Pegoraro has been a scientific advisory board or data safety monitoring board for PTC Therapeutics, Sarepta Therapeutics, Santhera Pharmaceuticals, Genzyme and Roche, received funding for travel and educational support from Genzyme and PTC Pharmaceuticals, received funding for travel support from Santhera and is receiving grant support from Santhera. Antonio Barbato received honoraria for lectures, advisory boards and meetings from Sanofi Genzyme and Takeda Shire. Renzo Mignani received honoraria for lectures, advisory boards and meetings from Sanofi-Genzyme, TakedaShire, Otsuka Pharmaceutical, and AmicusTherapeutics. Alberto B Burlina has received a speaker honoraria and travel support from Sanofi Genzyme, Actelion, Takeda, Nutricia, Danone, PIAM Medifood, Biomarin. Linda Landini has been an employee of Sanofi Genzyme. Gianluca De Danieli is an employee of Sanofi Genzyme. Stefano Bruni has been an employee of Sanofi Genzyme. Pasquale Strazzullo received honoraria and travel support as speaker and/or advisory board from Sanofi Genzyme and Takeda Shire., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)