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Epilepsy is one of the most frequently diagnosed neurological diseases, but the neurobiological basis of the disease remains poorly understood. Immunophenotyping CBA mice brain (NeuN and caspase-8) in parallel with hippocampal neurons’ functional status and survival rate assessment during acute epileptic PTZ-induced seizures is of particular interest. The aims of this study were to investigate the involvement of NeuN and caspase-8 in cell cycle regulation and the death of hippocampal neurons during PTZ-induced seizures in mice and to assess the therapeutic efficacy of Myricetin in the aforementioned experimental settings. Male CBA mice (n = 340) were divided into six groups to investigate the neuroprotective and antiepileptic effects of Myricetin and Valproic Acid in the PTZ-induced seizure model. Group I (control, n = 20) received a single intraperitoneal injection of NaCl 0.9% solution. Group II (PTZ only, n = 110) received a single intraperitoneal 45 mg/kg PTZ to induce seizures. Group III (Myricetin + PTZ, n = 90) was administered Myricetin orally at 200 mg/kg for 5 days, followed by a PTZ injection. Group IV (Valproic Acid + PTZ, n = 80) received intraperitoneal Valproic Acid at 100 mg/kg for 5 days, followed by PTZ. Group V (Myricetin + NaCl, n = 20) received Myricetin and NaCl. Group VI (Valproic Acid + NaCl, n = 20) received Valproic Acid and NaCl. Seizure severity was monitored using the modified Racine scale. Behavioral assessments included sensorimotor function tests, motor coordination using the rotarod test, and cognitive function via the Morris water maze. Brain tissues were collected and analyzed for oxidative stress markers, including malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH). Blood samples were analyzed for cytokine levels (IL-1β, IL-6, and TNF-α). Histological studies involved H&E and Nissl staining to evaluate general histopathology and neuronal density. Immunohistochemical analysis was conducted using antibodies against NeuN and caspase-8 to assess neuronal cell cycle regulation and apoptosis. PTZ-induced seizures caused significant oxidative stress and inflammation, leading to neuronal damage. Biochemical analyses showed elevated levels of MDA, SOD, GSH, IL-1β, IL-6, and TNF-α. Histological and immunohistochemical evaluations revealed a significant increase in caspase-8-positive neurons and a decrease in NeuN-positive neurons in the hippocampus and other brain regions, correlating with seizure severity. Myricetin and Valproic Acid treatments reduced oxidative stress markers and neuronal damage. Both treatments resulted in moderate neuronal protection, with fewer damaged neurons observed in the hippocampus, dentate gyrus, and other brain areas compared to the PTZ-only group. Summarizing, Myricetin administration showed promising neuroprotective effects. It significantly reduced oxidative stress markers, including MDA, and restored antioxidant enzyme activities (SOD and GSH), suggesting its antioxidative potential. Myricetin also effectively attenuated the elevation of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α, indicating strong anti-inflammatory properties. Behavioral assessments revealed that Myricetin improved cognitive and motor functions in PTZ-treated mice, with notable reductions in seizure severity and mortality rates. Histological analyses supported these behavioral findings, with Nissl staining showing reduced neuronal damage and NeuN staining indicating better preservation of neuronal integrity in Myricetin-treated groups. Additionally, caspase-8 staining suggested a significant reduction in neuronal apoptosis.

Patients affected by glioma frequently experience epileptic discharges; however, the causes of brain tumor-related epilepsy (BTRE) are still not completely understood. We investigated the mechanisms underlying BTRE by analyzing the effects of exosomes released by U87 glioma cells and by patient-derived glioma cells. Rat hippocampal neurons incubated for 24 hours with these exosomes exhibited increased spontaneous firing, while their resting membrane potential shifted positively by 10-15 mV. Voltage clamp recordings demonstrated that the activation of the [Na.sup.+] current shifted toward more hyperpolarized voltages by 10-15 mV. To understand the factors inducing hyperexcitability, we focused on exosomal cytokines. Western blot and ELISAs showed that TNF-[alpha] was present inside glioma-derived exosomes. Remarkably, incubation with TNF-[alpha] fully mimicked the phenotype induced by exosomes, with neurons firing continuously, while their resting membrane potential shifted positively. Real-time PCR revealed that both exosomes and TNF-[alpha] induced overexpression of the voltage-gated [Na.sup.+] channel Nav1.6, a low-threshold [Na.sup.+] channel responsible for hyperexcitability. When neurons were preincubated with infliximab, a specific TNF-[alpha] inhibitor, the hyperexcitability induced by exosomes and TNF-[alpha] was drastically reduced. We propose that infliximab, an FDA-approved drug to treat rheumatoid arthritis, could ameliorate the conditions of glioma patients with BTRE., Introduction Patients with brain tumors develop symptoms ranging from headaches to epileptic discharges to impairment of specific cognitive functions (1-3). The mechanisms leading to brain tumor-related epilepsy (BTRE) are not [...]

PurposePatients diagnosed with High Grade Gliomas (HGG) generally tend to have a relatively negative prognosis with a high risk of early tumor recurrence (TR) after post-operative radio-chemotherapy. The assessment of the pre-operative risk of early versus delayed TR can be crucial to develop a personalized surgical approach. The purpose of this article is to predict TR using MRI radiomic analysis.MethodsData were retrospectively collected from a database. A total of 248 patients were included based on the availability of 6-month TR results: 188 were used to train the model, the others to externally validate it. After manual segmentation of the tumor, Radiomic features were extracted and different machine learning models were implemented considering a combination of T1 and T2 weighted MR sequences. Receiver Operating Characteristic (ROC) curve was calculated with relative model performance metrics (accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV)) at the best threshold based on the Youden Index.ResultsModels performance were evaluated based on test set results. The best model resulted to be the XGBoost, with an area under ROC curve of 0.72 (95% CI: 0.56 - 0.87). At the best threshold, the model exhibits 0.75 (95% CI: 0.63 - 0.75) as accuracy, 0.62 (95% CI: 0.38 - 0.83) as sensitivity 0.80 (95% CI: 0.66 - 0.89 as specificity, 0.53 (95% CI: 0.31 - 0.73) as PPV, 0.88 (95% CI: 0.72 - 0.94) as NPV.ConclusionMRI radiomic analysis represents a powerful tool to predict late HGG recurrence, which can be useful to plan personalized surgical treatments and to offer pertinent patient pre-operative counseling.

Background: Donor organ shortage is a barrier to lung transplantation. Donation after circulatory death (DCD) may offer a solution, although it is underutilized. The objective of this study was to compare survival and other postoperative outcomes between DCD and donation after brain death (DBD). Methods: We performed a multicenter analysis of Multi-Institutional Extracorporeal Life Support (ECLS) Registry data from 11 lung transplant centers in the United States and Europe. Demographics and clinical parameters were compared using chi-square test and Fisher's exact test. Survival was assessed by Kaplan-Meier curves and compared by log-rank test with propensity score matching. Results: Of 1,585 patients included in the study, 135 (8.5%) received DCD lungs and 1,450 (91.5%) received DBD lungs. DCD recipients had higher rates of obstructive lung disease (p = 0.042), longer total ischemic time (p

Background: The use of extended-criteria donor (ECD) organs has increased in lung transplantation, but their impact on long-term outcomes remains unclear. This retrospective single-center study evaluates the impact of donor quality, as defined by the Eurotransplant (ET) lung donor score, on long-term graft function and survival. Methods: Records of recipients transplanted between January 2010 and May 2023 were reviewed. Eurotransplant lung donor scores (ET scores) were retrospectively calculated from the corresponding donor reports. Outcomes were compared between recipients of donor lungs with an ET score of 6 (group 1), 7 and 8 (group 2), and 9 to 13 (group 3, ECD lungs). Median follow-up was 64 (30-104) months. Results: In total, 280 (19%) patients were transplanted with ET score 6 lungs, 717 (48%) patients with ET scores 7 and 8 lungs, and 506 (34%) patients with ET scores 9 to 13 (ECD) lungs. The occurrence of primary graft dysfunction grade 3 at 72 hours (p = 0.672), duration of mechanical ventilation (p = 0.062), and in-hospital mortality (p = 0.713) did not differ between groups. Long-term graft survival (%) was lower in group 2 and 3 vs group 1 recipients (at 10 years: 51 and 48 vs 56, p = 0.052, respectively). Similarly, freedom from chronic lung allograft dysfunction (CLAD, %) was lower in group 2 and 3 vs group 1 recipients (at 10 years: 57 and 55 vs 63, p = 0.033, respectively). Donor smoking history was associated with worse CLAD-free survival (hazard ratio = 1.466, 95% confidence interval = 1.215-1.769, p

IntroductionPulmonary ischemia-reperfusion (IR) injury (IRI) plays a significant role in various lung disorders and is a key factor in the development of primary graft dysfunction following lung transplantation. Hemopexin (Hx) is the major serum scavenger protein for heme, which is a prooxidant and pro-inflammatory compound. In the current study, we hypothesized that Hx could confer beneficial effects in sterile inflammation induced by IR-mediated lung injury.MethodsTo examine this hypothesis, we administered Hx in an experimental mouse model of unilateral lung IRI.ResultsOur results demonstrate that treatment with Hx alleviated histopathological signs of inflammation in ischemic lungs, as evidenced by a reduction in the number of infiltrating neutrophils and decreased levels of perivascular edema. In addition, thrombotic vaso-occlusion in pulmonary blood vessels of IRI lungs was reduced by Hx. Immunohistochemical analysis revealed that Hx inhibited the up-regulation of heme oxygenase-1, an enzyme highly induced by heme, in ischemic lungs. Finally, Hx administration caused a decrease in the levels of circulating B- and CD8+ T-lymphocytes in the peripheral blood of mice with pulmonary IRI.ConclusionThese findings suggest that the serum heme scavenger protein Hx holds therapeutic promise in alleviating lung IRI-mediated sterile inflammation. Thus, Hx may represent a preemptive therapeutic approach in IR-related lung disorders such as primary graft dysfunction in lung transplantation.

Background: The primary co-occurrence of gonadal and extragonadal central nervous system (CNS) germ cell tumors (GCTs) has rarely been reported in the literature, and a common opinion on the underlying etiopathogenetic mechanism is lacking. Objective: We aim to investigate the pathophysiological mechanisms and genetic pathways underlying the primary co-occurrence of gonadal and CNS GCTs. Methods: We reviewed data from 29 consecutive patients with a diagnosis of CNS GCT, evaluated in our Hospital over the past 23 years, and searched for those who had at least a primary gonadal co-occurrence of GCT. A systematic review of the literature according to the PRISMA guidelines was also conducted. For a comprehensive and detailed search, PubMed, Ovid MEDLINE, and Ovid EMBASE databases have been consulted. Boolean operators and MeSH terms were used to find studies. Only articles published between 2000 and 2023 were considered. Results: Including our Institutional case report, a total of 7 patients with both testicular NGGCTs and CNS GCTs were identified (5 patients with metachronous tumors and patients with synchronous presentation). The average age at tumor diagnosis was 17 years. The cerebral histotypes reported were mixed GCTs (3 cases; 43%), pure germinomas (3 cases, 43%), and one yolk sac tumor (14%). Two out of seven cases (29%) were syndromic, one suffering from Down Syndrome and the other from Testicular Dysgenesis Syndrome. Regarding the etiology and molecular mechanism of GCT development, several gene mutations have been reported in the literature. Particularly, genetic alterations in the MAPK and/or PI3K/AKT/mTOR pathway, together with mutations of the KIT gene, have been shown to guarantee survival and transformation of mismigrated totipotent primordial germ cells, while suppressor genes allow their resistance against apoptotic death. Aberrant chromosomes have also been reported to be responsible for oncogenic transformation. It is also known that CNS and testicular GCTs share some genetic/epigenetic profiles. Conclusions: The primary co-occurrence of testicular NGGCT and extragonadal CNS GCTs is extremely rare. Genetic factors seem to play a paramount role in their etiopathogenesis. Additional research is needed to elucidate molecular mechanisms of oncogenesis in such patients.

Abstract Free heme is released from hemoproteins during hemolysis or ischemia reperfusion injury and can be pro‐inflammatory. Most studies on nephrotoxicity of hemolysis‐derived proteins focus on free hemoglobin (fHb) with heme as a prosthetic group. Measurement of heme in its free, non‐protein bound, form is challenging and not commonly used in clinical routine diagnostics. In contrast to fHb, the role of free heme in acute kidney injury (AKI) after cardiopulmonary bypass (CPB) surgery is unknown. Using an apo‐horseradish peroxidase‐based assay, we identified free heme during CPB surgery as predictor of AKI in patients undergoing cardiac valve replacement (n = 37). Free heme levels during CPB surgery correlated with depletion of hemopexin (Hx), a heme scavenger‐protein. In mice, the impact of high levels of circulating free heme on the development of AKI following transient renal ischemia and the therapeutic potential of Hx were investigated. C57BL/6 mice were subjected to bilateral renal ischemia/reperfusion injury for 15 min which did not cause AKI. However, additional administration of free heme in this model promoted overt AKI with reduced renal function, increased renal inflammation, and reduced renal perfusion on functional magnetic resonance imaging. Hx treatment attenuated AKI. Free heme administration to sham operated control mice did not cause AKI. In conclusion, free heme is a predictor of AKI in CPB surgery patients and promotes AKI in transient renal ischemia. Depletion of Hx in CPB surgery patients and attenuation of AKI by Hx in the in vivo model encourage further research on Hx therapy in patients with increased free heme levels during CPB surgery.

The present review aims to investigate the survival and functional outcomes in adult high-grade brainstem gliomas (BGSs) by comparing data from resective surgery and biopsy. MEDLINE, EMBASE and Cochrane Library were screened to conduct a systematic review of the literature, according to the PRISMA statement. Analysis was limited to articles including patients older than 18 years of age and those published from 1990 to September 2022. Case reports, review articles, meta-analyses, abstracts, reports of aggregated data, and reports on multimodal therapy where surgery was not the primary treatment were excluded. The ROBINS-I tool was applied to evaluate the risk of bias. Six studies were ultimately considered for the meta-analysis. The resective group was composed of 213 subjects and the bioptic group comprised 125. The analysis demonstrated a survival benefit in those patients in which an extensive resection was possible (STR HR 0.59 (95% CI 0.42, 0.82)) (GTR HR 0.63 (95% CI 0.43, 0.92)). Although surgical resection is associated with increased survival, the significantly higher complication rate makes it difficult to recommend surgery instead of biopsy for BSGs. Future investigations combining volumetric data and molecular profiles could add important data to better define the proper indication between resection and biopsy.

The 2021 WHO (World Health Organization) classification of brain tumors incorporated the rapid advances in the molecular, genetic, and pathogenesis understanding of brain tumor pathogenesis, behavior, and treatment response. It revolutionized brain tumor classification by placing great emphasis on molecular types and completely splitting adult-type and pediatric-type diffuse gliomas. Brainstem gliomas (BSGs) are the leading primary tumors of the brainstem, although they are quite uncommon in adults compared with the pediatric population, representing less than 2% of adult gliomas. Surgery is not always the treatment of choice since resection is rarely feasible and does not improve overall survival, and biopsies are not generally performed since the location is treacherous. Therefore, MRI (Magnetic Resonance Imaging) without and with gadolinium administration represents the optimal noninvasive radiological technique to suggest brainstem gliomas diagnosis, plan a multidisciplinary treatment and for follow-up evaluations. The MRI protocol encompasses morphological sequences as well as functional and advanced sequences, such as DWI/ADC (Diffusion-Weighted Imaging/Apparent Diffusion Coefficient), DTI (Diffusion Tensor Imaging), PWI (Perfusion-Weighted Imaging), and MRS (Magnetic Resonance Spectroscopy), which improve the accuracy of the diagnosis of BSGs by adding substantial information regarding the cellularity, the infiltrative behavior toward the v fiber tracts, the vascularity, and the molecular changes. Brainstem gliomas have been divided into four categories on the basis of their MRI radiological appearance, including diffuse intrinsic low-grade gliomas, enhancing malignant gliomas, localized tectal gliomas, and other forms. The aim of our review is to provide insight into the role of advanced MRI sequences in the diagnosis and follow-up of adult brainstem gliomas.

Background. Incidentally discovered low-grade gliomas (iLGGs) are very rare and little is still known about their associated functional imaging activation patterns, white-matter status, and plasticity potential. Recent studies shed light on several clinical factors responsible for the good clinical status observed in these patients versus those with their symptomatic counterpart (sLGGs), including small volume. Comparisons were typically carried out by comparing iLGGs with the wider and more heterogeneous sLGG group. In this study, we investigated whether iLGGs affect the brain differently from comparably small sLGGs. Method. Starting from a sample of 13 patients with iLGG, in the current comparative cross-sectional study, we identified a group of patients with sLGGs, primarily matched by lesion volume. We looked for potential differences between the two groups in language-related functional and structural parameters (the fMRI network associated with naming and white-matter fascicles). Results. The t-test did not show significant differences in the fMRI network, but these emerged when performing masking. No significant differences were observed at the white-matter level. Conclusions. Given that small volumes characterized both groups and that demographic variables were comparable, too, we hypothesized that differences between the two groups could be attributed to alternative lesion-related parameters. We discussed these findings from clinical and neurosurgical perspectives.

Extracorporeal photopheresis (ECP) is used by few lung transplant centers to treat chronic lung allograft dysfunction (CLAD). Although reported results suggest a beneficial effect on CLAD progression, evidence is limited to single center experiences. The aim of this study is to analyze outcomes of ECP in a large multicenter European cohort. The primary endpoint was patient survival after initiation of ECP. This study included 631 patients, 87% suffered from bronchiolitis obliterans syndrome (BOS), and 13% had restrictive allograft syndrome (RAS). Long-term stabilization was achieved in 42%, improvement in 9%, and no response in 26%. Within the first 12 months of therapy, 23% of patients died. Patients’ survival after initiation of ECP at 5 years was 56% in stable, 70% in responders, and 35% in non-responders (p = 0.001). In multivariable Cox regression, both stabilization (HR: 0.48, CI: 0.27–0.86, p = 0.013) and response (HR: 0.11, CI: 0.04–0.35, p < 0.001) to ECP were associated with survival. Absolute FEV1 at baseline was also protective (HR: 0.09, CI: 0.01–0.94, p = 0.046). RAS phenotype was the only risk factor for mortality (HR: 2.11, 1.16–3.83, p = 0.006). This study provides long-term outcomes of ECP use in CLAD patients in the largest published cohort to date. Two-thirds of the cohort had a sustained response to ECP with excellent long-term results.

Background: Executive functions are multi-component and are based on large-scale brain networks. For patients undergoing brain surgery in the prefrontal cortex, resection in the anterior prefrontal sites is assisted by continuous monitoring of their performance on several tasks measuring components of executive functions. In this study, we did not test patients during direct cortical stimulation, but during resection itself. We chose tests routinely used to assess executive functions and included them in a protocol for left (LH) and right (RH) hemisphere prefrontal resections. This protocol is meant to be used during real-time neuropsychological testing (RTNT)—an already established monitoring technique. Methods: We retrospectively reviewed a consecutive series of 29 adult patients with glioma in the superior and middle frontal areas who performed the RTNT sequence throughout the resection phase. The testing protocol comprised 10 tests for LH frontal resections and 9 tests for RH frontal resections. Results: RH patients showed a median performance on RTNT with significantly lower scores for visuo-spatial attention and emotion processing (95% Confidence Interval Lower bound of 66.55 and 82.57, respectively, χ2 (7) = 32.8, p < 0.001). LH patients showed a median performance on RTNT, with significantly lower scores for selective attention and working memory (95% Confidence Interval Lower bound of 51.12, χ2 (5) = 20.31 p < 0.001) and minimum scores for the same task and for the Stroop test (χ2 (5) = 17.86, p < 0.005). The delta for accuracy between the first and the last RTNT run was not statistically significant (RH patients: χ2 (7) = 10.49, p > 0.05, n.s.; LH patients: χ2 (5) = 3.35, p > 0.05, n.s.). Mean extent of resection was 95.33% ± 9.72 for the RH group and 94.64% ± 6.74 for the LH group. Patients showed good performance post- vs. pre-surgery. The greater difference in the number of LH patients scoring within the normal range was found for the symbol-digit modality test (83.3% to 62%), Stroop test (100% to 77%) and short-term memory (84.61% to 72.72%) and working memory (92.3% to 63.63%). For RH patients, the main changes were observed on the clock drawing test (100% to 77.7%) and cognitive estimation (100% to 72.7%). Conclusions: Frontal RTNT offers continuous and reliable feedback on the patients’ cognitive status during resection in frontal areas.

Background: Multiple radiomics models have been proposed for grading glioma using different algorithms, features, and sequences of magnetic resonance imaging. The research seeks to assess the present overall performance of radiomics for grading glioma. Methods: A systematic literature review of the databases Ovid MEDLINE PubMed, and Ovid EMBASE for publications published on radiomics for glioma grading between 2012 and 2023 was performed. The systematic review was carried out following the criteria of Preferred Reporting Items for Systematic Reviews and Meta-Analysis. Results: In the meta-analysis, a total of 7654 patients from 40 articles, were assessed. R-package mada was used for modeling the joint estimates of specificity (SPE) and sensitivity (SEN). Pooled event rates across studies were performed with a random-effects meta-analysis. The heterogeneity of SPE and SEN were based on the χ2 test. Overall values for SPE and SEN in the differentiation between high-grade gliomas (HGGs) and low-grade gliomas (LGGs) were 84% and 91%, respectively. With regards to the discrimination between World Health Organization (WHO) grade 4 and WHO grade 3, the overall SPE was 81% and the SEN was 89%. The modern non-linear classifiers showed a better trend, whereas textural features tend to be the best-performing (29%) and the most used. Conclusions: Our findings confirm that present radiomics’ diagnostic performance for glioma grading is superior in terms of SEN and SPE for the HGGs vs. LGGs discrimination task when compared to the WHO grade 4 vs. 3 task.

The human respiratory system is susceptible to a variety of diseases, ranging from chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis to acute respiratory distress syndrome (ARDS). Today, lung diseases represent one of the major challenges to the health care sector and represent one of the leading causes of death worldwide. Current treatment options often focus on managing symptoms rather than addressing the underlying cause of the disease. The limitations of conventional therapies highlight the urgent clinical need for innovative solutions capable of repairing damaged lung tissue at a fundamental level. Pluripotent stem cell technologies have now reached clinical maturity and hold immense potential to revolutionize the landscape of lung repair and regenerative medicine. Meanwhile, human embryonic (HESCs) and human-induced pluripotent stem cells (hiPSCs) can be coaxed to differentiate into lung-specific cell types such as bronchial and alveolar epithelial cells, or pulmonary endothelial cells. This holds the promise of regenerating damaged lung tissue and restoring normal respiratory function. While methods for targeted genetic engineering of hPSCs and lung cell differentiation have substantially advanced, the required GMP-grade clinical-scale production technologies as well as the development of suitable preclinical animal models and cell application strategies are less advanced. This review provides an overview of current perspectives on PSC-based therapies for lung repair, explores key advances, and envisions future directions in this dynamic field.

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder, characterized by progressive loss of both upper and lower motor neurons, resulting in clinical features such as muscle weakness, paralysis, and ultimately, respiratory failure. Nowadays, there is not effective treatment to reverse the progression of the disease, that leads to death within 3–5 years after the onset. Nevertheless, the induced pluripotent stem cells (iPS) technology could be the answer, providing disease modelling, drug testing, and cell-based therapies for this pathology. The aim of this work was to conduct a literature review of the past 5 years about the role of iPS in ALS, to better define the neurobiological mechanisms involved in the pathogenesis and the potential future therapies. The review also deals with advanced and currently available technologies used to reprogram cell lines and generate human motor neurons in vitro, which represent the source to study the pathological processes, the relationship between phenotype and genotype, the disease progression and the potential therapeutic targets of these group of disorders. Specific treatment options with stem cells involve Advance Gene Editing Technology, neuroprotective agents, and cells or exosomes transplantation, aimed to replace dead or damaged nerve cells. In summary, this review comprehensively addresses the role of human pluripotent stem cells (hPSCs) in motor neuron diseases (MND), with a focus on physiopathology, diagnostic and prognostic implications, specific and potential future treatment options. Understanding the biological mechanisms and practical implications of hPSCs in MND is crucial for advancing therapeutic strategies and improving outcomes for patients affected by these devastating diseases.