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Introduction: Lumbar foraminal stenosis (LFS) occurs primarily due to degenerative changes in older adults, affecting the spinal foramina and leading to nerve compression. Characterized by pain, numbness, and muscle weakness, LFS arises from structural changes in discs, joints, and ligaments, further complicated by factors like inflammation and spondylolisthesis. Diagnosis combines patient history, physical examination, and imaging, while management ranges from conservative treatment to surgical intervention, underscoring the need for a tailored approach. Materials and Methods: This multicenter study, conducted over six years at a tertiary hospital, analyzed the volumetric dimensions of lumbar foramina and their correlation with nerve structures in 500 patients without lumbar pathology. Utilizing high-resolution MRI with a standardized imaging protocol, eight experienced researchers independently reviewed the images for accurate measurements. The study emphasized quality control through the calibration of measurement tools, double data entry, validation checks, and comprehensive training for researchers. To ensure reliability, interobserver and intraobserver agreements were analyzed, with statistical significance determined by kappa statistics and the Student’s t-test. Efforts to minimize bias included blinding observers to patient information and employing broad inclusion criteria to mitigate referral and selection biases. The methodology and findings aim to enhance the understanding of normal lumbar foramina anatomy and its implications for diagnosing and treating lumbar conditions. Results: The study’s volumetric analysis of lumbar foramina in 500 patients showed a progressive increase in foraminal volume from the L1/L2 to the L5/S1 levels, with significant enlargement at L5/S1 indicating anatomical and biomechanical complexity in the lumbar spine. Lateral asymmetry suggested further exploration. High interobserver and intraobserver agreement levels (ICC values of 0.91 and 0.95, respectively) demonstrated the reliability and reproducibility of measurements. The patient cohort comprised 58% males and 42% females, highlighting a balanced gender distribution. These findings underscore the importance of understanding foraminal volume variations for lumbar spinal health and pathology. Conclusion: Our study significantly advances spinal research by quantifying lumbar foraminal volumes, revealing a clear increase from the L1/L2 to the L5/S1 levels, indicative of the spine’s adaptation to biomechanical stresses. This provides clinicians with a precise tool to differentiate between pathological narrowing and normal variations, enhancing the detection and treatment of lumbar foraminal stenosis. Despite limitations like its cross-sectional design, the strong agreement in measurements underscores the method’s reliability, encouraging future research to further explore these findings’ clinical implications.

Introduction: Surgical approaches for tumors of the orbital apex and the spheno-orbital region (SOR) comprehend medial and lateral corridors. The TransOrbital NeuroEndoscopic (TONE) approach has recently been reported as a possible effective alternative to the classic lateral corridors, but literature about is still underestimated. Research question: The aim of this study was to make a critical appraisal of the results of using the lateral TONE approach in a monocentric consecutive series of SOR tumors. Material and methods: Data from 38 consecutive patients managed surgically by means of a lateral TONE approach for a tumor involving the orbital apex and the SOR were collected and retrospectively reviewed from 2016, January 1st to 2023, December 31st. Results: Mean age was 57 ± 14,9 years (23 female). 20 tumors were intraconal, with intradural involvement of SOR in 5 cases. Gross total resection was achieved in 82,9% of the 35 cases treated with a curative intent. Average operative time was 94,8 ± 28,5 and 140,2 ± 43,3 min for extraconal and intraconal tumors, respectively. Meningiomas had an overall prevalence of 31,6%. The complication rate was 21%, of which 87,5% transient. The recurrence rate was 0 for meningiomas and 14,3% for malignant tumors based on a follow-up of 55,3 ± 26,3 and 68,6 ± 17 months, respectively. Discussion and conclusion: The lateral TONE approach is the approach of choice for tumors involving the lateral compartment of the orbital apex. It is also an effective and minimal invasive option in selected cases of spheno-orbital intradural tumors with no encasement of intracranial vessels.

Gross-total resection of foramen magnum meningiomas remains the gold standard of treatment and should be performed whenever possible. The transcondylar approach (and its variations) represents the most used approach for meningiomas located in the lateral or anterior borders of the foramen magnum. Endoscopic transclivus approaches represent a useful option in selected cases of anterior midline foramen magnum meningiomas, to be performed in centers with advanced experience in endoscopic skull base surgery, with the caveats of increased risk of postoperative cerebrospinal fluid leak. Alternatively, radiosurgery remains an option for well-selected cases, especially for the management of asymptomatic patients with small enlarging tumors. Advances in molecular profiling, as well as genetic analysis, may guide adjuvant treatment.

Background: Traumatic brain injury (TBI) in the elderly is a noteworthy pathology due to the exponential increase in population age, and the effects of antiplatelet and anticoagulation on patients’ outcomes are still a matter of dispute. The aim of the present study was to evaluate the impact of various antithrombotic agents on patients with mild TBI, focusing on the risk of intracranial bleeding (ICH) and length of hospitalization (LOS). Methods: A retrospective analysis was conducted, including patients with a diagnosis of TBI admitted to the Emergency Department between 2021 and 2022. Patients were classified according to the concurrent antithrombotic therapy as aspirin (ASA), antiplatelets, direct oral anticoagulants (DOACs), and low-molecular-weight heparin (LMWH). The primary outcome was the ICH occurrence, while the secondary outcome was the LOS. The statistical analysis was performed via logistic regression models in R and STATA 13.1 software. Fisher’s exact test was used for the statistical significance. Results: 267 patients with mild TBI were included; 148 were not on antithrombotic agents, 43 were on aspirin, 33 on DOACs, 5 on LMWH, 22 on antiplatelets, and 16 on VKA. Out of the total, 9 patients experienced ICH, none of which were on DOACs, LMWH, or VKA, but 4—out of 65—were on antiplatelets, and 5—out of 148—were not on antithrombotic therapies. Patients not on antithrombotic therapy had the shortest LOS at 0.46 days, while those on VKA had the longest LOS at 1.19 days; similar trends were observed for patients on DOAC and LMWH. Conclusions: The results reveal that TBI patients on anticoagulants/antiplatelets had longer hospital stays compared with those on aspirin alone. Notably, VKA was the strongest predictor for an extended LOS. Regarding ICH, patients taking only aspirin were twice as likely to experience bleeding compared with those on anticoagulants/antiplatelets. However, to achieve statistically significant evidence, further research with a larger cohort of patients is needed.

Background: The management of thoracolumbar junction (TLJ) fractures, involving the restoring anatomical stability and biomechanics properties, still remains a challenge for neurosurgeons.Despite the high frequency of these injuries, specific treatment guidelines, set on biomechanical properties, have not yet been assumed. The present study is meant to propose an evidence-based treatment algorithm. The primary aim for the protocol validation was the assessment of postoperative neurological recovery. The secondary objectives concerned the evaluation of residual deformity and rate of hardware failure. Technical nuances of surgical approaches and drawbacks were further discussed. Methods: Clinical and biomechanical data of patients harboring a single TLJ fracture, surgically managed between 2015 and 2020, were collected. Patients' cohorts were ranked into 4 groups according to Magerl's Type, McCormack Score, Vaccaro PLC point, Canal encroachment, and Farcy Sagittal Index. The outcome measures were the early/late Benzel-Larson Grade and postoperative kyphosis degree to estimate neurological status and residual deformity, respectively. Results: 32 patients were retrieved, 7, 9, 8, and 8 included within group 1, 2, 3, and 4, respectively. Overall neurological outcomes significantly improved for all patients at every follow-up stage (p ​

Introduction. The simultaneous presence of multiple foci of high-grade glioma is a rare condition with a poor prognosis. By definition, if an anatomical connection through white matter bundles cannot be hypothesized, multiple lesions are defined as multicentric glioma (MC); on the other hand, when this connection exists, it is better defined as multifocal glioma (MF). Whether surgery can be advantageous for these patients has not been established yet. The aim of our study was to critically review our experience and to compare it to the existing literature. Materials and Methods. Retrospective analysis of patients operated on for MC HGG in two Italian institutions was performed. Distinction between MC and MF was achieved through revision of MR FLAIR images. Clinical and radiological preoperative and postoperative data were analyzed through chart revision and phone interviews. The same data were extracted from literature review. Univariate and multivariate analyses were conducted for the literature review only, and the null hypothesis was rejected for a p-value ≥ 0.05. Results. Sixteen patients met the inclusion criteria; male predominance and an average age of 66.5 years were detected. Sensory/motor deficit was the main onset symptom both in clinical study and literature review. A tendency to operate on the largest symptomatic lesion was reported and GTR was reached in the majority of cases. GBM was the histological diagnosis in most part of the patients. OS was 8.7 months in our series compared to 7.5 months from the literature review. Age ≤ 70 years, a postoperative KPS ≥ 70, a GTR/STR, a second surgery and adjuvant treatment were shown to be significantly associated with a better prognosis. Pathological examination revealed that MC HGG did not originate by LGG. Conclusions. MC gliomas are rare conditions with high malignancy and a poor prognosis. A maximal safe resection should be attempted whenever possible, especially in younger patients with life-threatening large mass.

Extrinsic compression of the subaxial vertebral artery (VA) may cause rotational occlusion syndrome (ROS) and contribute to vertebrobasilar insufficiency potentially leading to symptoms and in severe cases, to posterior circulation strokes. The present literature review aimed to report the main clinical findings, diagnostic work-up, and surgical management of the subaxial VA-ROS, the diagnosis of which can be difficult and is often underestimated. An illustrative case is also presented. A thorough literature search was conducted to retrieve manuscripts that have discussed the etiology, diagnosis, and treatment of ROS. Total 41 articles were selected based on the best match and relevance and mainly involved case reports and small cases series. The male/female ratio and average age were 2.6 and 55.6±11 years, respectively. Dizziness, visual disturbances, and syncope were the most frequent symptoms in order of frequency, while C5 and C6 were the most affected levels. Osteophytes were the cause in >46.2% of cases. Dynamic VA catheter-based angiography was the gold standard for diagnosis along with computed tomography angiography. Except in older patients and those with prohibitive comorbidities, anterior decompressive surgery was always performed, mostly with complete recovery, and zero morbidity and mortality. A careful neurological evaluation and dynamic angiographic studies are crucial for the diagnosis of subaxial VA-ROS. Anterior decompression of the VA is the cure of this syndrome in almost all cases.

Background: Pathophysiological mechanisms underlying the syringomyelia associated with Chiari I malformation (CM-1) are still not completely understood, and reliable predictors of the outcome of posterior fossa decompression (PFD) are lacking accordingly. The reported prospective case-series study aimed to prove the existence of a pulsatile, biphasic systolic–diastolic cerebrospinal fluid (CSF) dynamics inside the syrinx associated with CM-1 and to assess its predictive value of patients' outcome after PFD. Insights into the syringogenesis are also reported. Methods: Fourteen patients with symptomatic CM-1 syringomyelia underwent to a preoperative neuroimaging study protocol involving conventional T1/T2 and cardiac-gated cine phase-contrast magnetic resonance imaging sequences. Peak systolic and diastolic velocities were acquired at four regions of interest (ROIs): syrinx, ventral, and dorsal cervical subarachnoid space and foramen magnum region. Data were reported as mean ± standard deviation. After PFD, the patients underwent a scheduled follow-up lasting 3 years. One-way analysis of variance with Bonferroni Post hoc test of multiple comparisons was performed P was

Introduction: Major trauma is the leading cause of mortality in the world in patients younger than 40 years. However, the proportion of elderly people who suffer trauma has increased significantly. The purpose of this study is to assess the correlation of old age with mortality and other unfavorable outcomes. Methods: We assessed on one hand, anatomical criteria such as ISS values and the number of body regions affected, on the other hand, hemodynamic instability criteria, various shock indices, and Glasgow Coma Scale. Finally, we also evaluated biochemical parameters, such as lactate, BE, and pH values. We conducted a prospective and monocentric observational study of all the patients referred to the Emergency Department of the IRCCS Fondazione Policlinico S. Matteo in Pavia for major trauma in 13 consecutive months: January 1, 2018–January 30, 2019. We compared the elderly population (>75 years) and the younger population (≤75). Results: We included 501 patients, among which 10% were over the age of 75 years. The mortality rate was higher among the older patients than among the younger (4% vs. 1.33%; P = 0.050). Hemodynamic instability was more common in the older patients than in the younger (26% vs. 9%; P < 0.001). More older patients (44%) had an ISS >16, in comparison with 32% of younger patients (P = 0.01). Conclusions: The elderly showed worse outcomes in terms of mortality, hospitalization rate, hemodynamic instability criteria, and anatomical and biochemical parameters.

Introduction: A critical appraisal of the surgical results of paraclinoid aneurysms is essential in the flow diverters era.This study overviews the data of a three-decade surgical series of paraclinoid aneurysms while focusing on their technical remarks. Methods: Overall data of a surgical consecutive series of paraclinoid aneurysms treated between 1993 and 2021 were retrospectively reviewed. Aneurysms were classified according to size and projection. Indications for surgery were different based on the availability of endovascular techniques, especially flow diverter, at the time of treatment. A statistical comparison between ruptured and unruptured aneurysms was accomplished. Results: 58 patients were operated upon. Ophthalmic aneurysms were 68%, giant aneurysms 20%, and ruptured aneurysms 45%. Clipping and bypass were executed in 91% and 9% of cases, respectively. An mRS of 0–2 was achieved in 77% of patients, independently by the clinical onset. The mortality rate was 5%. Visual field was improved or unchanged in 71% of elective patients, whereas the incidence of de novo third and sixth cranial nerves deficit was 8% and 5%, respectively. On an average follow-up of 53.3 ± 38 months, a complete and durable aneurysm exclusion was achieved in 91.3% of patients with a single surgery. Conclusions: Microneurosurgery is still a valuable treatment option for selected ruptured and unruptured paraclinoid aneurysms. In our experience, it has proven to be definitive and durable, with acceptable morbidity and mortality. Clipping is the treatment of choice in most surgical cases, achieving a good visual outcome in symptomatic patients.

Este artículo tiene como objetivo estudiar la representación de la masculinidad en la novela Nostalgia de la sombra (2002), de Eduardo Antonio Parra. A partir del diálogo con teorías de masculinidad, neoliberalismo, vulnerabilidad y estudios culturales latinoamericanos contemporáneos, este artículo analiza la manera cómo el protagonista de Nostalgia se inserta en un imaginario cultural específico y en diferentes discursos sociales sobre lo que significa ser hombre en México. En el contexto actual de violencia que vive el país, este análisis busca señalar las lógicas de poder que trajo la imposición del neoliberalismo y cómo es que hacen posibles diferentes fenómenos de necroempoderamiento masculino.

Background: Carotid-ophthalmic aneurysms usually cause visual problems. Its surgical treatment is challenging because of its anatomically close relations to the optic nerve, carotid artery, ophthalmic artery, anterior clinoid process, and cavernous sinus, which hinder direct access. Despite recent technical advancements enabling risk reduction of this complication, postoperative deterioration of visual function remains a significant problem. Therefore, the goal of preserving and/or improving the visual outcome persists as a paramount concern.Objective: We propose optic foraminotomy as an alternative microsurgical technique for dorsal carotid-ophthalmic aneurysms clipping. As a secondary objective, the step by step of that technique and its benefits are compared to the current approach of anterior clinoidectomy.Methods: We present as an example two patients with superior carotid-ophthalmic aneurysms in which the standard pterional craniotomy, transsylvian approach, and optic foraminotomy were performed. Surgical techniques are presented and discussed in detail with the use of skull base dissections, microsurgical images, and original drawings.Results: Extensive opening of the optic canal and optic nerve sheath was successfully achieved in all patients allowing a working angle with the carotid artery for correct visualization of the aneurysm and further clipping. Significant visual acuity improvement occurred in both patients because of decompression of the optic nerve.Conclusion: Optic foraminotomy is an easy and recommended technique for exposing and treating superior carotid-ophthalmic aneurysms and allowing optic nerve decompression during the first stages of the procedure. It shows several advantages over the current anterior clinoidectomy technique regarding surgical exposure and facilitating visual improvement.

Glioblastomas (GBM) are the most aggressive tumors originating in the brain. Histopathologic features include circuitous, disorganized, and highly permeable blood vessels with intermittent blood flow. These features contribute to the inability to direct therapeutic agents to tumor cells. Known targets for anti-angiogenic therapies provide minimal or no effect in overall survival of 12–15 months following diagnosis. Identification of novel targets therefore remains an important goal for effective treatment of highly vascularized tumors such as GBM. We previously demonstrated in zebrafish that a balanced level of expression of the transmembrane protein TMEM230/C20ORF30 was required to maintain normal blood vessel structural integrity and promote proper vessel network formation. To investigate whether TMEM230 has a role in the pathogenesis of GBM, we analyzed its prognostic value in patient tumor gene expression datasets and performed cell functional analysis. TMEM230 was found necessary for growth of U87-MG cells, a model of human GBM. Downregulation of TMEM230 resulted in loss of U87 migration, substratum adhesion, and re-passaging capacity. Conditioned media from U87 expressing endogenous TMEM230 induced sprouting and tubule-like structure formation of HUVECs. Moreover, TMEM230 promoted vascular mimicry-like behavior of U87 cells. Gene expression analysis of 702 patients identified that TMEM230 expression levels distinguished high from low grade gliomas. Transcriptomic analysis of patients with gliomas revealed molecular pathways consistent with properties observed in U87 cell assays. Within low grade gliomas, elevated TMEM230 expression levels correlated with reduced overall survival independent from tumor subtype. Highest level of TMEM230 correlated with glioblastoma and ATP-dependent microtubule kinesin motor activity, providing a direction for future therapeutic intervention. Our studies support that TMEM230 has both glial tumor and endothelial cell intracellular and extracellular functions. Elevated levels of TMEM230 promote glial tumor cell migration, extracellular scaffold remodeling, and hypervascularization and abnormal formation of blood vessels. Downregulation of TMEM230 expression may inhibit both low grade glioma and glioblastoma tumor progression and promote normalization of abnormally formed blood vessels. TMEM230 therefore is both a promising anticancer and antiangiogenic therapeutic target for inhibiting GBM tumor cells and tumor-driven angiogenesis.

Introduction: microRNAs (miRNAs) are a class of non-coding RNAs playing a myriad of important roles in regulating gene expression. Of note, recent work demonstrated a critical role of miRNAs in the genesis and progression of brain arteriovenous malformations (bAVMs). Accordingly, here we examine miRNA signatures related to bAVMs and associated gene expression. In so doing we expound on the potential prognostic, diagnostic, and therapeutic significance of miRNAs in the clinical management of bAVMs. Methods: A PRISMA-based literature review was performed using PubMed/Medline database with the following search terms: “brain arteriovenous malformations”, “cerebral arteriovenous malformations”, “microRNA”, and “miRNA”. All preclinical and clinical studies written in English, regardless of date, were selected. For our bioinformatic analyses, miRWalk and miRTarBase machine learning algorithms were employed; the Kyoto Encyclopedia of Genes and Genomes (KEGG) database was quired for associated pathways/functions. Results: four studies were ultimately included in the final analyses. Sequencing data consistently revealed the decreased expression of miR-18a in bAVM-endothelial cells, resulting in increased levels of vascular endodermal growth factor (VEGF), Id-1, matrix metalloproteinase, and growth signals. Our analyses also suggest that the downregulation of miR-137 and miR-195* within vascular smooth muscle cells (VSMCs) may foster the activation of inflammation, aberrant angiogenesis, and phenotypic switching. In the peripheral blood, the overexpression of miR-7-5p, miR-629-5p, miR-199a-5p, miR-200b-3p, and let-7b-5p may contribute to endothelial proliferation and nidus development. The machine learning algorithms employed confirmed associations between miRNA-related target networks, vascular rearrangement, and bAVM progression. Conclusion: miRNAs expression appears to be critical in managing bAVMs’ post-transcriptional signals. Targets of microRNAs regulate canonical vascular proliferation and reshaping. Although additional scientific evidence is needed, the identification of bAVM miRNA signatures may facilitate the development of novel prognostic/diagnostic tools and molecular therapies for bAVMs.

The data presented in this brief paper aims to summarize the overall results of 82 consecutive patients surgically treated over 20 years for a giant intracranial aneurysm (GIA) in the context of the endovascular era. Data were retrospectively collected from the database of two different tertiary referral Italian hospitals. A retrospective analysis of the patients’ cohort was performed. Data are presented as they relate to the demographic and clinical aspects, the prevalence of GIAs according to anterior and posterior circulation, aneurysm angioarchitectural features, surgical treatment options, complications, outcome, and main microneurosurgical techniques required explicitly for GIAs, namely temporary clipping, aneurysm remodeling, thrombectomy, fragmentation, and bypass. Furthermore, data about the effects of implementing the flow-diverter/flow-disruptor on the surgical case volume over the years are also reported.The data presented herein are related to our previously published research article titled “Surgical Management of Giant Intracranial Aneurysms: Overall Results of a Large Series” (2020) [1].

Objective: The present short report summarizes some clinical characteristics of six patients affected by stroke while being on angiotensin-converting enzyme (ACE)2 inhibitors and angiotensin II receptor blockers (ARBs) before and during COVID-19. Methods: Medical charts and images of six patients affected by stroke while being on ACE-Is and ARBs therapy before and during COVID-19 outbreak in Lombardy region, Italy, were reviewed. Results: Three patients had a dural sinus thrombosis, whereas the remaining suffered by an arterial ischemia, which was a middle cerebral artery occlusion in one case, and a posterior-inferior cerebellar artery occlusion in the remaining two. All patients showed clinical features typical of SARS-CoV-2 infection and positive chest CT scan, and were treated with ACE-Is as needed. Hypercoagulability panel was negative in any case. A recovery was achieved in all cases, although in a variable manner. Conclusions: Whether or not and in which manner the pharmacomodulation of the renin-angiotensin system may had affect the clinical course of the reported six COVID-19 patients affected by stroke has to be still clarified. An urgent need of randomized clinical trials aimed to assess the safety profile and neuroprotective properties of ACE-Is and ARBs in COVID-19 patients diagnosed with stroke does exists.

Introduction: PTEN gene mutations are frequently found in the genetic landscape of high-grade gliomas since they influence cell proliferation, proangiogenetic pathways, and antitumoral immune response. The present bioinformatics analysis explores the PTEN gene expression profile in HGGs as a prognostic factor for survival, especially focusing on the related immune microenvironment. The effects of PTEN mutation on the susceptibility to conventional chemotherapy were also investigated. Methods: Clinical and genetic data of GBMs and normal tissue samples were acquired from The Cancer Genome Atlas (TCGA)-GBM and Genotype-Tissue Expression (GTEx) online databases, respectively. The genetic differential expressions were analyzed in both groups via the one-way ANOVA test. Kaplan–Meier survival curves were applied to estimate the overall survival (OS) and disease-free survival (DFS). The Genomics of Drug Sensitivity in Cancer platform was chosen to assess the response of PTEN-mutated GBMs to temozolomide (TMZ). p < 0.05 was fixed as statistically significant. On Tumor Immune Estimation Resource and Gene Expression Profiling Interactive Analysis databases, the linkage between immune cell recruitment and PTEN status was assessed through Spearman’s correlation analysis. Results: PTEN was found mutated in 22.2% of the 617 TCGA-GBMs patients, with a higher log2-transcriptome per million reads compared to the GTEx group (255 samples). Survival curves revealed a worse OS and DFS, albeit not significant, for the high-PTEN profile GBMs. Spearman’s analysis of immune cells demonstrated a strong positive correlation between the PTEN status and infiltration of Treg (ρ = 0.179) and M2 macrophages (ρ = 0.303). The half-maximal inhibitor concentration of TMZ was proven to be lower for PTEN-mutated GBMs compared with PTEN wild-types. Conclusions: PTEN gene mutations prevail in GBMs and are strongly related to poor prognosis and least survival. The infiltrating immune lymphocytes Treg and M2 macrophages populate the glioma microenvironment and control the mechanisms of tumor progression, immune escape, and sensitivity to standard chemotherapy. Broader studies are required to confirm these findings and turn them into new therapeutic perspectives.

Background: The cranio-orbito-zygomatic (COZ) approach is a workhorse of skull base surgery, and each of its steps has a precise effect on target exposure and surgical freedom. The present study overviews the key techniques for execution and tailoring of the COZ approach, focusing on the quantitative effects resulting from removal of the orbitozygomatic (OZ) bar, orbital rim, and zygomatic arch. Methods: A PRISMA-based literature review was performed on the PubMed/Medline and Web of Science databases using the main keywords associated with the COZ approach. Articles in English without temporal restriction were included. Eligibility was limited to neurosurgical relevance. Results: A total of 78 articles were selected. The range of variants of the COZ approach involves a one-piece, two-piece, and three-piece technique, with a decreasing level of complexity and risk of complications. The two-piece technique includes an OZ and orbitopterional variant. Superolateral orbitotomy expands the subfrontal and transsylvian corridors, increasing surgical freedom to the basal forebrain, hypothalamic region, interpeduncular fossa, and basilar apex. Zygomatic osteotomy shortens the working distance of the pretemporal and subtemporal routes. Conclusion: Subtraction of the OZ bar causes a tremendous increase in angular exposure of the subfrontal, transsylvian, pretemporal, and subtemporal perspectives avoiding brain retraction, allowing for multiangled trajectories, and shortening the working distance. The COZ approach can be tailored based on the location of the lesion, thus optimizing the target exposure and surgical freedom and decreasing the risk of complications.

MicroRNAs (miRNAs) are ubiquitous regulators of gene expression, evolutionarily conserved in plants and mammals. In recent years, although a growing number of papers debate the role of plant miRNAs on human gene expression, the molecular mechanisms through which this effect is achieved are still not completely elucidated. Some evidence suggest that this interaction might be sequence specific, and in this work, we investigated this possibility by transcriptomic and bioinformatics approaches. Plant and human miRNA sequences from primary databases were collected and compared for their similarities (global or local alignments). Out of 2,588 human miRNAs, 1,606 showed a perfect match of their seed sequence with the 5′ end of 3,172 plant miRNAs. Further selections were applied based on the role of the human target genes or of the miRNA in cell cycle regulation (as an oncogene, tumor suppressor, or a biomarker for prognosis, or diagnosis in cancer). Based on these criteria, 20 human miRNAs were selected as potential functional analogous of 7 plant miRNAs, which were in turn transfected in different cell lines to evaluate their effect on cell proliferation. A significant decrease was observed in colorectal carcinoma HCT116 cell line. RNA-Seq demonstrated that 446 genes were differentially expressed 72 h after transfection. Noteworthy, we demonstrated that the plant mtr-miR-5754 and gma-miR4995 directly target the tumor-associated long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and nuclear paraspeckle assembly transcript 1 (NEAT1) in a sequence-specific manner. In conclusion, according to other recent discoveries, our study strengthens and expands the hypothesis that plant miRNAs can have a regulatory effect in mammals by targeting both protein-coding and non-coding RNA, thus suggesting new biotechnological applications.

Introduction: We evaluated the risk profile of elderly patients who came to the emergency department for mild head trauma. The primary goal was to determine the difference in the incidence of posttraumatic intracranial hemorrhage (ICH) after minor head injury (MHI). The secondary objective was to assess worse outcome, such as: hospitalization rate, rate of re-admission, need of neurosurgery. We also assess the admission process times and length of hospital stay. The ultimate goal was to optimize the diagnostic-observational management of minor head trauma in elderly patients. Material and methods: We evaluated all patients with MHI who came to our emergency department during 2017 and 2018. All patients underwent computed tomography. Results: We enrolled 2325 patients, of whom 1094 were 75 years of age or older. The population was divided into two categories according to age: The “elderly population” was 75 or older, and the younger patients were younger than 75. The elderly population, in comparison with the younger patients, had a higher rate of ICH (12.1% versus 5.1%), a higher hospitalization rate (11.7% versus 5.5%), and a higher rate of readmission within 30 days (6.8% versus 3.2%). The elderly population also had longer admission process times (8 h, 25 min, versus 4 h, 09 min) and longer lengths of hospital stay (9 h, 41 min, versus 5 h, 29 min). Of the younger patients, 92% (versus 41% of the elderly population) did not take any drugs, 6% (versus 39%) were receiving antiplatelet therapy, 1% (versus 13%) took vitamin K antagonists, and 1% (versus 7%) took oral direct-acting anticoagulants. Logistic regression models revealed that a 1-year increase in age raised the risk of bleeding by 2% on average; this finding was statistically significant (odds ratio [OR], 1023/year, p < 0.001). The rate of ICH increased significantly after the age of 75, by 180% (OR, 2.82; p < 0.001). Conclusions: These data suggest that age is an independent risk factor for ICH, whereby the age of 75 entails a 180% increase in the risk of bleeding.

Abstract Background High throughput technologies have provided the scientific community an unprecedented opportunity for large-scale analysis of genomes. Non-coding RNAs (ncRNAs), for a long time believed to be non-functional, are emerging as one of the most important and large family of gene regulators and key elements for genome maintenance. Functional studies have been able to assign to ncRNAs a wide spectrum of functions in primary biological processes, and for this reason they are assuming a growing importance as a potential new family of cancer therapeutic targets. Nevertheless, the number of functionally characterized ncRNAs is still too poor if compared to the number of new discovered ncRNAs. Thus platforms able to merge information from available resources addressing data integration issues are necessary and still insufficient to elucidate ncRNAs biological roles. Results In this paper, we describe a platform called Arena-Idb for the retrieval of comprehensive and non-redundant annotated ncRNAs interactions. Arena-Idb provides a framework for network reconstruction of ncRNA heterogeneous interactions (i.e., with other type of molecules) and relationships with human diseases which guide the integration of data, extracted from different sources, via mapping of entities and minimization of ambiguity. Conclusions Arena-Idb provides a schema and a visualization system to integrate ncRNA interactions that assists in discovering ncRNA functions through the extraction of heterogeneous interaction networks. The Arena-Idb is available at http://arenaidb.ba.itb.cnr.it

The region of Lombardy was the epicenter of the COVID-19 outbreak in Italy. Emergency Hospital 19 (EH19) was built in the Milan metropolitan area during the pandemic’s second wave as a facility of Humanitas Clinical and Research Center (HCRC). The present study aimed to assess whether the implementation of EH19 was effective in improving the quality of care of COVID-19 patients during the second wave compared with the first one. The demographics, mortality rate, and in-hospital length of stay (LOS) of two groups of patients were compared: the study group involved patients admitted at HCRC and managed in EH19 during the second pandemic wave, while the control group included patients managed exclusively at HCRC throughout the first wave. The study and control group included 903 (56.7%) and 690 (43.3%) patients, respectively. The study group was six years older on average and had more pre-existing comorbidities. EH19 was associated with a decrease in the intensive care unit admission rate (16.9% vs. 8.75%, p < 0.001), and an equal decrease in invasive oxygen therapy (3.8% vs. 0.23%, p < 0.001). Crude mortality was similar but overlap propensity score weighting revealed a trend toward a potential small decrease. The adjusted difference in LOS was not significant. The implementation of an additional COVID-19 hospital facility was effective in improving the overall quality of care of COVID-19 patients during the first wave of the pandemic when compared with the second. Further studies are necessary to validate the suggested approach.

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Introduction: High-grade gliomas (HGGs) still have a high rate of recurrence and lethality. Gene therapies were projected to overcome the therapeutic resilience of HGGs, due to the intrinsic genetic heterogenicity and immune evasion pathways. The present literature review strives to provide an updated overview of the novel gene therapies for HGGs treatment, highlighting evidence from clinical trials, molecular mechanisms, and future perspectives. Methods: An extensive literature review was conducted through PubMed/Medline and ClinicalTrials.gov databases, using the keywords “high-grade glioma,” “glioblastoma,” and “malignant brain tumor”, combined with “gene therapy,” “oncolytic viruses,” “suicide gene therapies,” “tumor suppressor genes,” “immunomodulatory genes,” and “gene target therapies”. Only articles in English and published in the last 15 years were chosen, further screened based on best relevance. Data were analyzed and described according to the PRISMA guidelines. Results: Viruses were the most vehicles employed for their feasibility and transduction efficiency. Apart from liposomes, other viral vehicles remain largely still experimental. Oncolytic viruses and suicide gene therapies proved great results in phase I, II preclinical, and clinical trials. Tumor suppressor, immunomodulatory, and target genes were widely tested, showing encouraging results especially for recurrent HGGs. Conclusions: Oncolytic virotherapy and suicide genes strategies are valuable second-line treatment options for relapsing HGGs. Immunomodulatory approaches, tumor suppressor, and target genes therapies may implement and upgrade standard chemoradiotherapy. Future research aims to improve safety profile and prolonging therapeutic effectiveness. Further clinical trials are needed to assess the efficacy of gene-based therapies.

The exact molecular pathways underlying the multifactorial natural history of intracranial aneurysms (IAs) are still largely unknown, to the point that their understanding represents an imperative challenge in neurovascular research. Wall shear stress (WSS) promotes the genesis of IAs through an endothelial dysfunction causing an inflammatory cascade, vessel remodeling, phenotypic switching of the smooth muscle cells, and myointimal hyperplasia. Aneurysm growth is supported by endothelial oxidative stress and inflammatory mediators, whereas low and high WSS determine the rupture in sidewall and endwall IAs, respectively. Angioarchitecture, age older than 60 years, female gender, hypertension, cigarette smoking, alcohol abuse, and hypercholesterolemia also contribute to growth and rupture. The improvements of aneurysm wall imaging techniques and the implementation of target therapies targeted against inflammatory cascade may contribute to significantly modify the natural history of IAs. This narrative review strives to summarize the recent advances in the comprehension of the mechanisms underlying the genesis, growth, and rupture of IAs.

Tandem intracranial aneurysms (TandIAs) are rare but inherently complex, and special technical considerations are required for their surgical management. The present case highlights the key surgical aspects of two carotid-ophthalmic TandIAs incidentally found in a 60-year-old female. Both the aneurysms were superiorly projecting, regular in size, and involved the left ophthalmic segment of the internal carotid artery (ICA). The minimum distance between the necks was 3 mm. The patient underwent microsurgery because of the reported major complications rate of the endovascular treatment in the case of a very short minimum distance between the TandIAs. After cervical ICA exposure, both the aneurysms were excluded through a pterional approach. Intradural anterior clinoidectomy and unroofing of the optic canal allowed the mobilization of the left optic nerve. The more distal aneurysm was clipped before the opening of the distal dural ring of the ICA. The proximal aneurysm was clipped with two straight clips stacked perpendicular to the ICA. A small remnant was intentionally left to avoid the stenosis of the ophthalmic artery. Postoperative angiography showed the exclusion of both the aneurysms with a small dog-ear of the more proximal one. The patient was discharged neurologically intact and, after one year, the remnant remained stable. Microsurgical clipping is a definitive and durable treatment for carotid-ophthalmic TandIAs. In the case of a very short minimum distance between the aneurysms, the distal one should be clipped first to make the anterior clinoidectomy, opening of the distal dural ring of the ICA, and clipping of the more proximal aneurysm easier.

Objective: Examination of the current trends and future perspectives of the cell-based therapies in neurosurgery. Methods: A PubMed/MEDLINE-based systematic review has been performed combining the main Medical Subject Headings (MeSH) regarding the cell- and tissue-based therapies with the “Brain”, “Spinal Cord”, “Spine” and “Skull” MeSH terms. Only articles in English published in the last 10 years and pertinent to neurosurgery have been selected. Results: A total of 1,173 relevant articles have been chosen. Somatic cells and gene-modification technologies have undergone the greatest development. Immunotherapies and gene therapies have been tested for the cure of glioblastoma, stem cells mainly for brain and spinal cord traumatic injuries. Stem cells have also found a rationale in the treatment of the cranial and spinal bony defects, and of the intervertebral disc degeneration, as well.Most of the completed or ongoing trials concerning the cell-based therapies in neurosurgery are on phase 2. Future perspectives involve the need to overcome issues related to immunogenicity, oncogenicity and routes for administration. Refinement and improvement of vector design and delivery are required within the gene therapies. Conclusion: The last decade has been characterised by a progressive evolution of neurosurgery from a purely mechanical phase to a new biological one. This trend has followed the rapid and parallel development of translational medicine and nanotechnologies.The introduction of new technologies, the optimisation of the already existing ones, and the reduction of costs are among the main challenges of the foreseeable future.

Introduction: The petroclival region is among the most challenging anatomical areas to deal with in skull base surgery. Drilling of the anterior part of the petrous bone during the anterior transpetrosal approach involves the risk of injury of the cochlea, superior semicircular canal, internal carotid artery, and internal auditory canal. A thorough understanding of the microneurosurgical anatomy of this region is mandatory to execute the transpetrosal approaches, decreasing the risk of complications. The aim of this study is to describe the anatomical structures of the petroclival region, highlighting the importance of neuronavigation for safe performance of the anterior transpetrosal approach. Methods: Three adult cadaveric human heads were formalin-fixed and injected with colored silicone. They underwent an axial 1 mm slab CT scan, which was used for neuronavigation during the surgical approaches. The anterior petrosectomy was performed with the aid of neuronavigation during the drilling of the petrous bone. The surgical management of a patient harboring a petroclival meningioma, operated on using an anterior transpetrosal approach, was reported as an illustrative case. Results: The anterior petrosectomy was completed accurately with wide exposure of the surgical target without injuring the cochlea and other structures in all three cadaveric specimens. In the surgical case, no approach-related complications occurred, and a gross total resection of the tumor was achieved. Conclusions: Deep knowledge of the location and relationships of the vital elements located within the temporal bone, along with the use of neuronavigation, are the key aspects to perform the anterior transpetrosal approach safely, reducing the risk of complications.

Background and objectives: In patients who receive antiplatelet therapy (APT), the bleeding risk profile after mild head trauma (MHT) still needs clarification. Some studies have demonstrated an association with bleeding risk, whereas others have not. We studied the population of our level II emergency department (ED) trauma center to determine the risk of bleeding in patients receiving APT and whether bleeding results not from antiplatelet agents but rather from age. We assessed the bleeding risk, the incidence of intracranial hemorrhage (ICH) that necessitated hospitalization for observation, the need for cranial neurosurgery, the severity of the patient’s condition at discharge, and the frequency of ED revisits for head trauma in patients receiving APT. Materials and Methods: This retrospective single-center study included 483 patients receiving APT who were in the ED for MHT in 2019. The control group consisted of 1443 patients in the ED with MHT over the same period who were not receiving APT or anticoagulant therapy. Our ED diagnostic therapeutic protocol mandates both triage and the medical examination to identify patients with MHT who are taking any anticoagulant or APT. Results: APT was not significantly associated with bleeding risk (p > 0.05); as a risk factor, age was significantly associated with the risk of bleeding, even after adjustment for therapy. Patients receiving APT had a greater need of surgery (1.2% vs. 0.4%; p < 0.0001) and a higher rate of hospitalization (52.9% vs. 37.4%; p < 0.0001), and their clinical condition was more severe (evaluated according to the exit code value on a one-dimensional quantitative five-point numerical scale) at the time of discharge (p = 0.013). The frequency of ED revisits due to head trauma did not differ between the two groups. Conclusions: The risk of bleeding in patients receiving APT who had MHT was no higher than that in the control group. However, the clinical condition of patients receiving APT, including hospital admission for ICH monitoring and cranial neurosurgical interventions, was more severe.

The resilience of high-grade gliomas (HGGs) against conventional chemotherapies is due to their heterogeneous genetic landscape, adaptive phenotypic changes, and immune escape mechanisms. Innovative immunotherapies have been developed to counteract the immunosuppressive capability of gliomas. Nevertheless, further research is needed to assess the efficacy of the immuno-based approach. The aim of this study is to review the newest immunotherapeutic approaches for glioma, focusing on the drug types, mechanisms of action, clinical pieces of evidence, and future challenges. A PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis)-based literature search was performed on PubMed/Medline and ClinicalTrials.gov databases using the keywords “active/adoptive immunotherapy,” “monoclonal antibodies,” “vaccine,” and “engineered T cell.”, combined with “malignant brain tumor”, “high-grade glioma.” Only articles written in English published in the last 10 years were selected, filtered based on best relevance. Active immunotherapies include systemic temozolomide, monoclonal antibodies, and vaccines. In several preclinical and clinical trials, adoptive immunotherapies, including T, natural killer, and natural killer T engineered cells, have been shown to be potential treatment options for relapsing gliomas. Systemic temozolomide is considered the backbone for newly diagnosed HGGs. Bevacizumab and rindopepimut are promising second-line treatments. Adoptive immunotherapies have been proven for relapsing tumors, but further evidence is needed.

MicroRNAs (miRNAs), a class of non-coding RNAs, seem to play a key role in complex diseases like multiple sclerosis (MS), as well as in many cognitive functions associated with the disease. In a previous cross-sectional evaluation on pediatric MS (PedMS) patients, the expression of some miRNAs and their target genes were found to be associated with the scores of some neuropsychiatric tests, thus suggesting that they may be involved in early processes of cognitive impairment. To verify these data, we asked the same patients to be re-evaluated after a 1-year interval; unfortunately, only nine of them agreed to this further clinical and molecular analysis. The main results showed that 13 differentially expressed miRNAs discriminated the two time-points. Among them, the expression of miR-182-5p, miR-320a-3p, miR-744-5p and miR-192-5p significantly correlated with the attention and information processing speed performances, whereas the expression of miR-182-5p, miR-451a, miR-4742-3p and miR-320a-3p correlated with the expressive language performances. The analysis of mRNA expression uncovered 58 predicted and/or validated miRNA-target pairs, including 23 target genes, some of them already associated with cognitive impairment, such as the transducing beta like 1 X-linked receptor-1 gene (TBL1XR1), correlated to disorders of neurodevelopment; the Snf2 related CREBBP activator protein gene (SRCAP) that was found implicated in a rare form of dementia; and the glia maturation factor beta gene (GMFB), which has been reported to be implicated in neurodegeneration and neuroinflammation. No molecular pathways involving the most targeted genes survived the adjustment for multiple data. Although preliminary, these findings showed the feasibility of the methods also applied to longitudinal investigations, as well as the reliability of the obtained results. These findings should be confirmed in larger PedMS cohorts in order to identify early markers of cognitive impairment, towards which more efficient therapeutic efforts can be addressed.

Background and objectives: Anticoagulants are thought to increase the risks of traumatic intracranial injury and poor clinical outcomes after blunt head trauma. The safety of using direct oral anticoagulants (DOACs) compared to vitamin K antagonists (VKAs) after intracranial hemorrhage (ICH) is unclear. This study aims to compare the incidence of post-traumatic ICH following mild head injury (MHI) and to assess the need for surgery, mortality rates, emergency department (ED) revisit rates, and the volume of ICH. Materials and Methods: This is a retrospective, single-center observational study on all patients admitted to our emergency department for mild head trauma from 1 January 2016, to 31 December 2018. We enrolled 234 anticoagulated patients, of which 156 were on VKAs and 78 on DOACs. Patients underwent computed tomography (CT) scans on arrival (T0) and after 24 h (T24). The control group consisted of patients not taking anticoagulants, had no clotting disorders, and who reported an MHI in the same period. About 54% in the control group had CTs performed. Results: The anticoagulated groups were comparable in baseline parameters. Patients on VKA developed ICH more frequently than patients on DOACs and the control group at 17%, 5.13%, and 7.5%, respectively. No significant difference between the two groups was noted in terms of surgery, intrahospital mortality rates, ED revisit rates, and the volume of ICH. Conclusions: Patients with mild head trauma on DOAC therapy had a similar prevalence of ICH to that of the control group. Meanwhile, patients on VKA therapy had about twice the ICH prevalence than that on the control group or patients on DOAC, which remained after correcting for age. No significant difference in the need for surgery was determined; however, this result must take into account the very small number of patients needing surgery.

Objective: To report the physical and technical principles, clinical applications, and outcomes of the minimal invasive piezoelectric osteotomy in a consecutive veterinary neurosurgical series. Methods: A series of 292 dogs and 32 cats underwent an osteotomy because a neurosurgical pathology performed with a Mectron Piezosurgery® bone scalpel (Mectron Medical Technology, Genoa, Italy) was retrospectively reviewed. Efficacy, precision, safety, and blood loss were evaluated intraoperatively by two different surgeons, on a case-by-case basis. Postoperative Rx and CT scans were used to assess the selectivity and precision of the osteotomy. A histological study on bony specimens at the osteotomized surface was carried out to evaluate the effects of piezoelectric cutting on the osteocytes and osteoblasts. All the patients underwent a six-months follow-up. A series of illustrative cases was reported. Results: All the osteotomies were clear-cut and precise. A complete sparing of soft and nervous tissues and vasculature was observed. The operative field was blood- and heat-free in all cases. A range of inserts, largely different in shape and length, were allowed to treat deep and difficult-to-reach sites. Two mechanical complications occurred. Average blood loss in dogs’ group was 52, 47, and 56 mL for traumatic, degenerative, and neoplastic lesions, respectively, whereas it was 25 mL for traumatized cats. A fast recovery of functions was observed in most of the treated cases, early on, at the first sixth-month evaluation. Histology on bone flaps showed the presence of live osteocytes and osteoblasts at the osteotomized surface in 92% of cases. Conclusions: Piezosurgery is based on the physical principle of the indirect piezo effect. Piezoelectric osteotomy is selective, effective, and safe in bone cutting during neurosurgical veterinary procedures. It can be considered a minimal invasive technique, as it is able to spare the neighboring soft tissues and neurovascular structures.

Background and Objectives: Trauma coagulopathy begins at the moment of trauma. This study investigated whether coagulopathy upon arrival in the emergency room (ER) is correlated with increased hemotransfusion requirement, more hemodynamic instability, more severe anatomical damage, a greater need for hospitalization, and hospitalization in the intensive care unit (ICU). We also analyzed whether trauma coagulopathy is correlated with unfavorable indices, such as acidemia, lactate increase, and base excess (BE) increase. Material and Methods: We conducted a prospective, monocentric, observational study of all patients (n = 503) referred to the Department of Emergency and Acceptance, IRCCS Fondazione Policlinico San Matteo, Pavia, for major trauma from 1 January 2018 to 30 January 2019. Results: Of the 503 patients, 204 had trauma coagulopathy (group 1), whereas 299 patients (group 2) did not. Group 1 had a higher hemotransfusion rate than group 2. In group 1, 15% of patients showed hemodynamic instability compared with only 8% of group 2. The shock index (SI) distribution was worse in group 1 than in group 2. Group 1 was more often hypotensive, tachycardic, and with low oxygen saturation, and had a more severe injury severity score than group 2. In addition, 47% of group 1 had three or more body districts involved compared with 23% of group 2. The hospitalization rate was higher in group 1 than in group 2 (76% vs. 58%). The length of hospitalization was >10 days for 45% of group 1 compared with 28% of group 2. The hospitalization rate in the ICU was higher in group 1 than in group 2 (22% vs. 14.8%). The average duration of ICU hospitalization was longer in group 1 than in group 2 (12.5 vs. 9.78 days). Mortality was higher in group 1 than in group 2 (3.92% vs. 0.98%). Group 1 more often had acidemia and high lactates than group 2. Group 1 also more often had BE Conclusions: Trauma coagulopathy patients, upon arrival in the ER, have greater hemotransfusion (p = 0.016) requirements and need hospitalization (p = 0.032) more frequently than patients without trauma coagulopathy. Trauma coagulopathy seems to be more present in patients with a higher injury severity score (ISS) (p = 0.000) and a greater number of anatomical districts involved (p = 0.000). Head trauma (p = 0.000) and abdominal trauma (p = 0.057) seem related to the development of trauma coagulopathy. Males seem more exposed than females in developing trauma coagulopathy (p = 0.018). Upon arrival in the ER, the presence of tachycardia or alteration of SI and its derivatives can allow early detection of patients with trauma coagulopathy.

Circulating platelets (PLTs) are able to affect glioblastoma (GBM) microenvironment by supplying oncopromoter and pro-angiogenic factors. Among these mediators, sphingosine-1-phophate (S1P) has emerged as a potent bioactive lipid enhancing cell proliferation and survival. Here, we investigated the effect of “tumor education”, characterizing PLTs from GBM patients in terms of activation state, protein content, and pro-angiogenic potential. PLTs from healthy donors (HD-PLTs) and GBM patients (GBM-PLTs) were collected, activated, and analyzed by flow cytometry, immunofluorescence, and Western blotting. To assess the pro-angiogenic contribution of GBM-PLTs, a functional cord formation assay was performed on GBM endothelial cells (GECs) with PLT-releasate. GBM-PLTs expressed higher positivity for P-selectin compared to HD-PLTs, both in basal conditions and after stimulation with adenosine triphosphate (ADP) and thrombin receptor activating peptide (TRAP). PLTs showed higher expression of VEGFR-1, VEGFR-2, VWF, S1P, S1PR1, SphK1, and SPNS. Interestingly, increased concentrations of VEGF and its receptors VEGFR1 and VEGFR2, VWF, and S1P were found in GBM-PLT-releasate with respect to HD-PLTs. Finally, GBM-PLT-releasate showed a pro-angiogenic effect on GECs, increasing the vascular network’s complexity. Overall, our results demonstrated the contribution of PLTs to GBM angiogenesis and aggressiveness, advancing the potential of an anti-PLT therapy and the usefulness of PLT cargo as predictive and monitoring biomarkers.

Attention Deficit Hyperactivity Disorder (ADHD) is a childhood-onset neurodevelopmental disorder, whose etiology and pathogenesis are still largely unknown. In order to uncover novel regulatory networks and molecular pathways possibly related to ADHD, we performed an integrated miRNA and mRNA expression profiling analysis in peripheral blood samples of children with ADHD and age-matched typically developing (TD) children. The expression levels of 13 miRNAs were evaluated with microfluidic qPCR, and differentially expressed (DE) mRNAs were detected on an Illumina HiSeq 2500 genome analyzer. The miRNA targetome was identified using an integrated approach of validated and predicted interaction data extracted from seven different bioinformatic tools. Gene Ontology (GO) and pathway enrichment analyses were carried out. Results showed that six miRNAs (miR-652-3p, miR-942-5p, let-7b-5p, miR-181a-5p, miR-320a, and miR-148b-3p) and 560 genes were significantly DE in children with ADHD compared to TD subjects. After correction for multiple testing, only three miRNAs (miR-652-3p, miR-148b-3p, and miR-942-5p) remained significant. Genes known to be associated with ADHD (e.g., B4GALT2, SLC6A9 TLE1, ANK3, TRIO, TAF1, and SYNE1) were confirmed to be significantly DE in our study. Integrated miRNA and mRNA expression data identified critical key hubs involved in ADHD. Finally, the GO and pathway enrichment analyses of all DE genes showed their deep involvement in immune functions, reinforcing the hypothesis that an immune imbalance might contribute to the ADHD etiology. Despite the relatively small sample size, in this study we were able to build a complex miRNA-target interaction network in children with ADHD that might help in deciphering the disease pathogenesis. Validation in larger samples should be performed in order to possibly suggest novel therapeutic strategies for treating this complex disease.

The relevance of nitric oxide synthase 2 (NOS2) as a prognostic factor in Glioblastoma Multiforme (GBM) malignancy is emerging. We analyzed the effect of NOS2 inhibitor 1400W on the autophagic flux and extracellular vesicle (EV) secretion in U87MG glioma cells. The effects of glioma stem cells (GSC)-derived EVs on adherent U87MG were evaluated. Cell proliferation and migration were examined while using Cell Counting Kit-8 assay (CCK-8) and scratch wound healing assay. Cell cycle profile and apoptosis were analyzed by flow cytometry. Autophagy-associated acidic vesicular organelles were detected and quantified by acridine orange staining. The number and size of EVs were assessed by nanoparticle tracking analysis. EV ultrastructure was verified by transmission electron microscopy (TEM). WB was used to analyze protein expression and acid sphingomyelinase was determined through ceramide levels. 1400W induced autophagy and EV secretion in both adherent U87MG and GSCs. EVs secreted by 1400W-treated GSC, but not those from untreated cells, were able to inhibit adherent U87MG cell growth and migration while also inducing a relevant level of autophagy. The hypothesis of NOS2 expression as GBM profile marker or interesting therapeutic target is supported by our findings. Autophagy and EV release following treatment with the NOS2 inhibitor could represent useful elements to better understand the complex biomolecular frame of GBM.

MicroRNAs (miRNAs) and transcription factors (TFs) play key roles in complex multifactorial diseases like multiple sclerosis (MS). Starting from the miRNomic profile previously associated with a cohort of pediatric MS (PedMS) patients, we applied a combined molecular and computational approach in order to verify published data in patients with adult-onset MS (AOMS). Six out of the 13 selected miRNAs (miR-320a, miR-125a-5p, miR-652-3p, miR-185-5p, miR-942-5p, miR-25-3p) were significantly upregulated in PedMS and AOMS patients, suggesting that they may be considered circulating biomarkers distinctive of the disease independently from age. A computational and unbiased miRNA-based screening of target genes not necessarily associated to MS was then performed in order to provide an extensive view of the genetic mechanisms underlying the disease. A comprehensive MS-specific miRNA-TF co-regulatory network was hypothesized; among others, SP1, RELA, NF-κB, TP53, AR, MYC, HDAC1, and STAT3 regulated the transcription of 61 targets. Interestingly, NF-κB and STAT3 cooperatively regulate the expression of immune response genes and control the cross-talk between inflammatory and immune cells. Further functional analysis will be performed on the identified critical hubs. Above all, in our view, this approach supports the need of multidisciplinary strategies for shedding light into the pathogenesis of MS.