Objective: It was aimed to investigate the cerebral vascular territories in stroke patients with NVAF as an etiologic factor. Material and Methods: A total of 104 patients who were referred to our hospital between January 2015 and September 2016, who were over 55 years of age, identified or documented as having a standard ECG or Holter ECG record on their medical history, and diagnosed with stroke were included. Our study was designed as a retrospective analysis of prospective data. Detailed history, physical examination and electrocardiography (ECG) evaluations of the patients were performed. Descriptive statistics were used in the detection of findings, and t-test, Pearson-square test and Fisher's exact test were used for differences analysis. Results: 53.8% (N = 56) of the patients were male and 46.2% (N = 48) were female. The mean age was 73.5. MCA was the most common site of vascular involvement in NVAF-dependent strokes. In MCA vascular territory, ischemic infarcts were detected most frequently in the upper and lower divisions. SCA and PCA followed MCA. Approximately 64% of the NVAF-related strokes were anterior circulation infarction (ASE) and 22% were posterior circulation infarct (PSE). There was a significant difference in age and past stroke history factors in favor of ASE (p<0.05). There was no significant difference between ASE and PSE in HT, cardiac history and DM factors (p>0.05). Conclusion: It was emphasized that the area of the vessel that underwent ischemia in the acutely displayed infarcts and the etiological factor for this vessel area could be predicted

Metabolomic analysis of biological fluids and tissues has become an increasingly routine tool in the biological toolbox. However, challenges remain to be overcome, including developing strategies to maximise coverage of the metabolome without requiring large sample volumes. Here we describe a multimodal strategy that combines data using both LC-MS and GC-MS from a unique vial with a sample of plasma (20µl) or a sample of brain tissue (3mg). Using a split phase extraction the non-aqueous phase was analyzed by reversed phase (RP) LC-MS, whilst the aqueous phase was analyzed using hydrophilic liquid interaction chromatography (HILIC)LC-MS, with both phases also analysed using GC-MS after derivatization of the extract. Analytical performance was assessed in 7 rat cerebellum samples and a pilot study of 40 plasma samples (20 vs. 20: AD vs. healthy controls). The method, which uses four hours of instrument time, measured 20,707 metabolite features in brain samples and 17,266 in plasma samples, from those 44.1% features displayed CV’s below 15% and 75.2% below 30%. The method has potential to resolve subtle biological differences and to correlate metabolite composition directly to clinical outcomes including MMSE, age and ADCS-ADL. This method can acquire in the order of 20K metabolic features when low volumes are available.

Following traumatic brain injury (TBI), secondary brain damage due to chronic inflammation is the most predominant cause of the delayed onset of mood and memory disorders. Currently no therapeutic approach is available to effectively mitigate secondary brain injury after TBI. One reason is the blood-brain barrier (BBB), which prevents passage of most therapeutic agents into the brain. Peptides have been among the leading candidates for CNS therapy due to their low immunogenicity and toxicity, bioavailability, and ease of modification. In this study, we demonstrated that non-invasive intranasal administration of KAFAK, a cell penetrating anti-inflammatory peptide, traversed the BBB in a murine model of diffuse, moderate TBI. Notably, KAFAK treatment reduced the production of pro-inflammatory cytokines that contribute to secondary injury. Furthermore, behavioral tests showed improved or restored neurological, memory, and locomotor performance in KAFAK-treated mice. This study demonstrates KAFAK's ability to cross the blood-brain barrier, to lower pro-inflammatory cytokine levels in vivo, and to restore function after a moderate TBI.

Glioblastoma multiforme (GBM) is a glioma and the most aggressive type of brain tumor with a dismal average survival time, despite the standard of care. One promising alternative therapy is boron neutron capture therapy (BNCT), which is a noninvasive therapy for treating locally invasive malignant tumors, including glioma. BNCT involves boron-10-released radiation directly into tumor cells with minimal damage to healthy tissues. This therapy lacks clinically approved targeted blood-brain-barrier-permeating delivery vehicles for therapeutic drug/ boron-10. Nanoparticles, particularly gold nanoparticles (GNPs), are selective and effective drug-delivery vehicles because of their desirable properties, facile synthesis, and biocompatibility. This review discusses historical and current GNP therapeutic applications as a drug delivery vehicle for treating glioma. Furthermore, GNPs loaded with therapeutic drugs, imaging agents, and GBM-targeting antibodies/ peptides to treat GBM will be discussed. Additionally, the importance of upper and lower limits on therapeutic efficacy will be described and explored followed by highlighting their advantages, limitations, and possible toxicity. Recent research and selected important findings for GNP-mediated pharmaceutics in GBM will also be considered.

Survival of Medulloblastoma (MB) depends on various factors, including the gene expression profiles of MB tumor tissues. In this study, we identified 967 MB survival related genes (SRBs) using the gene expression dataset of Cavalli et al. (2017) and the Cox proportional hazards regression model. Notably, the SRGs were over-represented on chromosomes 6 and 17, known for the abnormalities monosomy 6 and isochromosome 17 in MB. The most significant SRG was HMGA1 (high mobility group AT-hook 1), which is a known oncogene and a histone H1 competitor. High expression of HMGA1 was associated with worse survival, primarily in the Group 3γ subtype. The high expression of HMGA1 was unrelated to any known somatic copy number alteration. Most SRGs on chromosome 17p were associated with low expression in Group 4β, the MB subtype with 93% deletion of 17p and 98% copy gain of 17q. Pathway analysis showed that both chromosomes 6 and 17 included SRGs related to telomere maintenance and provide a rationale for testing telomerase inhibitors in Group 3 MBs. We conclude that HMGA1, along with other SRGs on chromosome 6 and 17 warrant further investigation as potential therapeutic targets in selected subgroups or subtypes of MB.

This study aimed to investigates obesity-related glomerulopathy (ORG) at cellular, structural, and transcriptomic levels. Thirty Wistar rats were randomized into two groups: control (n=15) and study groups (n=15) that were fed a standard (SD) and high-fat diet (HFD), respectively. After 10 weeks, the weight, kidney function, histological features, and transcriptomic changes were assessed. HFD group exhibited increased weight gain (55.8% vs 29.2%; P< 0.001) and albuminuria (10384.04 ng/ml vs 5845.45 ng/ml; P<0.001) compared to controls. The HFD group exhibited early stages of ORG lesions, with a predominance of mesangial matrix increase and podocyte hypertrophy (PH). These lesions correlated with differentially expressed (DE) genes and miRNAs. Functional analysis showed that four DE miRNAs in the kidneys of the HFD group negatively regulated the PTEN gene, which promotes podocyte endocytosis of lipids in ORG. Among these four miRNAs, miR-205 was upregulated in the urine of the HFD group. HFD-fed Wistar rats developed early stages of ORG, with a specific targetome of miRNAs and gene expression. The upregulation of miR-205 in the kidney and its isolation in urine are associated with lipid endocytosis in podocytes, which could become a plausible biomarker of the early stages of ORG and lead to future therapeutic research.

Objective To investigate nailfold capillary parameters in community-dwelling individuals aged over 60 years who have hypertension and do not exercise regularly. Furthermore, the study examined the correlations between capillary function and other health-related indicators. Design A single- center pilot trial Setting Faculty of Health, Tsukuba University of Technology, Japan Participants hypertensive community-dwelling elderly people Intervention Microcirculation was observed before and 1 min after arm-curl exercise by means microscopy of capillary with non-exercised limb. Additionally, we examined other health-related indicators. Outcome measures: Acute effects of reperfusion on nailfold density, flow, and diameters. Secondary outcomes included the correlations between microvascular parameters and other health-related indicators. We hypothesized that brief exercise could enhance microcirculation reperfusion and correlate with other health-related parameters.　 Results: There were 20 participants with a mean (SD) age of 67.1 (5.8) years. The capillary flow rate changed from 2.3±6.7 to 2.7±0.2 log µm/s (P

.Background: Negative outcomes associated with medications (NOM) and drug-related problems (DRP) significantly impact individuals with kidney replacement therapy (KRT) given the complexities of managing kidney disease and associated comorbidities. The present study aims to assess the frequency of NOMs/DRPs among KRT patients and identify contributing factors. Methods: A cross-sectional study was conducted at the Virgen de las Nieves University Hospital (Granada, Spain), involving 117 outpatient adults with KRT. Data were collected from February 2021 to July 2023 using electronic records, semi-structured interviews (Dáder Method), and discussions with nephrology specialists. NOMs/DRPs were identified following treatment guidelines. Binary logistic regression determined associated factors (p-value < 0.05). Results: Across 117 patients, 2,436 NOMs and 3,303 DRPs were identified, averaging 20.82 NOMs and 28.23 DRPs per patient. Prevalent NOMs included untreated conditions (58.95%), quantitative ineffectiveness (35.43%), and non-quantitative safety problems (5.13%). Dominant DRPs were undertreated conditions (37.63%), wrong dose/posology/length (33.00%), risk of adverse drug reactions (ADR) (16.14%), and non-adherence (6.87%). Patients with ADR, undertreated condi-tions, and anemia were associated with quantitative ineffectiveness. Risk of ADR and vitamin D deficiency/insufficiency correlated with non-quantitative safety problems. Conclusions: KRT pa-tients exhibited a substantial prevalence of NOMs/DRPs. Further research is needed to deepen our understanding of these complexities for improved patient care.

Background: Micronutrient deficiencies are common at the time of cancer diagnosis and are associated with worse prognosis. Little is known about them in cancer rehabilitation. Methods: Data from routine health related quality of life (HRQOL) were analyzed at an inpatient cancer rehabilitation center. Rehabilitation patients completed the EORTC QLQ-C30 questionnaire before and after multidisciplinary rehabilitation treatment, and three month after discharge. Selenium and zinc status was measured in whole blood at these three time points. In case of selenium deficiency up to 600 µg selenium per day as sodium selenite was supplemented. Results: A total of 271 patients (breast, colon, and pancreatic cancer) were included in the analysis. There was clinically meaningful improvement in many domains of the EORTC QLQ-C30 during rehabilitation. However, effect often waned in the three months after. Prevalence for selenium deficiency varied between 34 to 90 percent depending on cancer type (breast &lt; colon &lt; pancreas). In contrast, zinc deficiency was rare. Daily selenium supplementation of 600 µg was more efficient to correct selenium deficiency compared to 300 µg selenium per day. Rehabilitation and increasing selenium status after rehabilitation were associated with improved global quality of life, physical and emotional functioning, and fatigue. In cancer patients with decreasing selenium status, values of global quality of life, physical and emotional functioning, and fatigue were back to the values at the beginning of rehabilitation. Conclusions: Selenium deficiency is common in cancer patients admitted to a cancer rehabilitation clinic. Selenium supplementation during rehabilitation effectively corrected selenium deficiency in most cases. The positive effects of rehabilitation persisted longer, when selenium status did not decrease after rehabilitation.

: Molecular targeting strategies have been used for years to control cancer progression and are often based on targeting various enzymes involved in metabolic pathways. Keeping that in mind, it is essential to know the role of each enzyme in a particular metabolic pathway. In this review, we are providing in-depth knowledge of various enzymes such as ceramidase, sphingosine kinase, sphingomyelin synthase, dihydroceramide desaturase, and ceramide synthase, which are associated with multiple types of cancer that depend on ceramide metabolism. Focus has also been given to discussing physicochemical properties of well-studied inhibitors of natural products origin and their related structures for these enzymes. Targeting ceramide metabolism exhibited promise in mono and combination therapies at preclinical stages to prevent cancer progression and paved the way for the significance of sphingolipid metabolism in cancer treatments. Targeting ceramide metabolizing enzymes will help the medicinal chemist to design potent and selective small molecules for treating cancer progression at various levels.

The root system plays an irreplaceable role in plant growth. Its improvement can increase crop productivity. However, such system is still mysterious for us. The underlying mechanism has not been fully uncovered. The investigation on proteins related to the root system is an important means to complete this task. In the previous time, lack of root-related proteins makes it impossible to adopt machine learning methods for designing efficient models for the discovery of novel root-related proteins. Recently, a public database on root-related proteins was set up and machine learning methods can be applied in this field. In this study, we proposed a machine learning based model, named Graph-Root, for identification of root-related proteins. The features derived from protein sequences and one network were extracted, where the former features were processed by graph convolutional neural network and multi-head attention, and the later features abstracted the linkage between proteins. These features were fed into the fully connected layer to make prediction. The 5-fold cross-validation and independent tests suggested its good performance. It also outperformed the only one previous model, SVM-Root. Furthermore, the importance of each feature type and component in the proposed model was investigated.

Patients with Parkinson’s Disease (PD) experience REM sleep behavior disorder (RBD) more frequently than healthy controls. RBD is associated with torpid disease evolution. To test the hypothesis that differential genetic signatures might contribute to the torpid disease evolution in PD patients with RBD. We compared the rate of genetic mutations in PD patients with or without probable RBD. Patients with a clinical diagnosis of PD in the Parkinson’s Progression Markers Initiative (PPMI) database entered the study. We excluded those with missing data or a diagnosis change over the first five years from the initial PD diagnosis. Probable RBD (pRBD) was confirmed by a REM Sleep Behavior Disorder Screening Questionnaire score &gt;5 points. Logistic regression and Machine Learning (ML) algorithms were used to relate Single Nucleotide Polymorphism (SNPs) in PD-related genes with pRBD. We included 330 PD patients fulfilling all inclusion and exclusion criteria. The final logistic multivariate model revealed that the following SNPs increased the risk of pRBD: GBA_N370S_rs76763715 (OR, 95% CI: 3.38, 1.45-7.93), SNCA_A53T_rs104893877 (8.21, 2.26-36.34), ANK2. CAMK2D_rs78738012 (2.12, 1.08-4.10), and ZNF184_rs9468199 (1.89, 1.08-3.33). Conversely, SNP COQ7. SYT17_rs11343 reduced pRBD risk (0.36, 0.15-0.78). The ML algorithms led to similar results. The predictive models were highly specific (95-99%) but lacked sensitivity (9-39%). We found a distinctive genetic signature for pRBD in PD. The high specificity and low sensitivity of the predictive models suggest that genetic mutations are necessary but not sufficient to develop RBD in PD. Additional investigations are needed.

Hypertension (HT) is a very common risk factor and a frequent cause of morbidity and mortality worldwide mainly due to much increase in overweight (OW) and obesity that manifests in various forms of cardiovascular disease (CVD). There are a number of factors that may cause overweight hypertension (OHT). However, we planned to conduct the present work to study the HT and OHT men for finding the variation, interrelationship and association of important cytokines mainly serum leptin (Lep) and tumor necrosis factor-alpha (TNF-α), serum testosterone (ST), total cholesterol (TC) and inflammatory status by measuring interleukin-6 (IL-6). Three groups of subjects, the normal controls (NC; n:98; age range: 51-60 years), HT (n: 97; age range: 51-60 years) subjects, and OHT (n: 97; age range: 51-60 years) subjects were studied. Comparisons for Lep, ST, TNF-α, IL-6 and TC levels for the subject groups showed significant variations. The ST indicated significant difference only for NC vs. OHT. The IL-6 gave significant difference for NC vs. OHT and HT vs. OHT. The one-way ANOVA showed significant difference among groups for BMI, TC, IL-6, TNF-α, ST and Lep levels. Significant positive linear correlation for all groups among Lep, TNF-α, IL-6 and TC were found. The ST against TC for HT and OHT groups presented non-significant negative linear correlations. The ST showed significant negative linear correlation with other variables. Conclusively, the present study uncovers the interactive impact of serum leptin, TNF-α, testosterone, total cholesterol and IL-6 in hypertensive and overweight-related hypertensive men.

To date, the impact of COVID-19 vaccination on formerly menstruating women remains unknown. For this reason, a retrospective observational cross-sectional study was conducted (N= 548) using an online survey. General characteristics, medical history, and adverse events following COVID-19 vaccination were recorded. In comparison with the first dose, significantly higher percentages of respondents experienced menstrual-related disturbances (dose 1: 38.5% vs. dose 2: 44.8%; McNemar=9.15; mid P-value=0.002), as well as the simultaneous occurrence of two or more of these symptoms (dose 1: 11.2% vs. dose 2: 15.3%; McNemar=13.53; mid P-value=0.044) after receiving the second one. Among them, those related with the length and flow stand out, being of long-term nature in about 17-20% of cases. Interindividual factors influencing this unexpected event after receiving the dose 1 may include weight (AOR 1.02, CI 95% 1.01–1.03, P&lt;.001), perimenopause (AOR 2.28, CI 95% 1.37–3.77, P=.001), pre-existing diagnoses of non-autoimmune rheumatic/articular conditions (AOR 0.31, CI 95% 0.10–1.00, P=0.05), hormonal contraceptive use (AOR 0.25, CI 95% 0.07-0.82, P=0.02), suffering from other vaccine side effects − such as arm pain (AOR 0.61, CI 95% 0.39–0.95, P=0.03), headache (AOR 0.53, CI 95% 0.35 – 0.80, P=.003), swollen glands (AOR 0.29, CI 95% 0.15 – 0.60, P=.001) and nauseas (AOR 0.35, CI 95% 0.14 – 0.86, P=0.02) – and the number of previous pregnancies (AOR 2.70, CI 95% 1.54 – 4.76, P=.001). Formerly menstruating women may experience long-term menstrual-related disturbances following COVID-19 vaccination.

This study analyses key aspects of the professional life of primary school teachers in a southern European context. In the social changes of last two decades profoundly impacted the well-being of teachers putting a strain on their ability to adapt to sometimes unfair working conditions. For this purpose twenty teachers (M = 38.85; DS = 9.17) were interviewed from different areas of Italy, data were analyzed using the Grounded Theory Method. Through data analysis were summa-rize and emphasize eight core themes. The results show the effects of a gradual impoverishment of the recognition of the role of teacher, highlighting the difficulty for teachers of renegotiating more flexible workload assessments and of reinforcing psycho-emotional skills for the development of a teaching methodology attentive to the psycho-emotional needs of pupils. Schools emerge as a rigid working context, in which a competent organizational function is often absent. Practical psychological implications are discussed.

Tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI) significantly improve the outcomes of patients with advanced clear cell renal cell carcinoma (ccRCC), but high-grade toxicities can occur, particularly during combination therapy. Herein, we report a patient with advanced metastatic ccRCC, who developed grade 4 cholestasis during combined therapy with nivolumab and cabozantinib. After the exclusion of common disorders associated with choles-tasis and a failure of corticosteroids (CS), a liver biopsy was performed that demonstrated severe ductopenia. Consequently, a diagnosis of vanishing bile duct syndrome related to TKI and ICI administration was made, resulting in CS discontinuation and ursodeoxycholic acid administra-tion. After a 7-months follow-up, liver tests had returned to normal values. Immunological studies revealed that our patient had developed robust T-cells and macrophages infiltrates in his lung metastasis, as well as in skin and liver tissues at the onset of toxicities. At the same time, peripheral blood immunophenotyping revealed significant changes in T-cell subsets suggesting their potential role in the pathophysiology of the disease.

Grapevine is one of the most relevant crops in the world being used for economically important products such as wine. Yet, relevant grapevine cultivars are heavily affected by diseases such as the downy mildew disease caused by Plasmopara viticola. Improvements on grapevine resistance are made mainly by breeding techniques where resistance traits are introgressed into cultivars with desired grape characteristics. However, there is still a lack of knowledge on how resistant or tolerant cultivars tackle the P. viticola pathogen. In this study, using a shotgun proteomics LC-MS/MS approach, we unravel the protein modulation of a highly tolerant grapevine cultivar, V. vinifera ‘Regent’, in the first hours post inoculation (hpi) with P. viticola. At 6 hpi, proteins related to defence and to response to stimuli are negatively modulated while at 12 hpi there is an accumulation of proteins belonging to both categories. The co-occurrence of effector-triggered susceptibility (ETS) and effector-triggered immunity (ETI) is detected at both time-points, showing that these defence processes present high plasticity. The results obtained in this study unravel the tolerant grapevine defence strategy towards P. viticola and may provide valuable insights on resistance associated candidates and mechanisms, which may play an important role in the definition of new strategies on breeding approaches.

The 2030 Agenda sets out seventeen Sustainable Development Goals (SDGs). The educational goal is to promote the education of citizens on sustainable development, among other things. Educating today's digital citizens on sustainability means training them for justice and social activism, commitment and political engagement. However, research into the subject shows a lack of consistency in the education of university students. This paper presents a study of students of Education, on education on sustainability through the practice of active and critical digital citizenship. A quasi-experimental method was used to learn about the behaviours of digital citizens, and intervention was carried out by means of an SDG-focused workshop and observation of the final level of commitment. The results show a positive level of commitment and digital activism around content related to sustainable development, which can be addressed from the university syllabus in a cross-curricular way.

Deregulation of cell growth and development lead to cancer, a severe condition that claims millions of lives worldwide. Targeted or selective approaches used during cancer treatment determine the efficacy and outcome of the therapy. In order to enhance specificity and targeting and better treatment options for cancer, novel and alternative modalities are currently under development. Photodynamic therapy has the potential to eradicate cancer and combination therapy would yield even greater outcomes. Nanomedicine-aided cancer therapy shows enhanced specificity for cancer cells and minimal side-effects coupled with effective cancer destruction both in vitro and in vivo. Nanocarriers used in drug-delivery systems are well able to penetrate cancer stem cell niche, simultaneously killing cancer cells and eradicate drug-resistant cancer stem cells, yielding therapeutic efficiency up to 100 fold against drug-resistant cancer in comparison with free drugs. Safety precautions should be considered when using Nano-mediated therapy as the effects of extended exposure to biological environments are still to be determined.

Background: many studies, on for example taste-visual dissonance, have shown that the influence of the visual cortex on taste sensation is enormous. The aim of the presented work is to investigate, using fNIRS, whether a taste stimulus, in this case the taste of bitter, also causes stimulation of the visual cortex in fNIR study. Methods: 51 participants (204 examinations, 9 996 records) were examined with fNIRS, which collects signals from whole left hemisphere. Differences between the maximum and minimum changes in oxyHb concentrations (ΔoxyHb) for the areas of the brain cortex considered responsible for recording visual and gustatory signals were analyzed. Protocol I, II, III and IV – activation with distillate water, coffee with lower concentration, reference (no stimulation) and coffee with higher concentration respectively, were used. Results: We recorded high signals for teste activation on channels covered gustatory cortex, which confirms the correctness of the choice of research method. What seems important, and somewhat surprising, is the fact that we also received high signals for the channels 45-49, which cover the visual cortex. The statistical analysis does not show any statistical differences between the protocols I, II and IV (different taste activation – water, coffee A and coffee B) for specific channels. As a results of the analysis of the correlation between the subjective bitterness assessment solutions, and the signal ΔoxyHb height, it was observed that statically important correlation, although weak, occurs only for 14 and gustatory channels, only for coffee with a higher concentration. Additionally we recorded the only statistically significant difference between women and men for protocol I (water), where the ΔoxyHb signal was twice as high for women. Conclusions: In conclusion, we can clearly state that the senses of sight and taste work closely together. Moreover, this cooperation is not one-sided - not only the visual activation affects the perception of taste, but interestingly, the taste stimulus can generate a hemodynamic response - activity in the visual cortex.

Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disorder of the white matter. Pathophysiology is thought to be immune mediated as in most cases the condition follows an infection or triggering incident. More recent literature has demonstrated that there may be a link between autoimmune conditions and ADEM. Here we present a case of ADEM in a middle-aged woman with systemic lupus erythematosus that recovered well after treatment with corticosteroids and Rituximab.

In the last three decades the presence of phospholipids in the nucleus has been shown and thoroughly investigated. A great interest raised about nuclear inositol lipids mainly because of their role in signalling acting. Here we review the main issues of nuclear phospholipid localization and the role of nuclear inositol lipids and their related enzymes in cellular signaling both in physiological and pathological conditions.

One of the main causes of the dismal prognosis in patients who survive the initial bleeding after aneurysmal subarachnoidal hemorrhage is the delayed cerebral ischaemia caused by vasospasm. Studies suggest that cerebral magnesium and pH may potentially play a role in the pathophysiology of this adverse event. Using phosphorous magnetic resonance spectrocopy (31P-MRS) we calculated the cerebral magnesium (Mg) and pH level in 13 patients who suffered aSAH. The values between the group that developed clinically significant vasospasm (n=7) and the group that did not (n=6) were compared. The results of this study showed significantly lower cerebral Mg levels (p=0.019) and higher pH (p&lt;0.001) in cumulative group (all brain voxels together) in patients who developed clinically significant vasospasm. Further clinical studies on a larger group of carefully selected patients are needed in order to predict clinically significant vasospasm.

In our country, the aging society is rapidly progressing, with an increase in patients with chronic kidney disease (CKD) and those undergoing dialysis, coupled with the aging of the population. As a result, the number of individuals with cognitive impairment (CI) is rising, and addressing this issue has become an urgent problem. One characteristic of dementia in CKD patients is the high frequency of vascular dementia, making the prevention through the management of classical risk factors such as hypertension, diabetes mellitus, dyslipidemia, smoking, etc., associated with atherosclerosis and arteriosclerosis. Other effective measures, including the use of renin-angiotensin system inhibitors, addressing anemia, exercise therapy, and lifestyle improvements, have been reported. Incidence and progression of CI may also be influenced by the type of dialysis or kidney replacement therapy, with reports suggesting that long-duration dialysis, low-temperature hemodialysis, peritoneal dialysis, and kidney transplantation (KTx) can have a possible preferable effect on preserving cognitive function.

Pericyte and their tunnelling nanotubes (P-TNTs) have been described as involved in the early phases of angiogenesis in the human normal developing brain and glioblastoma, being a common feature of combined endothelium/pericyte vessel sprouts. Based on the few data available so far about this ‘alternative’ pericyte-TNT-driven mode of angiogenesis, whose precise function in vessel growth through vascular cells communication, has still to be determined, this study aims to cast light on the regulative molecules involved in this process, governed by intimate pericyte-endothelial interactions. After considering the existence of the sprout guiding pericyte and P-TNT, as shown by pioneering ultrastructural studies as well as by more recent observations with NG2/CD146 pericyte markers and basal lamina molecules, a step-by-step profile of the process has been suggested and an investigation undertaken on ‘unconventional’, pro-angiogenic ligand/receptor systems, that may have a role aside from the canonical pathways. In this context, a possible candidate worthy of investigation is the c-KIT receptor, a member of the tyrosine kinase family of proteins, which also includes the well-known VEGFR and PDGFR. According to the obtained results showing a primary localization of c-KIT on endothelial cells and pointing out a differential distribution of the receptor on normal vs glioblastoma vessels, it seems conceivable to propose the stem cell factor/c-KIT signaling as a key factor in pericyte-TNT-driven angiogenesis, advancing this alternative mode of angiogenesis and the c- KIT pathway as possible targets for devising effective antiangiogenic therapeutic strategies.

As an essential component of our innate immune system, the complement system is responsible for our defense against pathogens. The complement cascade has complex roles in the central nervous system (CNS), most of what we know about it stems from its role in brain development. However, in recent years, numerous reports have implicated the classical complement cascade in both brain development and decline. More specifically, complement dysfunction has been implicated in neurodegenerative disorders, such as Alzheimer’s disease (AD), which is the most common form of dementia. Synapse loss is one of the main pathological hallmarks of AD and correlates with memory impairment. Throughout the course of AD progression, synapses are tagged with complement proteins and are consequently removed by microglia which express complement receptors. Notably, astrocytes are also capable of secreting signals that induce the expression of complement proteins in the CNS. Both astrocytes and microglia are implicated in neuroinflammation, another hallmark of AD pathogenesis. In this review, we provide an overview of previously known and newly established roles for the complement cascade in the CNS and we explore how complement interactions with microglia, astrocytes, and other risk factors such as TREM2 and ApoE4, modulate the processes of neurodegeneration in both amyloid and tau models of AD.

Presenting a case report about a 14-year-old female patient presenting with a history of weakness in all four limbs since the age of 5. The patient has a history of difficulty in walking, wearing footwear, climbing stairs, and performing fine motor tasks. During the neurological examination showed mild spasticity, muscle weakness, areflexia, ill-sustained clonus, and sensory deficits. Radiological examination, including a contrast-enhanced MRI of the brain was done which showed findings that are consistent with Megalencephalic leukoencephalopathy with subcortical cysts, also known as Van der Knaap disease.

Three-quarters of a million babies are born extremely preterm (< 28 weeks’ gestation) world-wide with devastating outcomes: 20% die in the newborn period, a further 35% develop bronchopul-monary dysplasia (BPD) and 10% suffer from cerebral palsy. Pioglitazone, a Peroxisome Proliferator Activated Receptor Gamma (PPARγ) agonist, may reduce the incidence of BPD and improve neurodevelopment in extreme preterm babies. Pioglitazone exerts an anti-inflammatory action mediated through Nuclear Factor-kappa B repression. PPARγ signalling is underactive in preterm babies as adiponectin remains low during the neonatal pe-riod. In newborn animal models, pioglitazone is shown to be protective against BPD, necrotising en-terocolitis, and lipopolysaccharide-induced brain injury. Single Nucleotide Polymorphisms of PPARγ are associated with inhibited preterm brain development and impaired neurodevelop-ment. Pioglitazone was well tolerated by the foetus in reproductive toxicology experiments. Bladder cancer, bone fractures, and macular oedema seen rarely in adults may be avoided with a short treatment course. Other effects of pioglitazone including improved glycaemic control and lipid metabolism may provide added benefit in prematurity. Currently, there is no formulation of pioglitazone suited for administration to preterm babies A liquid formulation of pioglitazone needs to be developed before clinical trials. The potential benefits are likely to outweigh any anticipated safety concerns.

Since there are no morphological clues capable of making a pathologist suspect a possible mammary origin of a metastatic lesion without adequate clinical information, the histologic diagnosis of brain metastasis from BC is still based on the immunohistochemical expression of mammary gland markers such as GATA-3, ERs, PgRs and HER-2. The present retrospective study aimed to select purely morphological features capable to suggest the mammary origin of a metastatic carcinoma to the brain. The following histological features were collected on a series of 30 cases of brain metastases from breast cancer:(i) solid growth pattern; (ii) presence of comedonecrosis; (iii) glandular differentiation. Our results showed that most cases histologically exhibited solid growth pattern with at least focal comedonecrosis, producing an overall morphology closely reminiscent of mammary high-grade ductal carcinoma in situ. Although the above-mentioned morphological parameters are not strictly specific to a mammary origin, they may have an important diagnostic utility in leading pathologists to suspect a possible breast primary tumor and to include GATA-3, ERs, PgRs and HER-2 to the immunohistochemical panel.

As the human-body controls depend on the brain neuro current, here assay is related to thinking nerve detection. For this purpose, the brain current was analyzed by electrochemical three-electrode systems using 0.1-mm micro wire in vivo probe, which probe was made by using carbon nanotube paste coated needle type. Here working electrode was inserted in the rat brain’s muscle core with a 0.3-mm-diameter needle type Ag/AgCl Cl-coated Ag wire reference, and counter electrode of 0.1-mm-diameter Pt micro needle was inserted 5 mm deep into the in vivo muscle skin, under anesthesia with 2.0 ~ -2.0 V potential windows, 50 mv/s cyclic scan and 1.0x10-5A chrono amperometric sensitivity on the body systems. Under the optimum conditions, diagnostic application was performed to such as smell signal, muscular strength, five sense assay and thinking neuro current.

Background: Early diagnosis of acute brain injury (ABI) is critical for patients on venoarterial extracorporeal membrane oxygenation (VA-ECMO) to guide anticoagulation strategy; however, neurological assessment in ECMO is often limited by patient sedation. Methods: In this pilot study of adults from June 2018 to May 2019, plasma samples of glial fibrillary acidic protein (GFAP), neurofilament light chain (NFL), and Tau were collected daily after VA-ECMO cannulation and measured using a multiplex platform. Primary outcomes were the occurrence of ABI, assessed clinically, and neurologic outcome, assessed by modified Rankin Scale (mRS). Results: Of 20 consented patients (median age=48.5 years; 55% female), 8 (40%) had ABI and 15 (75%) had unfavorable neurologic outcomes at discharge. 10 (50%) patients were centrally cannulated. The median duration on ECMO was 4.5 days (IQR: 2.5-9.5). Peak GFAP, NFL, and Tau levels were higher in patients with ABI vs. without (AUC = 0.77; 0.85; 0.57, respectively) and in patients with unfavorable vs. favorable neurologic outcomes (AUC = 0.64; 0.59; 0.73, respectively). GFAP elevated first, NFL elevated to the highest degree, and Tau showed limited change regardless of ABI. Conclusion: Plasma biomarkers may facilitate early detection of ABIs in VA-ECMO where neurological exam is limited and assist timely clinical decision-making.

Background: Hepatic interstitial T-lymphocytes (T-Li), Natural Killer (NK) and NK-T cells play an important role in both innate and adaptive immunity and contribute to the regulation of ischemia/reperfusion injury (IRI) after transplantation of abdominal organ. Methods: The cellular concentrations and phenotypes of NK, T-Li, NK-T were analyzed retrospectively in a consecutive series of hepatic perfusates after surgical removal of whole livers on the bench previously collected from adult multi-organ donors after brain death. (DBD), and compared with the demographic and pathological characteristics of the patients transplanted at our Institute with kidneys taken from the same donors. The liver interstitial cells were purified from the perfusate by density gradient centrifugation and the phenotype was determined by flow cytometric investigation using the following immunological markers: CD3, CD4, CD8 and CD56 in order to determine the relative percentage of T-Li, NK-T and NK cells. Results: The perfusates of 42 DBDs, and the related clinical outcome of kidney transplant recipients from 2010 to 2020, were analyzed. T-Li were significantly associated with the time in days of delayed functional recovery of transplanted kidneys (DGF) (p = 0.02), to onset of secondary infection from Cytomegalovirus (p = 0.03). On COX analysis, percent cell concentration of T-Li and time to DGF were significantly associated with an increased relative risk (HR) of organ survival (HR = 1.038, p = 0.04; and HR = 1.029, p = 0.01, respectively). The specificity of the NK and NK-T cell proportions were not associated with any relevant clinical outcomes in kidney transplant patients. Conclusions: The present study points to a new potential role of T-Li cells detected in the context of liver perfusate DBD, and could detect potential impacts in organ allocation, surgical harvesting techniques and in the analysis of IRI pathophysiological events after kidney transplants from multi-organ DBDs.

Translation of basic animal research to find effective methods of diagnosing and treating human neurological disorders requires parallel analysis infrastructures. Small animals such as mice provide exploratory animal disease models. However, many interventions developed using small animal models fail to translate to human use due to physical or biological differences. Recently, large-animal minipigs have emerged in neuroscience due to both brain similarity and economic advantages. Medical image processing is a crucial part of research as it allows researchers to monitor their experiments and understand disease development. However, although many algorithms are created and optimized for MR analysis of human data, those tools are not directly applicable or sufficiently sensitive to measure minipig data. In this work, we propose PigSNIPE - a pipeline for the automated handling, processing, and analyzing of large-scale data sets of minipig MR images. The pipeline allows for image registration, AC-PC alignment, landmark detection, skull stripping, brainmasks and intracranial volume segmentation (DICE 0.98), tissue segmentation (DICE 0.82), and caudate-putamen brain segmentation (DICE 0.8) in under two minutes. To the best of our knowledge, this is the first automated pipeline tool aimed at large animal images.

The gut microbiome is a collection of microorganisms and parasites that reside in the gastrointestinal tract. There are many factors that can affect the composition of this community, such as age, sex, medications, and environmental triggers. The relationship between the human host and the gut microbiota is very important for both the survival and development of the organism. The disruption of this relationship can lead to the development of various inflammatory diseases. CBD and THC are used to treat muscle spasticity associated with multiple sclerosis. It is now clear these compounds also benefit patients with neuroinflammation. A study that investigated the role of gut microbiota in treating the inflammation and paralysis in a mouse model demonstrated that treatment with CBD and THC produced significant decrease in the inflammation levels. They also exhibited a significant increase in the number of anti-inflammatory cytokines. The presence of certain cannabinoids can suppress neuroinflammation and prevent microbial dysbiosis. Several studies have revealed the role of the gut microbiota in the development and maintenance of skeletal integrity and bone mineral density. The gut is a major source of nutrients, including vitamins B and K. It can also influence the development and maintenance of bone matrix. The presence of the gut microbiota can influence the actions of certain T regulatory cells, which can lead to the development of bone formation and proliferation. In addition, its metabolites can prevent bone loss. The gut microbiota can help maintain the bone's equilibrium and prevent the development of metabolic diseases, such as osteoporosis. In this review, the dual functions gut microbiota plays in the regulation of gut-bone axis and gut-brain axis and the impact of CBD on these roles are discussed in detail.

The evolving global SARS-CoV-2 pandemic emphasizes how unprepared we are for the emergence of the next lethal viral pathogen. A list of potential candidates was created by the World Health Organization which named Nipah virus infection as the highly lethal prototypic member of that list. Building on our earlier viral pandemic preparedness research into SARS-CoV-2 we have created computer simulations of Nipah virus infection complicated by encephalitis, the most common cause of Nipah-associated mortality. In the current experiments, we first created updated simulations of wild-type whole-brain organoids (aiWBO). Upon validation, the aiWBO were infected with the simulated Nipah virus genome. The Nipah encephalitis simulations (aiWBO-NiV) were then used to find optimal single, double, and triple protein combinations for candidates as potential targets for vaccine development. Our data suggest that the use of multi-viral proteins/epitopes chimera is the most promising approach to Nipah vaccine development and that employing artificial intelligence to guide the identification of promising vaccine candidates is an efficient and cost-effective strategy for future viral pandemic preparedness.

The blood-brain barrier (BBB), built by brain endothelial cells (BECs), is impermeable to biologics. Liposomes and other nanoparticles are good candidates for delivery of biologics across the BECs, as they can encapsulate numerous molecules of interest in an omnipotent manner. The liposomes need attachment of a targeting molecule, as BECs unfortunately are virtually incapable of uptake of non-targeted liposomes from the circulation. Experiments of independent research groups have qualified antibodies targeting the transferrin receptor as superior for targeted delivery of nanoparticles to BECs. Functionalization of nanoparticles via conjugation with anti-transferrin receptor antibodies leads to nanoparticle uptake by endothelial cells of both brain capillaries and post-capillary venules. Reducing the density of transferrin receptor-targeted antibodies conjugated to liposomes limits uptake in BECs. Opposing the transport of nanoparticles conjugated to high-affine anti-transferrin receptor antibodies, lowering the affinity of the targeting antibodies or implementing monovalent antibodies increase uptake by BECs and allows for further transport across the BBB. The novel demonstration of transport of targeted liposomes in post-capillary venules from blood to the brain is interesting and clearly warrants further mechanistic pursuit. The recent evidence for passing targeted nanoparticles through the BBB shows great promise for future drug delivery of biologics to the brain.

Methylmercury is a neurotoxin present in fish tissues that permeates the blood-brain barrier after consumption. Previous research has shown that methylmercury is harmful to neurons, causing pH alterations, oxidative stress, excitotoxicity, and parenchymal damage. Methylmercury is a known factor of neurological disorders including Alzheimer's and Parkinson's. The method by which methylmercury passes through the blood-brain barrier is largely unknown. According to preliminary studies, one way methylmercury crosses the blood-brain barrier is by creating a complex with L-Cysteine, which facilitates its passage by the LATs system through mimicking another amino acid existing in the body. The human blood-brain barrier was studied using C. elegans as a model organism. It was hypothesized that if methylmercury passes through the blood-brain barrier of C. elegans faster with L-Cysteine present than without L-Cysteine present, the methylmercury's adverse effects (death and locomotive difficulty) will occur sooner. Each of the four experimental groups contained one C. elegans: the control, the L-Cysteine group, the methylmercury group, and the methylmercury and L-Cysteine combination group. The effects of L-Cysteine and methylmercury on C. elegans were studied using three metrics: viability, locomotive disability, and time for locomotive effects to occur. The group that received both methylmercury and L-Cysteine had reduced viability rates and a decreased time for locomotive difficulty to develop, supporting the hypothesis. These findings suggest that L-Cysteine aids methylmercury permeation through the blood-brain barrier. Because the experiment indicates how methylmercury penetrates the blood-brain barrier, these results aid in finding a therapeutic solution to reverse methylmercury neurotoxicity in the brain. Additionally, this study further opens channels into potential therapeutic and preventative measures for dementia, improving morbidity and mortality in neurodegenerative diseases.

Glial fibrillary acidic protein (GFAP) is the major intermediate filament III protein of astroglia cells which is upregulated in traumatic brain injury (TBI). Here we reported that GFAP is truncated at both the C- and N-terminals by cytosolic protease calpain to GFAP breakdown products (GBDP) of 46-40K then 38K following pro-necrotic (A23187) and pro-apoptotic (staurosporine) challenges to primary cultured astroglia or neuron-glia mixed cells. In addition, with another pro-apoptotic challenge (EDTA) where caspases are activated but not calpain, GFAP was fragmented internally, generating a C-terminal GBDP of 20 kDa. Following controlled cortical impact in mice, GBDP of 46-40K and 38K were formed from day 3 to 28 post-injury. Purified GFAP protein treated with calpain-1 and -2 generates (i) major N-terminal cleavage sites between A-56 and A-75, and (ii) major C-terminal cleavage sites between T-383 and Q-388, producing a limit fragment of 38K. Caspase-6 treated GFAP was cleaved at D-78, R-79, D-266 and A-267, where GFAP was relatively resistant to caspase-3. We also derived a GBDP-38K N-terminal-specific antibody which only labels injured astroglia cell body in both cultured astroglia and mouse cortex and hippocampus after TBI. As a clinical translation, we observed that CSF samples collected from severe human TBI have elevated levels of GBDP-38K as well as two C-terminally released GFAP peptides (DGEVIKES and DGEVIKE). Thus, in addition to intact GFAP, both the GBDP-38K as well as unique GFAP released C-terminal proteolytic peptides species might have the potential in tracking brain injury progression.

Objective A trained T1 class Convolutional Neural Network (CNN) model will be used to examine its ability to successfully identify motor imagery when fed pre-processed electroencephalography (EEG) data. In theory, and if the model has been trained accurately, it should be able to identify a class and label it accordingly. The CNN model will then be restored and used to try and identify the same class of motor imagery data using much smaller sampled data in an attempt to simulate live data. Approach PyCharm, a Python platform, will be used to house and process the CNN. The raw data used for the training of the CNN will be sourced from the PhysioBank website. The EEG signal data will then be pre-processed using Brainstorm software that is a toolbox used in conjunction with MATLAB. The sample data used to validate and test the trained CNN, will be also be extracted from Brainstorm but in a much smaller size compared to the training data which is comprised of thousands of images. The sample size would be comparable to a person wearing a Brain Computer Interface (BCI), offering approximately 20 seconds of motor imagery signal data. Results The raw EEG data was successfully extracted and pre-processed. The deep learning model was trained using the extracted image data along with their corresponding labels. After training, it was able to accurately identify the T1 class label at 100 percent. The python coding was then modified to restore the trained model and feed it test sample data in which it was found to recognise 6 out of 10 lines of T1 signal image data. The result suggested that the initial training of the model required a different, more varying approach, so that it would be able to detect varying sample signal image data. The outcome of which could mean that the model could be used in applications for multiple patients wearing the same BCI hardware to control a device or interface.

Brain tissue segmentation is an important component of clinical diagnosis of brain diseases by means of multi-modal magnetic resonance imaging (MR). Brain tissue segmentation is developed by many unsupervised methods in literature. The most commonly used unsupervised methods are: K-Means, Expectation Maximization and Fuzzy Clustering. Fuzzy clustering methods offer considerable benefits compared with the aforementioned methods as they are capable of handling brain images which are complex, largely uncertain and imprecise in nature. However, this approach suffers from the intrinsic noise and intensity inhomogeneity (IIH) in the data resulted from the acquisition process. To resolve these issues, we propose a fuzzy consensus clustering algorithm that defines a membership function resulted from a voting schema to cluster the pixels. In particular, we first pre-process the MRI data and employ several segmentation techniques based on traditional fuzzy sets and intuitionistic sets. Then, we adopted a voting schema to fuse the results of the applied clustering methods. Finally, to evaluate the proposed method, we used the well-known performance measures (boundary measure, overlap measure and volume measure) on two publicly available datasets (OASIS and IBSR18). The experimental results show the superior performance of the proposed method in comparison with the recent state of the arts.

We validated a new noninvasive tool (B4C) to assess intracranial pressure waveform (ICPW) morphology in a set of neurocritical patients, correlating the data with ICPW obtained from invasive catheter monitoring. Materials and Methods: Patients undergoing invasive intracranial pressure (ICP) monitoring were consecutively evaluated using the B4C sensor. Ultrasound-guided manual internal jugular vein (IJV) compression was performed to elevate ICP from the baseline. ICP values, amplitudes, and time intervals (P2/P1 ratio and time-to-peak [TTP]) between the ICP and B4C waveform peaks were analyzed. Results: Among 41 patients, the main causes for ICP monitoring included traumatic brain injury, subarachnoid hemorrhage, and stroke. Bland-Altman’s plot indicated agreement between the ICPW parameters obtained using both techniques. The strongest Pearson’s correlation for P2/P1 and TTP was observed among patients with no cranial damage (r = 0.72 and 0.85, respectively) in detriment of those who have undergone craniotomies or craniectomies. P2/P1 values of 1 were equivalent between the two techniques (area under the receiver operator curve [AUROC], 0.9) whereas B4C cut-off 1.2 was predictive of intracranial hypertension (AUROC 0.9, p < 000.1 for ICP > 20 mmHg). Conclusion: B4C provided biometric amplitude ratios correlated with ICPW variation morphology and is useful for noninvasive critical care monitoring.

Background: Morphological alterations in intracranial pressure pulse waveform (ICPPW) secondary to intracranial hypertension (ICP >20 mmHg) and reduction in intracranial compliance (ICC) are well known indicators of neurological severity. To date, no studies have documented the ICPPW modifications after intracranial hypertension resolution with decompressive craniectomy (DC). The present study aimed to assess the morphological alterations in ICPPW among neurocritical care patients with and without DC, by comparing the variations of ICPPW features according to elevations in mean ICP values. Methods: Patients requiring ICP monitoring because of severe traumatic or spontaneous conditions were included. Mean ICP values were compared with ICPPW features (P2/P1 ratio, TTP and pulse amplitude). Elevation in ICP was produced by means of ultrasound-guided manual internal jugular veins compression. Results were distributed for three groups: intact skull (exclusive burr hole for ICP monitoring), craniotomy/large fractures (group 2) or DC (group 3). Results: 57 patients were analyzed. 21 (36%) presented no skull defects, whereas 15 (26%) had DC. ICP was not significantly different between groups: ±13.59 for intact and ±17.66 mmHg for DC, with ICP induced elevation also similar between groups (p= 0.56). Significant elevation was observed for P2/P1 ratio for groups 1 and 2, whereas reduction was observed in group 3 (elevation of ±0.09 for groups 1 and 2, whereas reduction of 0.03 for group 3, p=0.01). Conclusion: In the present study, intracranial pressure pulse waveform analysis indicated that intracranial compliance was significantly more impaired among decompressive craniectomy patients, although ICPPW indicated DC to be protective for further influences of ICP elevations over the brain. Analysis of ICPPW seems to be an alternative to real time ICC assessment.

In this paper, we propose methods for brain tumor detection in MRI images based on ensemble learning. We build upon prior research on ensemble methods by testing the concatenation of pre-trained models: features extracted via transfer learning are merged and segmented by classification algorithms or a stacked ensemble of those algorithms. The proposed approach achieved accuracy scores of 0.98 , outperforming a benchmark VGG-16 model. Considerations to granular computing are given in the paper as well.

The dynamical processes of living systems are characterized by the cooperative interaction of many units. This claim enables us to portray the embryo-fetal development of the central and peripheral nervous systems in terms of assemblies of building blocks. We describe how the structure and arrangement of nervous fibers is - at least partially - dictated by biophysical and topological constraints. The far-flung field of soft-matter polymers/nematic colloids sheds new light on the neurulation in mammalian embryos, suggesting an intriguing testable hypothesis: the development of the central and peripheral nervous systems might be correlated with the occurrence of local thermal changes in embryo-fetal tissues. Further, we show a correlation between the fullerene-like arrangement of the cortical microcolumns and the Frank-Kasper phases of artificial quasicrystals assemblies. The last, but not the least, we explain how and why the multisynaptic ascending nervous fibers connecting the peripheral receptors to the neocortical areas can be viewed as the real counterpart of mathematical tools such as knot theory and braid groups. Their group structure and generator operations point towards a novel approach to long-standing questions concerning human sensation and perception, leading to the suggestion that the very arrangement and intermingling of the peripheral nervous fibers contributes to the cortical brain activity. In touch with the old claims of D’Arcy Thompson, we conclude that the arrangement and the pattern make the function in a variety of biological instances, leading to countless testable hypotheses.

The heterogeneity of tumor infiltrating lymphocytes is not well characterized in brain metastasis. To address this, we performed a targeted analysis of immune cell subsets in brain metastasis tissues to test which immunosuppressive routes are involved in brain metastasis. We performed multiplex immunofluorescence (mIF), using commercially available validated antibodies on twenty formalin-fixed paraffin embedded whole sections. We quantitated the subsets of immune cells utilizing a targeted panel of proteins including PanCK, CD8, CD4, VISTA and Iba1, and analyzed an average of 15000 cells per sample. We classified tumours as either high (>30%) or low (<30%) tumour infiltrating lymphocytes (TILs) and found that increased TILs density correlated with survival. We next sought out to phenotype these TILs using mIF. The tumours with low TILs (n=9) had significantly higher expression of the immune-checkpoint molecule VISTA in tumor cells (p<0.01) as well as in their microenvironment (p<0.001). Contrastingly, the brain metastatic tumours with high TILs (n=8) displayed higher levels of activated microglia, as measured by Iba1 expression. Low TILs-tumours displayed CD8+ T-cells that co-express VISTA (p<0.01) significantly more compared to high TILs group, where CD8+ T-cells significantly co-express Iba1 (p<0.05). Interestingly, no definite phenotypes of CD4+ subsets were observed. These results were supported by RNA analysis of a publicly available, independent cohort. In conclusion, our work contributes to a growing understanding of the immune surveillance escape routes active in brain metastasis.

Despite existing strong evidence on oxidative markers overproduction following ischemia/reperfusion (I/R), the mechanism by which oxidative enzyme Cytochrome P450-2E1 (CYP2E1) contributes to I/R outcomes is not clear. In this study, we sought to evaluate the functional significance of CYP2E1 in I/R. CYP2E1 KO mice and controls were subjected to middle cerebral artery occlusion (MCAo-90min) followed by 24hr of reperfusion to induce focal I/R injury models. Then, histological and chemical analyses were conducted to investigate the role of CYP2E1 in lesion volume, oxidative stress, and inflammation exacerbation. Also, the role of CYP2E1 on the BBB integrity was investigated by measuring 20-Hydroxyecosatetraenoic acid (20-HETE) activity, as well as, in vivo BBB transfer rate. Following I/R, the CYP2E1 KO mice exhibited a significantly lower lesion volume, and neurological deficits compared to controls (p<0.005). Also, ROS production, apoptosis, and the neurodegeneration were significantly lower in the CYP2E1(-/-) I/R group (p<0.001). The BBB damage was significantly lower in CYP2E1(-/-) mice compared to WT (p<0.001), while 20-HETE production was increased by 41%. Besides, inflammatory cytokines expression and the number of activated microglia were significantly lower in CYP2E1(-/-) mice following I/R. CYP2E1 suppression ameliorates I/R injury and protects BBB integrity by reducing both oxidative stress and inflammation.

The effect of Alzheimer's disease (AD) medications on CD4+ T cells homing has not been thoroughly investigated. Alzheimer's disturbs the life of at least five million persons in the USA. CD4+ T cells could both exacerbate and reduce AD symptoms. Regulating CD4+ T cells homing to the leaky blood-brain barrier (BBB) constitutes a new hope for enhancing AD prognosis. Alzheimer's drugs such as Donepezil (Aricept), Rivastigmine (Exelon), Galantamine (Razadyne) and memantine are known to play an important part in regulating the neurotransmitters mechanisms. However, little is known about the effect of these drugs on CD4+ T cells homing. In this review, we focus on current and new drugs that could modulate CD4+ T cells interactions with the BBB in AD.

Neuroscientists are able to detect physical changes in information entropy in available neurodata. However, the information paradigm is inadequate to fully describe nervous dynamics and mental activities such as perception. This paper provides an effort to build explanations to neural dynamics alternative to thermodynamic and information accounts. We recall the Banach–Tarski paradox (BTP), which informally states that, when pieces of a ball are moved and rotated without changing their shape, a synergy between two balls of the same volume is achieved instead of the original one. We show how and why BTP might display this physical and biological synergy meaningfully, making it possible to tackle nervous activities. The anatomical and functional structure of the central nervous system’s nodes and edges allows to perform a sequence of moves inside the connectome that doubles the amount of available cortical oscillations. In particular, a BTP-based mechanism permits scale-invariant nervous oscillations to amplify and propagate towards far apart brain areas. Paraphrasing the BPT’s definition, we could state that: when a few components of a self-similar nervous oscillation are moved and rotated throughout the cortical connectome, two self-similar oscillations are achieved instead of the original one. Furthermore, based on topological structures, we illustrate how, counterintuitively, the amplification of scale-free oscillations does not require information transfer.

As a medical student (Granada University Medical School, Spain), interested in Pediatrics, expended countless hours at the hospital pediatric facilities and got to know many of the children and their medical problems. A particular case, still vivid on my mind, awaken my scientific curiosity. One day, walking and talking with a seven years old child he unexpectedly felt down unconscious with multiple, incontrollable and erratic muscular contractions involving face, body and extremities and salivating. I was overwhelmed thinking it was the child’ last hour. At the time, my knowledge of epilepsy was nil. Following the seizures, the child was up, talking and walking with me as if nothing has happened and without any knowledge of the event. What could have caused the brain motor cortex to suddenly discharge that amount of altered activity causing generalized and erratic muscular contractions remains inexplicable. I migrated to USA, become a Pediatric (Developmental) Pathologist and Director of the Pediatrics Autopsy Service (1962-1999) at the Dartmouth-Hitchcock Medical Center, New Hampshire. I carried out countless postmortem studied of children brains, normal (unaltered) as well as those altered by hemorrhagic, hypoxic-ischemic and/or traumatic damage. With an NIH Fellowship, I spend one year (1967-68) at the Cajal Institute (Madrid, Spain) studying Cajal’ old Golgi preparations and learning about the method. Some of my Golgi studies of children’ brains have been published: The Human Brain. Prenatal Development and Structure, Springer, Heidelberg, Germany, 2012. The present monograph explores the developmental neuropathology of selected perinatal cortical injuries through their acute, subacute and chronic stages. Including: a) how an altered neuronal activity evolves in a damaged cortical region; b) how it moves through the cortex (epileptic auras); and c) how it reaches the motor cortex to be discharged as erratic and incontrollable muscular contractions. Understanding these processes should provide insights into the pathogenesis of epilepsy secondary to perinatal brain damage.

High-frequency neuroelectric signals like electroencephalography (EEG) or magnetoencephalography (MEG) provide a unique opportunity to infer causal relationships between local activity of brain areas. While causal inference is commonly performed through Classical Granger causality (GC) based on multivariate autoregressive models, this method may encounter important limitations (e.g. data paucity) in the case of high dimensional data from densely connected systems like the brain. Additionally, physiological signals often present long-range dependencies which commonly require high autoregressive model orders / number of parameters. We present a generalization of autoregressive models for GC estimation based on Wiener-Volterra decompositions with Laguerre polynomials as basis functions. In this basis, the introduction of only one additional global parameter allows to capture arbitrary long dependencies without increasing model order, hence retaining model simplicity, linearity and ease of parameters estimation. We validate our method in synthetic data generated from families of complex, densely connected networks and demonstrate superior performance as compared to classical GC. Additionally, we apply our framework to studying the directed human brain connectome through MEG data from 89 subjects drawn from the Human Connectome Project (HCP) database, showing that it is able to reproduce current knowledge as well as to uncover previously unknown directed influences between cortical and limbic brain regions.

Traumatic brain injury (TBI) is a major source of worldwide morbidity and mortality. Patients suffering from TBI exhibit a higher susceptibility to bone loss and an increased rate of bone fractures; however, the underlying mechanisms remain poorly defined. Herein, we observed significantly lower bone quality and elevated levels of inflammation in bone and bone marrow niche after controlled cortical impact-induced TBI in in-vivo CD-1 mice. Further, we identified dysregulated NFB signaling, an established mediator of osteoclast differentiation and bone loss, within the bone marrow niche of TBI mice. Ex vivo studies revealed increased osteoclast differentiation in bone marrow-derived cells from TBI mice, as compared to sham injured mice. Finally, we found bone marrow derived extracellular vesicles (EVs) from TBI mice enhanced the colony forming ability and osteoclast differentiation efficacy of bone marrow cells and activated NFB signaling genes in bone marrow-derived cells. Taken together, we provide evidence that TBI-induced inflammatory stress on bone and the bone marrow niche may activate NFB leading to accelerated bone loss. Targeted inhibition of these signaling pathways may reverse TBI-induced bone loss and reduce fracture rates.

Defensive behavior is a function of specific survival circuits, the “aversive brain system”, that are thought to be conserved across vertebrates, and involve threat detection and the organization of defensive responses to reduce or eliminate threat. In mammals, these circuits involve amygdalar and hypothalamic subnuclei and midbrain circuits. The increased interest in teleost fishes as model organisms in neuroscience created a demand to understand which brain circuits are involved in defensive behavior. Telencephalic and habenular circuits represent a “forebrain circuit” for threat processing and organization of responses, being important to mounting appropriate coping responses. Specific hypothalamic circuits organize neuroendocrine and neurovegetative outputs, but are the less well-studied in fish. A “midbrain circuit” is represented by projections to interneurons in the optic tectum which mediate fast escape responses via projections to the central gray and/or the brainstem escape network. Threatening stimuli (especially visual stimuli) can bypass the “high road” and directly activate this system, initiating escape responses. Increased attention to these circuits in an evolutionary framework is still needed.

Starting from the tenets of human imagination, i.e., the concepts of lines, points and infinity, we provide a biological demonstration that the skeptical claim “human beings cannot attain knowledge of the world” holds true. We show that the Euclidean account of the point as “that of which there is no part” is just a conceptual device, untenable in our physical/biological realm: terms like “lines, surfaces and volumes” label non-existent, arbitrary properties. We also elucidate the psychological and neuroscientific features hardwired in our brain that lead us humans to think to points and lines as truly occurring in our environment. Therefore, our current scientific descriptions of objects’ shapes, graphs and biological trajectories in phase spaces need to be revisited, leading to a proper portrayal of the real world’s events. In order to provide also a positive account, we view miniscule bounded physical surface regions as the basic objects in a biological context in a traversal of spacetime instead of the usual Euclidean points. Our account makes it possible to erase a painstaking problem that causes many theories to break down and/or being incapable of describing extreme events: the unwanted occurrence of infinite values in equations, such as singularity in the description of black holes. We propose a novel approach, based on point-free geometrical standpoints, that banishes infinitesimals and leads to a tenable physical/biological geometry. We conclude that points, lines, volumes and infinity do not describe the world, rather they are fictions introduced by ancient surveyors of land surfaces.

Neural microprobes represent an important component of neural prosthetic systems where implanted microprobes record the electro-potentials generated by specific thoughts in the brain and convey the signals to algorithms trained to interpret these thoughts. Here, we present novel elongated multi-site neural probe that can reach depths greater than 10mm. We hypothesize that reaching such depth allows the recording of cognitive signals required to drive cognitive prosthetics. The impedance of the recording sites on the probes was on the order of 500 kΩ at 1 kHz, which is consistent with probes used for neurophysiological recordings. The probes were made porous using Xenon Difluoride (XeF₂) dry etching to improve the biocompatibility and their adherence to the surrounding neural tissue. Numerical studies were performed to determine the reliability of the porous probes. We implanted the elongated probe in rats and show that the elongated probes are capable of simultaneously recording both spikes and local field potentials (LFPs) from various recording sites.

Cognitive impairment is a condition which affects aging patient populations and is becoming more prevalent as the geriatric population expands. It is categorized by the extent of cognitive decline, memory loss, functional abilities, and the capability to perform daily tasks. Based on the degree of impairment, it is classified as mild cognitive impairment or dementia. Considering the debilitating nature of cognitive decline and its impact on quality of life, prevention is key. In addition, given the gradual progression of the underlying causes of cognitive decline, early diagnosis and appropriate management has the potential to offer clinical advantages and better patient outcomes. Management options discussed vary from pharmaceutical regimens to neurosurgical interventions, with differing outcomes based on etiology of cognitive impairment.

Backgorund and Objectives: In this study, we aimed to evaluate and compare the changes in visual and structural outcomes in patients with intravitreal aflibercept (IVA)-resistant neovascular age-related macular degeneration (nAMD) switched to either intravitreal brolucizumab (IVBr) or intravitreal faricimab (IVF) injections in a clinical setting. Materials and Methods: This obser-vational clinical study included 20 eyes of 20 patients switched to brolucizumab and 15 eyes of 14 patients switched to faricimab for aflibercept-resistant nAMD. We measured the structural outcome (central macular thickness (CMT)) and the visual outcome (best-corrected visual acuity (BCVA); logMAR) as follows: just before the most recent IVA injection (B0), one month after the most recent IVA injection (B1), just before the first IVBr or IVF injection (A0), one month after (A1) and three months after (A3) the first IVBr or IVF injection. Results: BCVA showed significant im-provement at A1 (0.25 ± 0.34) and at A3 (0.19 ± 0.24) compared to A0 (0.38 ± 0.35) in IVBr group (p = 0.0156, p = 0.0166, respectively). CMT (μm) was significantly thinner at A1 (IVBr; 240.55 ± 51.82, IVF; 234.91 ± 47.29) and at A3 (IVBr; 243.21 ± 76.15, IVF; 250.50 ± 72.61) compared to at A0 (IVBr; 303.55 ± 79.18, IVF; 270.33 ± 77.62) in IVBr group (A1; p = 0.0093, A3; p = 0.0026) and in IVF group (A1; p = 0.0161, A3; p = 0.0093). There was no significant difference in BCVA and CMT improvement observed between two groups at any time point (p > 0.05 for all). Conclusion: Switching from aflibercept to either brolucizumab or faricimab has a significant anatomical ef-fect on eyes with aflibercept-resistant nAMD and both treatments appear to be effective short-term treatment options. There is a trend towards greater visual improvements and reductions in CMT with brolucizumab.

Depression is diagnosed when a specific set of symptoms appear over a defined period with a certain intensity. According to the DSM-5, Major Depressive Disorder (MDD) is diagnosed when five or more symptoms are present over a two-week period. Depression, a debilitating mental health disorder affecting millions worldwide, poses a complex challenge for researchers and clinicians. In children and adolescents, depression can result in negative outcomes such as substance abuse, academic problems, risky sexual behavior, physical health issues, impaired social relationships, and a thirty-fold increased risk of suicide. This paper presents the findings of a study that evaluated the effectiveness of Cognitive Behavioral Therapy (CBT) alone and CBT combined with selective ser-otonin reuptake inhibitors (SSRIs) in a remediation program. The study included 16 children and adolescents with depression (8 males and 8 females) and 16 typically developing peers (8 males and 8 females) aged 9 to 15 years (M = 11.94, SD = 2.02). Baseline evaluations using Event-Related Po-tentials (ERPs), the Children Depression Inventory (CDI), and reaction time tests showed that participants with depression had cognitive deficits in attention and memory, indicated by longer P300 latencies. After undergoing remediation with either CBT alone or CBT combined with med-ication, the children and adolescents with depression exhibited lower CDI scores and shorter P300 latencies and reaction times compared to before remediation and relative to the control group.

This study explores the multifaceted influence of litter size, maternal care, exercise, and aging on rats' neurobehavioral plasticity and dentate gyrus microglia dynamics. Body weight evolution revealed a progressive increase until maturity, followed by a decline during aging, with larger litters exhibiting lower weights initially. Notably, exercised rats from smaller litters displayed higher body weights during mature and aged stages. Dentate gyrus volumes showed no significant differences among groups, except for aged sedentary rats from smaller litters, which exhibited a reduction. Maternal care varied significantly based on litter size, with large litter dams showing lower frequencies of caregiving behaviors. Behavioral assays highlighted the detrimental impact of a sedentary lifestyle and reduced maternal care/large litters on spatial memory, mitigated by exercise in aged rats from smaller litters. Microglial dynamics in the layers of dentate gyrus revealed age-related changes modulated by litter size and exercise. Exercise interventions mitigated microgliosis associated with aging, particularly in aged rats. These findings underscore the complex interplay between early-life experiences, exercise, microglial dynamics, and neurobehavioral outcomes during aging.

Chemo-resistance is a substantial challenge in the realm of cancer treatment that requires exploring new therapeutic approaches for effective mitigation. Achieving this goal requires examination of the molecular mechanisms involved in both tumor growth and therapeutic interventions. The potential of NRF2 (Nuclear factor E2-related factor 2) in addressing resistance to chemotherapy across diverse cancer types highlights its value as a promising therapeutic approach based on cancer characteristics. Manipulating the NRF2 signaling pathway has a dual impact, offering promise for both preventing and treating cancer, as well as inhibiting carcinogenesis. The influence of the NRF2/KEAP1 pathway on the progression of tumor formation and resistance to drugs has been well-documented. The interplay between the NRF2 signaling pathway and processes such as endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and autophagy plays a crucial protective role. A deeper understanding of NRF2's role in the modulating these pathways is necessary to develop novel approaches for improving chemotherapeutic efficacy. This article discusses the significance of the NRF2-KEAP1 pathway in preventing/promoting cancer and resistance mechanisms to various chemotherapeutic agents, with a focus on the complementary effects of antioxidants via NRF2-mediated signaling pathways. This study aims to provide a molecular basis for targeting NRF2 via inhibitors/activators as promising therapeutic strategies to overcome chemo-resistance.

We compared the functional and morphologic effects in the loading dose between patients with treatment-naïve neovascular age-related macular degeneration treated with either intravitreal aflibercept (IVA) or intravitreal faricimab (IVF) injection in clinical settings. This retrospective study included 30 eyes from 28 patients who started IVA treatment between June and September 2022 and 30 eyes from 29 patients who started IVF treatment between October 2022 and March 2023. The mean best corrected visual acuity (BCVA) significantly improved from pre-treatment after loading dose in the IVA group (from 0.46 ± 0.46 to 0.36 ± 0.37, p=0.0047) and not in the IVF group (from 0.46 ± 0.41 to 0.44 ± 0.45, p=0.60). The mean central retinal thickness (CRT) significantly improved in both groups. The proportion of eyes with residual exudative change was greater in the IVF group than in the IVA group at 2 months after the first treatment. (p=0.026) We further analyzed the patients who obtained complete resolution of exudative changes after the loading dose. The IVA group had a significant improvement in BCVA, whereas the IVF group did not p=0.0047 and 0.20, respectively) Although IVA and IVF significantly improved the CRT, the BCVA improved significantly in IVA group and not in IVF group.

Frontotemporal lobar degeneration (FTLD) belongs to a heterogeneous group of highly complex neurodegenerative diseases and represents the second cause of presenile dementia in individuals under 65. Frontotemporal-TDP is a subgroup of frontotemporal dementia characterized by the aggregation of abnormal protein deposits, predominantly transactive response DNA-binding protein 43 (TDP-43), in the frontal and temporal brain regions. These deposits lead to progressive degeneration of neurons resulting in cognitive and behavioral impairments. Limbic age-related encephalopathy (LATE) pertains to age-related cognitive decline primarily affecting the limbic system which is crucial for memory, emotions, and learning. Though distinct, emerging research suggests a potential overlap in pathogenic processes, with some cases of limbic encephalopathy displaying TDP-43 pathology. Genetic factors play a pivotal role in both disorders. Mutations in various genes, such as progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72), have been identified as causative in frontotemporal-TDP. Similarly, specific genetic variants have been associated with an increased risk of developing LATE. Understanding these genetic links provides crucial insights into disease mechanisms and the potential for targeted therapies.

The health of inmates living in a restricted environment are affected by oral health behaviours and is related to their oral health-related quality of life (OHRQoL). We investigated oral health behaviours and oral symptoms among male inmates and analysed factors related to OHRQoL. Three hundred and seventy-six male inmates in two prisons were investigated using a self-reported questionnaire. The survey items included oral health behaviours, oral symptoms, self-esteem, and OHRQoL level. We analysed cross-correlations and factors related to OHRQoL. Toothbrushing after lunch and dinner was practiced by 83.5% of male inmates. ‘Food impaction’ was experienced by 45.4%. The OHRQoL level among male inmates was low, at 39.90 points. A hierarchical multiple regression model that controlled for general characteristics identified the following OHRQoL factors, in order of significance: trouble biting/chewing (β = -0.307), toothache (β = -0.154), temporomandibular joint disorder (β = -0.099), and periodontal health (β = 0.089). Self-esteem and OHRQoL were not significantly correlated. To ensure oral health in male inmates, the results of this study suggests that an oral health education programme, as well as provision of adequate dental care services, is required to increase appropriate oral health practice rates.

Background: Increasing number of long-term gastrointestinal (GI) cancer survivors highlights the importance of understanding factors that contribute to their health-related quality of life (HRQoL). We investigated the risk factors of HRQoL, in-cluding demographics, clinical characteristics, and social and behavioral determinants of health (SBDH). Methods: Adult GI cancer survivors (n = 3,201) in the BRFSS surveys from 2014-2021 (except for 2015) were analyzed. Unadjusted/adjusted logistic regression was used. Results: The majority were female (54%) and White (78%), with a median age of 67. Survivors who were 65 years or older, diagnosed with colorectal cancer, or who had fewer comorbidities were more likely to report significantly better HRQoL. Significant social factors of poor HRQoL were being unmarried, racial and ethnic minorities, low socioeconomic status, and poor health care access. Significant behavioral factors of poor HRQoL were lack of physical activity, heavy alcohol consumption, and current smoking, with lack of physical activity being the most significant factor. Conclusions: The SBDH have a critical role in HRQoL. Future studies are warranted to develop a tailored survivorship intervention, such as physical rehabilitation and to ex-plore machine learning/artificial intelligence predictive models to identify cancer sur-vivors at a high risk of developing poor HRQoL.

Polycystic ovary syndrome (PCOS) usually comes along with metabolic disturbances attributed to androgen excess and obesity, but the contribution of each has not been defined, and the occurrence of metabolic disturbances is frequently not investigated. We evaluated 99 PCOS and 41 non-PCOS women. Clinical biomarkers of glucose-, liver-, and endothelial-related metabolic alterations were measured; participants were categorized into four groups according with obesity (OB) and hyperandrogenemia (HA) statuses: Healthy (no-HA, lean), HA (HA, lean), OB (no-HA, OB), and HAOB (HA, OB). Metabolic disturbances were highly frequent in PCOS women (70%). BMI correlated with all biomarkers, while free testosterone (FT) only with glucose- and hepatic-related indicators. Despite insulin sensitivity and liver enzymes were associated with FT, women with obesity exhibited lower M [coeff = 8.56 – 0.080(FT) –3.71(Ob); p &lt;0.001)] and higher aspartate aminotransferase (coeff = 26.27 + 0.532(FT) + 8.08(Ob); p = 0.015)] than lean at the same level of FT. Women with obesity exhibited greater risk of metabolic disorders than lean, independently of hyperandrogenemia. Clinicians are compelled to search for metabolic alterations in PCOS women; obesity must be handled in all cases, but hyperandrogenemia needs to be managed also in those with glucose- or liver-related disturbances.

(1) Background: This article reviews the available scientific literature on drug-related problems and negative outcomes associated with medications identified by medication review with follow-up for end-stage renal disease and discussed with the physicians; (2) Methods: A systematic review was conducted of the scientific literature retrieved from the following databases: MEDLINE (via PubMed), Web of Science, SCOPUS, Cochrane Library: The Cochrane Central Register and Control Trials (CENTRAL) and Literatura Latinoamericana y del Caribe (LILACS), Medicina en Español (MEDES), and the SciELO bibliographic database (collection of scientific journals). The following terms were used as descriptors and searched in free text: "end-stage renal disease", "medication review", and "drug-related problems” and “negative outcomes associated with medication". The following limits were applied: "humans" and "adults (more than 18 years)”; (3) Results: A total of 59 references were recovered and after applying inclusion/exclusion criteria, 16 articles were selected. Of these selected articles, 15 provided information on drug-related problems and only 1 on negative outcomes associated with medications; (4) Conclusions: It can be concluded that drug-related problems and negative outcomes associated with medication affect patients with end-stage renal disease, mainly those receiving renal replacement therapy. More evidence is needed, especially on negative outcomes associated with medication.

Background: According to metacognitive theory, Cognitive–Attentional Syndrome (CAS) is a transdiagnostic factor and main mechanism of psychopathology maintenance. The main goal of this study was to examine whether CAS predicted symptoms of stress and trauma-related symptomatology in the first months of the COVID-19 pandemic and three months later. Methods: Initially 1,792 participants were recruited online via social media; data was collected at two time points. Measures included the Cognitive–Attentional Syndrome Questionnaire, Adjustment Disorder – New Module 20, the International Trauma Questionnaire, and additional measures. Results: Structural equation modeling was conducted in order to determine relations between reported stressors, CAS, and symptomatology. At both time points, CAS was a significant mediator between stressors and symptoms of adjustment disorder. Despite the decrease in the intensity of adjustment disorder symptoms between waves, it was a significant predictor of other psychopathology at both time points, except for traumatic stress. Conclusions: The findings confirm the assumption that CAS is a transdiagnostic factor of psychopathology, and has a mediating role in the relationship between stressors and adjustment disorder and co-occurring symptomatology. The effect was particularly significant in the initial phase of the pandemic, which was highly stressful for many people.

Neovascular age-related macular degeneration (nAMD) leads to visual impairment if not treated timely. Intravitreal anti-VEGF drugs have revolutionized nAMD treatment in two decades. We evaluated visual outcomes of anti-VEGF treatment in nAMD. A real-life population-based cohort study. Data included parameters for age, sex, age at the diagnosis, laterality, chronicity, symptoms, visual outcomes, lens status, and history of intravitreal injections. A total of 1088 eyes (827 patients) with nAMD were included. Visual acuity was stable or improved in 984 eyes (90%) after an average 36±25 months follow-up. Bevacitzumab was the first-line drug in 1083 (99.5%) eyes. Vision improved ≥15 ETDRS letters in 377 (35%), > 5 ETDRS letters in 309 (28%) and was stable (±5 ETDRS letters) in 298 (27%) eyes after anti-VEGF treatment. The loss of 5-<15 ETDRS letters in 44 (4%) and ≥15 ETDRS letters in 60 (6%) eyes was noted. At the diagnosis of nAMD, 110 out of 827 patients (13%) fulfilled the criteria of visual impairment, whereas 179 patients (22%) were visually impaired after the follow-up. Improvement or stabilization in vision was noted in 90% of the anti-VEGF-treated eyes with nAMD. In addition, anti-VEGF agents are crucial in diminishing nAMD-related visual impairment.

Forestry workers play a crucial role in implementing forest management programs, but their outdoor work exposes them to rising temperatures caused by global climate change, which poses potential health risks related to heat. This study focuses on Indonesian forestry workers and examines the relationship between their knowledge of heat-related issues, risk perception, and precautionary behavior in dealing with increasing workplace heat exposure. Developing effective precautionary behavior is essential for preventing heat-related health disorders and promoting health protection programs. To facilitate a comprehensive comparison of the three variables, interviews were conducted with two groups of outdoor workers, comprising 210 forestry workers and 215 paddy farmers. The findings indicate that increasing knowledge about heat-related issues promotes precautionary behavior, and risk perception acts as a mediator between knowledge and behavior. Additionally, the study highlights that the emotion of "dread" intensifies perceived risk and predicts positive behavior change. To enhance heat-related knowledge, exploring the potential use of a "fear" tone is important. In conclusion, comprehensive strategies need to be implemented to promote precautionary behavior among vulnerable forestry workers, particularly manual laborers.

Cause-Related Marketing (CRM) has emerged as a new concept that links CSR activities to marketing, enabling corporations to pursue both building company-consumer partnership and gaining sustainable mutual benefits that are elicited from the partnership. Among various cause-related marketing activities, on-line cause-related advertising is the most commonly used one. The purpose of this study is to examine the effects of on-line cause-related advertising and moderating role of ethical consumption propensity. In particular, this study intends to contribute to successful development of on-line cause-related advertising strategy by focusing on the relationship between the four factors: customers' perception of on-line cause-related advertising, brand-consumer relationship, brand attachment and loyalty. The results of this study are as follows: First, customers' perception of on-line cause-related advertising was related positively to consumer-brand- relationship. Second, brand-consumer relationship was related positively to brand attachment and customer loyalty. Third, brand attachment was related positively to customer loyalty. Furthermore, from the consumer’s psychological viewpoint, ethical consumption propensity had a significant moderating effect to between customers' perception of cause-related advertising and brand-consumer relationship as well as brand attachment. The results of this study may contribute to the existing literature as an new empirical attempt to examine the effect of the on-line cause-related advertising.

TomoBreast hypothesized that hypofractionated 15 fractions/3 weeks image-guided radiation therapy (H-IGRT) can reduce lung-heart toxicity, as compared with normofractionated 25-33 fractions/5-7 weeks conventional radiation therapy (CRT). 123 women with stage I-II operated breast cancer were randomized to receive CRT (N=64) or H-IGRT (N=59). The primary endpoint used a four-items measure of the time to 10% alteration in any of patient self-reported measure, physician clinical evaluation, echocardiography or lung function tests, analyzed by intention-to-treat without exclusion. Results found comparable survivals, but H-IGRT significantly reduced the toxicity measured by lung diffusion capacity and alveolar volume as compared with CRT, G1 in 53% (31/59) versus 72% (44/61) patients, P=0.006; G2, 29% versus 48%, P=0.020. H-IGRT significantly reduced the risk of composite cardio-pulmonary alteration at 5 years, 10.2% versus 26.7%, P=0.024. In conclusion, TomoBreast is a proof-of-concept that image-guided radiation-therapy can improve the overall balance of lung-heart outcomes in breast cancer adjuvant therapy. Furthermore, the significance of the findings supports the efficacy of a small trial size design, which can be critical when clinical research resources are limited.

Novel strategies have been developed to reduce or to avoid the intravitreal injections (IVTs) of the antiangiogenic (ranibizumab; RBZ) and the anti-inflammatory (triamcinolone acetonide; TA) agents used to treat vitreoretinal diseases. One of the strategies include liposomes. In this study, it was evaluated the safety and efficacy of topical triamcinolone-loaded liposomes formulation (TALF) as an adjuvant to intravitreal RBZ therapy in treatment-naive patients with neovascular age related macular degeneration (nAMD). Subjects were randomly assigned to the RBZ-TALF or the RBZ-pro re nata (RBZ-PRN) group. Patients from the RBZ-TALF group were instructed to apply TALF for a 12-month period after a single dose of RBZ. Patients from the RBZ-PRN group received three monthly RBZ-IVTs. Retreatment with RBZ was considered in case of nAMD reactivation. Related to safety, non-ocular abnormalities were observed during TALF therapy. Owing to the efficacy, non-significant differences are identified in visual acuity or central foveal thickness when the RBZ-PRN and RBZ-TALF groups are compared. Importantly the average number of RBZ injections was significantly lower in the RBZ-TALF group (2.5 ± 1.4 vs 6.1 ± 1.3 IVTs; p=0004). Therefore, TALF used as an adjuvant to RBZ reduce the number of RBZ-IVTs retreatment with optimal visual and anatomic results.

As Automated Driving Systems (ADS) technology gets assimilated into the market, the driver’s obligation will be changed to a supervisory role. A key point to consider is the driver’s engagement in the secondary task to maintain the driver/user in the control loop. The paper’s objective is to monitor driver engagement with a game and identify any impacts the task has on hazard recognition. We designed a driving simulation using Unity3D and incorporated three tasks: No-task, AR-Video, and AR-Game tasks. The driver engaged in an AR object interception game while monitoring the road for threatening road scenarios. From the results, there was less than 1 second difference between the means of gaming task (mean = 2.55s, std = 0.1002s) to no-task (mean = 2.55s, std = 0.1002s). Game scoring followed three profiles/phases: learning, saturation, and decline profile. From the profiles, it is possible to quantify/infer drivers’ engagement with the game task. The paper proposes alternative monitoring that has utility, i.e., entertaining the user. Further experiments AR-Game focusing on real-world car environment will be performed to confirm the performance following the recommendations derived from the current test.

Aging is accompanied by frontal lobe and non-dominant hemisphere recruitment that supports executive functioning, such as inhibitory control, which is crucial to all cognitive functions. Yet, the spatio-temporal sequence of processing underlying successful inhibition and how it changes with age is understudied. Thus, we assessed N200 (conflict monitoring) and P300 (response inhibition, performance evaluation) event-related potentials (ERPs) in young and healthy older adults during comparably performed successful stop-signal inhibition. We additionally interrogated the continuous spatio-temporal dynamics of N200- and P300-related activation within each group. Young adults had left hemisphere dominant N200, while older adults had overall larger amplitudes and right hemisphere dominance. N200 activation was biphasic in both groups but differed in scalp topography. P300 also differed, with larger right amplitudes in young, but bilateral amplitudes in old, with old larger than young in the left hemisphere. P300 was characterized by an early parieto-occipital peak in both groups, followed by a parietal slow wave only in older adults. A temporally similar but topographically different final wave followed in both groups that showed anterior recruitment in older adults. These findings illuminate differential age-related spatio-temporal recruitment patterns for conflict monitoring and response inhibition that are critically important for understanding age-related compensatory activation.

This study aims to develop a performance evaluation system that can facilitate performance evaluation at region, hospital, and department levels to enable better cost management for sustainable development. A multi-level system of performance evaluation informs a hierarchical assessment of cost management from regions to hospitals to departments using diagnosis-related group (DRGs). Various metrics are developed employing the variances between targets and actuals where targets are determined from two perspectives: benchmarking using external regional prices and change management using internal data. Targets for the latter are statistically based and specifically incorporate variability. The model is applied to two hospitals, twenty departments, nine DRGs and 1071 inpatients. The analyses indicate that the approach can provide a practical evaluation tool that allows for particular characteristics at multiple levels. The system provides macro-micro and external-internal perspectives in performance, enabling high-level variances to be decomposed thereby identifying sources of performance variability and financial impact.

This study explored intraindividual multidimensional profiles integrating psychosocial factors, namely, body image and satisfaction, weight-related self-stigma, positivity, and happiness, and behavioural-lifestyle factors, namely, adherence to a healthy diet, among Spanish adults with overweight or obesity. We further aimed to investigate the association of excess weight (i.e., measured body mass index, BMI) with the abovementioned multidimensional configurations. A convenience sample of adult individuals with excessive weight completed self-reports regarding the study variables, and their weight and height were measured. With a perspective centered on the individual, a cluster analysis established three distinct intraindividual psychosocial and diet-related profiles: a group of healthy individuals with excess weight; a group of individuals who were negatively affected by their excessive weight and showed the most distressed profile; and a group of dysfunctional individuals who seemed to be excessively unrealistic and optimistic regarding their excessive weight and unhealthy lifestyles. Furthermore, individuals in the affected cluster had higher obesity. The results showed that there are specific psychosocial and lifestyle profiles in the adult population with excess weight and that there are relationships among psychological, behavioural, and body-composition factors. For clinical application purposes, it is important to account for the heterogeneity within individuals who are obese and to individualize the interventions, with a focus from weight change to individual's overall well-being.

This study explored intraindividual multidimensional profiles integrating psychosocial factors, namely, body image and satisfaction, weight-related self-stigma, positivity, and happiness, and behavioural-lifestyle factors, namely, adherence to a healthy diet, among Spanish adults with overweight or obesity. We further aimed to investigate the association of excess weight (i.e., measured body mass index, BMI) with the abovementioned multidimensional configurations. A convenience sample of adult individuals with excessive weight completed self-reports regarding the study variables, and their weight and height were measured. With a perspective centred on the individual, a cluster analysis established three distinct intraindividual psychosocial and diet-related profiles: a group of healthy individuals with excess weight; a group of individuals who were negatively affected by their excessive weight and showed the most distressed profile; and a group of dysfunctional individuals who seemed to be excessively unrealistic and optimistic regarding their excessive weight and unhealthy lifestyles. Furthermore, individuals in the affected cluster had higher obesity. The results showed that there are specific psychosocial and lifestyle profiles in the adult population with excess weight and that there are relationships among psychological, behavioural, and body-composition factors. For clinical application purposes, it is important to account for the heterogeneity within individuals who are obese.

Telecommuting is a flexible form of work that has progressively spread over the last 40 years and which has been strongly encouraged by the measures to limit the Covid19 pandemic. There is still limited evi-dence on the effects it has on workers' health. In this survey we invited 905 workers of companies that made a limited use of telework to fill out a questionnaire to evaluate: Intrusive leadership of managers (IL), the request for work outside traditional hours (OFF-TAJD), workaholism (BWAS), effort / reward imbalance (ERI), happiness and common mental issues (CMIs), anxiety and depression, assessed by the Goldberg scale (GADS). The interaction between these variables has been studied by structural equation modeling (SEM). Intrusive leadership and working after hours were significantly associated with occu-pational stress. Workaholism is a relevant moderator of this interaction: intrusive leadership significantly increased the stress of workaholic workers. Intrusive leadership and overtime work were associated with reduced happiness, anxiety and depression. These results indicate the need to guarantee the right to disconnect, to limit the effect of the OFF-TAJD. In addition to this, companies should implement policies to prevent intrusive leadership and workaholism.

The Japanese Association for Acute Medicine Committee recently proposed a novel classification system for the severity of heat-related illnesses. The illnesses are simply classified into three stages based on symptoms and management or treatment. Stages I, II, and III broadly correspond to heat cramp and syncope, heat exhaustion, and heat stroke, respectively. Our objective was to examine whether this novel severity classification is useful in the diagnosis by healthcare professionals of patients with severe heat-related illness and organ failure. A nationwide surveillance study of heat-related illnesses was conducted between June 1 and September 30, 2012, at emergency departments in Japan. Among the 2130 patients who attended 102 emergency departments, the severity of their heat-related illness was recorded for 1799 patients, who were included in this study. In the patients with heat cramp and syncope or heat exhaustion (but not heat stroke), the blood test data (alanine aminotransferase, creatinine, blood urea nitrogen, and platelet counts) for those classified as stage III were significantly higher than those of patients classified as stage I or II. There were no deaths among the patients classified as stage I. This novel classification may avoid underestimating the severity of heat-related illness.

Background: Appendicular skeletal muscle (or lean) mass (ALM) estimated using dual-energy X-ray absorptiometry (DXA) is considered to be a preferred method for sarcopenia studies. However, DXA is expensive, has limited portability, and requires radiation exposure. Bioelectrical impedance analysis (BIA) is inexpensive, easy to use, and portable; thus BIA might be useful in sarcopenia investigations. However, a large variety of models have been commercially supplied by different companies, and for most consumer products, the equations estimating ALM are not disclosed. It is therefore difficult to use these equations for research purposes. In particular, the BIA equation is often age-dependent, which leads to fundamental difficulty in examining age-related ALM loss. The aims of the current study were as follows: (1) to develop and validate an equation to estimate ALM using multi-frequency BIA (MF-BIA) based on theoretical models, and (2) to establish sarcopenia cutoff values using the equation for the Japanese population. Methods: We measured height (Ht), weight, and ALM obtained using DXA and a standing-posture 8-electrode MF-BIA (5, 50, 250 kHz) in 756 Japanese individuals aged 18 to 86-years-old (222 men and 301 women as developing equation group and 97 men and 136 women as a cross validation group). The traditional impedance index (Ht²/Z₅₀) and impedance ratio of high and low frequency (Z₂₅₀/Z₅) of hand to foot values were calculated. Multiple regression analyses were conducted with ALM as dependent variable in men and women separately. Results: We created the following equations: ALM = (0.6947 × (Ht²/Z₅₀)) + (−55.24 × (Z₂₅₀/Z₅)) + (−10,940 × (1/Z₅₀)) + 51.33 for men, and ALM = (0.6144 × (Ht²/Z₅₀)) + (−36.61 × (Z₂₅₀/Z₅)) + (−9332 × (1/Z₅₀)) + 37.91 for women. Additionally, we conducted measurements in 1624 men and 1368 women aged 18 to 40 years to establish sarcopenia cutoff values in the Japanese population. The mean values minus 2 standard deviations of the skeletal muscle mass index (ALM/Ht²) in these participants were 6.8 and 5.7 kg/m² in men and women, respectively. Conclusion: The current study established and validated a theoretical and age-independent equation using MF-BIA to estimate ALM and provided reasonable sarcopenia cutoff values.

This study investigated the neuroprotective effects of methyl 3,4-dihydroxybenzoate (MDHB) against t-butylhydroperoxide(TBHP) induced oxidative damage in SH-SY5Y (human neuroblastoma cells) and the underlying mechanisms. SH-SY5Y were cultured in DMEM+10% FBS for 24 hours and pretreated with different concentrations of MDHB or N-acetyl-L-cysteine (NAC) for 4 hours prior to the addition of 40 μM TBHP for 24 hours. Cell viability was analyzed using the methyl thiazolyl tetrazolium (MTT) and lactate dehydrogenase (LDH) assays. An annexin V-FITC assay was used to detect cell apoptosis rate. The 2',7'-dichlorofluorescin diacetate (DCFH-DA) assay was used to determine intracellular ROS levels. The activities of antioxidative enzymes (GSH-Px and SOD) were measured using commercially available kits. The oxidative DNA damage marker 8-OHdG was detected using ELISA. Western blotting was used to determine the expression of Bcl-2, Bax, caspase 3, p-Akt and Akt proteins in treated SH-SY5Y cells. Our results showed that MDHB is an effective neuroprotective compound that can mitigate oxidative stress and inhibit apoptosis in SH-SY5Y cells

Schizophrenia is a disease with a complex etiology that significantly impairs the functioning of patients. In recent years, there has been increasing focus on the importance of the gut microbiota in the context of the gut-brain axis. In our study, we analyzed data on the gut-brain axis in schizophrenia, as well as the impact of eating habits, the use of various supplements, and diets on schizophrenia. Additionally, the study investigated the impact of antipsychotics on the development of metabolic disorders such as diabetes, dyslipidemia, and obesity. There may be significant clinical benefits to be gained from therapies supported by supplements such as omega-3 fatty acids, B vitamins, and probiotics. The results suggest the need for a holistic approach to the treatment of schizophrenia, incorporating both drug therapy and dietary interventions.

Background. Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy worldwide. Brain metastasis (BM) is quite an uncommon presentation. However, the likelihood of central nervous system (CNS) metastasization should be considered in the context of disseminated disease. The therapeutic management of BMs is an unmet clinical need, to date. Case presentation. We identified across different Cancer Centers six cases of both BRCA wild-type and BRCA-mutated EOC spreading to the CNS. They presented either with a single brain lesion or with multiple lesions and most of them had intracranial-only disease. All cases received Poly-ADP ribose polymerase inhibitor (PARPi) maintenance, as by clinical practice, for a long time within a multimodal treatment approach. We also provide an insight into the available body of work regarding the management of this intriguing disease setting, with a glimpse of future therapeutic challenges. Conclusion. Despite the lack of unanimous guidelines, multimodal care pathways should be encouraged for optimal disease control of this unfortunate patient’s subset. Albeit not being directly investigated in BM patients, the PARPi maintenance is deemed to have a valuable role in this setting. Prospective research, aimed to implement worthwhile strategies in the multimodal patient journey of BMs from EOC, is eagerly awaited.

Targeting drugs to the central nervous system (CNS) is challenging due to the presence of the blood-brain barrier. (BBB). The cutting edge in nanotechnology generates optimism to overcome the growing challenges in biomedical sciences through effective engineering of nanogels. The primary objective of the present report was to develop and characterize biocompatible natural chitosan (CS)-based NG that can be tracked thanks to the tricarbocyanine (CNN) fluorescent probe addition of the biopolymer backbone. FTIR shed light on the chemical groups involved in the CS and CNN interactions and between CNN-CS with tripolyphosphate, the cross-linking agent. Both in vitro and in vivo experiments were carried out to determine if CS-NG can be utilized as therapeutic delivery vehicles directed towards the brain. An ionic gelation method was chosen to generate cationic CNN-CS-NG. DLS and TEM confirmed that these entities size fell into nanoscale. CNN-CS-NG was found to be non-cytotoxic as determined in the SH-SY5Y neuroblastoma cell line through biocompatibility assays. After cellular internalization, the occurrence of an endo-lysosomal escape (a crucial event for an efficient drug delivery) of CNN-CS-NG was detected. Furthermore, CNN-CS-NG administered intraperitoneally to female CF-1 mice were detected in different brain regions after 2 h of administration using fluorescence microscopy. To conclude, the obtained findings in the present report can be useful in the field of neuro-nanomedicine when designing drug vehicles with the purpose of delivering drugs to the CNS.

The management of brain tumors presents numerous challenges, despite the employment of multimodal therapies including surgical intervention, radiotherapy, chemotherapy, and immunotherapy. Owing to the distinct location of brain tumors and the presence of the blood-brain barrier (BBB), these tumors exhibit considerable heterogeneity and invasiveness at a histological level. Recent advancements in hydrogel research for the local treatment of brain tumors have sought to overcome the primary challenge of delivering therapeutics past the BBB, thereby ensuring efficient accumulation within brain tumor tissues. This article elaborates on various hydrogel-based delivery vectors, examining their efficacy in the local treatment of brain tumors. Additionally, it reviews the fundamental principles involved in designing intelligent hydrogels that can circumvent the BBB and penetrate larger tumor areas, thereby facilitating precise, controlled drug release. Hydrogel-based drug delivery systems (DDSs) are posited to offer a groundbreaking approach in addressing the challenges and limitations inherent in traditional oncological therapies, which are significantly impeded by the unique structural and pathological characteristics of brain tumors.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative condition caused by repeated traumatic brain injuries (TBIs) leading to cognitive, behavioral, and motor dysfunctions. This study examined the relationship between cognitive impairment and clinical syndromes among 145 CTE patients aged 18 to 75 years who underwent inpatient treatment at the Ternopil Regional Clinical Psychoneurological Hospital between 2021 and 2022. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA), with results classified into four categories: normal, mild impairment, moderate impairment, and dementia. Statistical analysis revealed significant associations between cognitive impairment and specific neuroimaging changes, including ventricular dilatation. Clinical syndromes, such as cognitive disorder syndrome, also showed significant associations with cognitive impairment (p &lt; 0.001). Using logistic regression, we developed a predictive model to estimate the probability of cognitive impairment based on various clinical features, including memory loss, attention deficits, and sleep disturbances. The model demonstrated high accuracy, with a receiver operating characteristic (ROC) curve showing a sensitivity of 91.0% and a specificity of 92.5%, yielding an area under the curve (AUC) of 0.964 (95% CI: 0.934 - 0.994). These findings suggest that specific neuroimaging and clinical features can predict cognitive impairment in CTE patients.

Angiostrongylus cantonensis, a zoonotic parasite, can invade the human central nervous system (CNS) and cause acute eosinophilic meningitis or eosinophilic meningoencephalitis. Mice infected with A. cantonensis show elevated levels of pro-inflammatory cytokines, plasminogen activators, and matrix metalloproteinase-9, resulting in disruption of the blood-brain barrier (BBB) and immune cell infiltration into the CNS. Caveolin-1 (Cav-1) regulates the permeability of the BBB, which affects immune cells and cerebrospinal fluid. This intricate interaction ultimately fuels the progression of brain damage and edema. This study aims to investigate the regulatory role of Cav-1 in the pathogenesis of meningoencephalitis induced by A. cantonensis infection. We investigate pathological alterations by triphenyl-tetrazolium chloride, brain water content, BBB permeability, Western blot analysis, and gelatin zymography in BALB/c mice after A. cantonensis. The study evaluates the critical role of Cav-1 regulation through the TLR4 / MyD88 signaling pathway, modulates tight junction proteins, influences BBB permeability, and contributes to brain damage in A. cantonensis-induced meningoencephalitis.

In this article, we consider the relationship between the brain and the immune system in the context of the Orch OR (Orchestrated Objective Reduction) theory of consciousness. Orch OR is a theory that postulates that consciousness arises from quantum computations occurring inside microtubules. The immune system is capable of acquiring, learning, and remembering information, thus showing all the attributes of natural intelligence. We argue that the immune system also has the attribute of consciousness and can gain access to an amount of information greater than what is accessible to the brain since it is not constrained by brain's reducing valve that is responsible for cognitive bottlenecks. We also describe the role of meditation and religious chanting in affecting the brain and immune system. We speculate that some effects of religious chanting on the immune system may not be mediated by the brain. Finally, we examine the role of the immune system in connecting with the consciousness embedded in the universe.

The Brain-Computer Interface (BCI) technology has emerged as a groundbreaking innovation with profound implications across diverse domains, particularly in healthcare. By establishing a direct communication pathway between the human brain and external devices, BCI systems offer unprecedented opportunities for diagnosis, treatment, and rehabilitation, thereby reshaping the landscape of medical practice. However, despite its immense potential, the widespread adoption of BCI technology in clinical settings faces several challenges. These include the need for robust signal acquisition and processing techniques, ensuring user safety and privacy, addressing ethical considerations, and optimizing user training and adaptation. Overcoming these challenges is crucial to unleashing the complete potential of BCI technology in healthcare and realizing its promise of personalized, patient-centric care. This review work underscores the transformative potential of BCI technology in revolutionizing medical practice. This paper offers a comprehensive analysis of medical-oriented BCI applications by exploring the various uses of BCI technology and its potential to transform patient care.

Breast cancer brain metastasis (BCBM) is a challenging condition with limited treatment options and poor prognosis. Understanding the interactions between tumor cells and the blood-brain barrier (BBB) is critical for developing novel therapeutic strategies. One promising target is estrogen receptor β (ERβ), which promotes the expression of key tight junction proteins, sealing the BBB and reducing its permeability. In this study, we investigated the effects of 17β-estradiol (E2) and the selective ERβ agonist diarylpropionitrile (DPN) on endothelial and cancer cells. Western blot analysis revealed the expression patterns of ERs in these cell lines, and estrogen treatment upregulated claudin-5 expression in brain endothelial cells. Using in vitro models of the BBB, we found that DPN treatment significantly increased BBB tightness about suppressed BBB transmigration activity of representative HER2-positive (BT-474) and triple-negative (MDA-MB-231) breast cancer cell lines. However, the efficacy of DPN treatment decreased when cancer cells were pre-differentiated in the presence of E2. Our results support ERβ as a potential target for the prevention and treatment of BCBM and suggest that targeted vector-based approaches may be effective for future preventive and therapeutic implications.

Coenzyme CoQ10 (CoQ10) is an endogenous lipid-soluble antioxidant that effectively protects lipids, proteins and DNA from oxidation due to its ability to undergo redox transitions between oxidized and reduced forms. Various oxidative stress-associated infectious and somatic diseases have been observed to disrupt the balance of CoQ10 concentration in tissues. As a high molecular weight polar lipophilic compound, CoQ10 exhibits very limited oral bioavailability, which restrains its therapeutic potential. Nevertheless, numerous studies have confirmed the clinical efficacy of CoQ10 therapy through the oral administration of high doses over extended time periods. Experimental studies have demonstrated that in emergency situations, intravenous administration of both oxidized and reduced forms CoQ10 leads to a rapid increase in its concentration in organ tissues, offering protection in ischemic conditions for organ tissues. This suggests that the cardio- and neuroprotective efficacy of intravenously administered CoQ10 forms could present new opportunities in treating acute ischemic conditions. Based on these findings, the review provides reasoning supporting further research and implementation of CoQ10 dosage forms for intravenous administration in emergency situations into clinical practice.

Background: Mounting evidence supports the role of the endocannabinoid system in neurophysiology, includ-ing blood-brain barrier (BBB) function. Recent work has demonstrated that activation of endocannabinoid re-ceptors can mitigate insults to the BBB during neurological disorders, like traumatic brain injury, cortical spreading depression and stroke. As alterations to the BBB are associated with worsening clinical outcomes in these conditions, studies herein sought to examine the impact of endocannabinoid depletion on BBB integrity. Methods: Barrier integrity was investigated in vitro via bEnd.3 cell monolayers to assess endocannabinoid syn-thesis, barrier function, calcium influx, junctional protein expression, and proteome-wide changes. Results: In-hibition of 2-AG synthesis using DAGLα inhibition and siRNA inhibition of DAGLα led to loss of barrier in-tegrity via altered expression of VE-cadherin, which could be partially rescued by exogenous application of 2-AG. Moreover, the deleterious effects of DAGLα inhibition on BBB integrity showed both calcium and PKC (protein kinase C)-dependency. Conclusions: These data indicate that disruption of 2-AG homeostasis in brain endothelial cells, in the absence of insult, is sufficient to disrupt BBB integrity thus supporting the role of the endocannabinoid system in neurovascular disorders.

The purpose of this study is to ​​explore the use of a custom Transformer model in brain-computer interfaces (BCIs) that translate the neural activity present when an individual with limited verbal and fine-motor skills attempts to handwrite. As found in previous studies, Transformers have performed better than recurrent neural networks (RNNs) in translation tasks which are similar to its usage here in decoding neural signals into intended handwritten text. Due to the known benefits of a Transformer, the hypothesis was that the Transformer would show promise in the context of a BCI through the recorded metrics. The neural signals of a tetraplegic individual, when they attempted to handwrite, were provided by existing research. Four trials were conducted using data with or without augmentation which the model used when training to separately minimize training loss and validation loss. When comparing the results of a BCI with the implementation of a Transformer model with the original RNN BCI (the original data source), the Transformer model performed less favorably across all four trials. Although the results do not indicate that the Transformer model currently outperforms an RNN BCI, it is important to note that further testing of the model's capabilities (such as training it with a larger and more preferable dataset and/or for longer, comparing training times between the RNN and Transformer, and/or seeing how the Transformer is improved with an offline autocorrect feature) is necessary before determining whether Transformers can enhance communication in this manner.

Gangliosides are highly abundant in the human brain where they are involved in major biological events. In brain cancers, alterations of ganglioside pattern occur, some of which being correlated with the neoplastic transformation, while others with the tumor proliferation. Of all the techniques, mass spectrometry (MS) has proven to be one of the most effective in gangliosidomics, due to its ability to characterize heterogeneous mixtures and discover species with biomarker value. This review highlights the most significant achievements of MS in the analysis of gangliosides in human brain cancers. The first part presents the state-of-the-art in the MS development for discovery of ganglioside markers in primary brain tumors, with a particular emphasis on the ion mobility separation (IMS) MS and its contribution to the elucidation of the gangliosidome associated with aggressive tumors. The second part is focused on the MS of gangliosides in brain metastases, highlighting the ability of matrix-assisted laser desorption/ionization (MALDI)-MS, microfluidics-MS and tandem MS to decipher and structurally characterize species involved in the metastatic process. In the end, several conclusions and perspectives are presented, among which the need for development of a reliable software and a user-friendly structural database as a search platform in brain tumor diagnostics.

Background: Alongside their long-term effects - post-concussion syndrome (PCS) - mild traumatic brain injuries (mTBI) are significant public health concerns. Currently, there is a lack of reliable biomarkers for diagnosing and monitoring mTBI and PCS. Exosomes are small extracellular vesicles secreted by cells that have recently emerged as a potential source of biomarkers for mTBI and PCS due to their ability to cross the blood-brain barrier and reflect the pathophysiology of brain injury. This study aimed to investigate the role of salivary exosomal biomarkers in mTBI and PCS. Methods: A systematic review using the PRISMA guidelines was conducted, and studies were selected based on their relevance to the topic. Results: Studies have shown that exosomal tau, phosphorylated tau (p-tau), amyloid beta (Aβ), and microRNAs (miRNAs) are potential biomarkers for mTBI and PCS. Specifically, elevated levels of exosomal tau and p-tau have been associated with mTBI and PCS, as well as with repetitive mTBI. Dysregulated exosomal miRNAs have also been observed in individuals with mTBI and PCS. Additionally, exosomal Prion cellular protein (PRPc), coagulation factor XIII (XIIIa), synaptogyrin-3, IL-6, and aquaporins have been identified as promising biomarkers for mTBI and PCS. Conclusion: Salivary exosomal biomarkers have the potential to serve as non-invasive and easily accessible diagnostic and prognostic tools for mTBI and PCS. Further studies are needed to validate these biomarkers and to develop standardized protocols for their use in clinical settings. Salivary exosomal biomarkers can improve the diagnosis, monitoring, and treatment of mTBI and PCS, leading to improved patient outcomes.

Traumatic brain injury (TBI) is among the leading causes of mortality and long-term impairment globally. TBI has a dynamic pathology encompassing a variety of metabolic and molecular events that occur in two phases, primary and secondary. An external forceful blow to the brain initiates the primary phase, which is followed by a secondary phase that involves the release of calcium ions (Ca2+) and the initiation of a cascade of inflammatory processes, including mitochondrial dysfunction, rise in oxidative stress, activation of glial cells, and damage to the blood-brain barrier (BBB), resulting in paracellular leakage. There is currently no FDA-approved drug for TBI, but existing approaches rely on delivering small and macromolecular treatments, which are severely constrained by the BBB, poor retention, off-target toxicity, and complex pathology of TBI. Therefore, there is a demand for innovative and alternative therapeutics with effective delivery tactics for diagnosis and treatment of TBI. Tissue engineering and use of biomaterials is one such alternative approach. With this approach, neuronal stem cell therapy is combined with synthetically generated tissue materials such as hydrogels, self-assembling peptides, and electrospun nanofibers, which may induce neurite outgrowth, differentiation of human neural stem cells, and nerve gap bridging in TBI. This review examines tissue engineering and the use of biomaterials as potential treatments for TBI, including their synthesis, mechanisms of action, and limitations. The review also discusses challenges facing tissue engineering and biomaterial technology including survival rate of transplanted stem cells and the development of biodegradable, biocompatible, and mechanically flexible biomaterials. A better understanding of the mechanisms and drawbacks of these novel therapeutic approaches will help guide the design of future TBI therapies.

Network neuroscience delves into comprehending the intricate arrangement and interactions within the neural networks of the brain. By merging insights from both neuroscience and network theory, it investigates the brain's structure and function through the lens of interconnected nodes (symbolizing brain regions) and edges (symbolizing the connections among these regions) forming a dynamic network. Graph metrics play a pivotal role in neuroscience by providing quantifiable insights into the intricate connectivity patterns within the brain's neural networks. Frequently, nodes are extracted from functional or structural atlases, which can lead to diverse shapes and sizes. Nevertheless, our understanding of how these differing node characteristics and definitions impact the computed graph metrics in neuroimaging data remains limited. This study adopts a data-driven methodology to delineate functional nodes, subsequently examining the influence of their sizes on resultant graph metrics. By employing the Neuromark framework, an entirely automated independent component analysis (ICA) is applied to resting state fMRI data. Through this, functional network connectivity (FNC) matrices are computed—capturing Pearson correlations between component-time courses—while employing a proportional threshold to streamline node connections based on these correlations. Subsequently, various global and local graph metrics are computed, offering insights into network characteristics. Global metrics provide an overarching summary of the network structure, while local measures delve into structural intricacies at the individual component level. Node sizes are computed based on voxel counts surpassing a designated threshold. Next, we calculated the Pearson correlation between the obtained node sizes and the graph metrics, which we term 'node-metric coupling' (NMC). Our findings revealed consistent and noteworthy correlations between the values of graph metrics and the dimensions of brain nodes. To delve deeper into the implications of this correlation, we examined the node-metric coupling within a dataset comprising Alzheimer's disease, mild cognitive impairment, and control subjects. The disparities observed in node-metric coupling among these groups underscore the necessity of accounting for this factor during analysis. The two principal outcomes of this study are as follows: Firstly, the substantial interplay between varying node sizes within a given atlas and the resultant graph metrics; and secondly, the potential utility of node-metric coupling as a viable biomarker for brain disorders. These discoveries hold significant ramifications. While comparing studies employing diverse atlases is already a challenge, our work highlights an additional, critical source of variability: accounting for node sizes. Consequently, the association between intra-atlas node size and graph metric should be thoughtfully acknowledged in future neuroimaging investigations.

Autism Spectrum Disorder (ASD), a neurodevelopmental disorder characterized by persistent deficits in social interaction and communication manifests in early childhood and is followed by restricted and stereotyped behaviors, interests or activities in adolescence and adulthood (DSM-V). Although genetics and environmental factors have been implicated, the exact causes of ASD have yet to be fully characterized. New evidence suggests that dysbiosis or perturbation in gut microbiota (GM) and exposure to lead (Pb) may play important roles in ASD etiology. Pb is a toxic heavy metal that has been linked to a wide range of negative health outcomes including anemia, encephalopathy, gastroenteric diseases and more importantly cognitive and behavioral problems inherent to ASD. Pb exposure can disrupt GM, which is essential for maintaining overall health. GM, consisting of trillions of microorganisms, has been shown to play a crucial role in the development of various physiological and psychological functions. GM interacts with the brain in a bidirectional manner referred to as “Gut-Brain Axis (GBA).” In this review, following a general overview of ASD and GM, the interaction of Pb with GM in the context of ASD is emphasized. Potential exploitation of this interaction for therapeutic purposes is also touched upon.

The pathogen Cryptococcus neoformans is a major cause of fungal meningitis in humans. As with other melanotic microorganisms associated with human diseases, the cell wall-associated melanin of C. neoformans is a major virulence factor that contributes to its ability to evade host immune responses. The levels of melanin substrate and the regulation of melanin formation could be influenced by the microbiota-gut-brain axis. Moreover, recent studies show that C. neoformans infection causes dysbiosis in the human gut microbiome. In this review, we discuss the potential association between cryptococcal meningitis and the gut microbiome. Additionally, we emphasize the promising prospects of targeting the gut microbiome as a means of diagnosing and treating this debilitating disease.

Complex interactions between gene variants and environmental risk factors underlie the pathophysiological pathways in major psychiatric disorders. Autism Spectrum Disorder is a psychiatric condition in which susceptible alleles along with epigenetic memories contribute to the mutational landscape of the ailing brain. The present work reviews recent evolutionary, molecular, and epigenetic mechanisms potentially linked to the etiology of autism. First, we present a clinical vignette to describe clusters of maladaptive behaviors frequently diagnosed in autistic patients. Next, we microdissect brain regions pertinent to the nosology of autism as well as cell networks from the bilateral body plan. Lastly, we catalog a number of pathogenic environments associated with disease risk factors. This set of perspectives provides emerging insights into the dynamic interplay between epigenetic and environmental variation in the development of Autism Spectrum Disorders.

Brain plasticity is induced by learning during wakefulness and is consolidated during sleep. But the molecular mechanisms involved are poorly understood and their relation to experience-dependent changes in brain activity remains to be clarified. Localized mRNA translation is im-portant for the structural changes at synapses supporting brain plasticity consolidation. Sleep has been shown activate the translation mTOR pathway, via phosphorylation of 4E-BPs, during brain plasticity, but whether this activation is specific to synapses is not known. We investigated this question using acute exposure of rats to an enriched environment (EE). We measured brain activity with EEGs and 4E-BPs phosphorylation at cortical and cerebellar synapses with Western Blot. Sleep significantly increased the conversion of 4E-BPs to its hyperphosphorylated form at synapses, especially after EE exposure. EE exposure increased oscillations in the alpha band dur-ing active exploration and in the theta to beta (4-30Hz) range, as well as spindle density, during NREM sleep. Theta activity during exploration and NREM spindle frequency predicted changes in 4E-BPs hyperphosphorylation at synapses. Our results provide a link between EEG and mo-lecular markers of plasticity across wake and sleep.