Meningeal lymphatic function promotes oligodendrocyte survival and brain myelination.

The precise neurophysiological changes prompted by meningeal lymphatic dysfunction remain unclear. Here, we showed that inducing meningeal lymphatic vessel ablation in adult mice led to gene expression changes in glial cells, followed by reductions in mature oligodendrocyte numbers and specific lipid species in the brain. These phenomena were accompanied by altered meningeal adaptive immunity and brain myeloid cell activation. During brain remyelination, meningeal lymphatic dysfunction provoked a state of immunosuppression in the brain that contributed to delayed spontaneous oligodendrocyte replenishment and axonal loss. The deficiencies in mature oligodendrocytes and neuroinflammation due to impaired meningeal lymphatic function were solely recapitulated in immunocompetent mice. Patients diagnosed with multiple sclerosis presented reduced vascular endothelial growth factor C in the cerebrospinal fluid, particularly shortly after clinical relapses, possibly indicative of poor meningeal lymphatic function. These data demonstrate that meningeal lymphatics regulate oligodendrocyte function and brain myelination, which might have implications for human demyelinating diseases.

Abundant transcriptomic alterations in the human cerebellum of patients with a C9orf72 repeat expansion.

The most prominent genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is a repeat expansion in the gene C9orf72. Importantly, the transcriptomic consequences of the C9orf72 repeat expansion remain largely unclear. Here, we used short-read RNA sequencing (RNAseq) to profile the cerebellar transcriptome, detecting alterations in patients with a C9orf72 repeat expansion. We focused on the cerebellum, since key C9orf72-related pathologies are abundant in this neuroanatomical region, yet TDP-43 pathology and neuronal loss are minimal. Consistent with previous work, we showed a reduction in the expression of the C9orf72 gene and an elevation in homeobox genes, when comparing patients with the expansion to both patients without the C9orf72 repeat expansion and control subjects. Interestingly, we identified more than 1000 alternative splicing events, including 4 in genes previously associated with ALS and/or FTLD. We also found an increase of cryptic splicing in C9orf72 patients compared to patients without the expansion and controls. Furthermore, we demonstrated that the expression level of select RNA-binding proteins is associated with cryptic splice junction inclusion. Overall, this study explores the presence of widespread transcriptomic changes in the cerebellum, a region not confounded by severe neurodegeneration, in post-mortem tissue from C9orf72 patients.

Comparative effectiveness of preventive treatment with dimethyl fumarate-loaded solid lipid nanoparticles and oral dimethyl fumarate in a mouse model of multiple sclerosis.

BACKGROUND: Orally administered dimethyl fumarate (DMF) presents gastrointestinal adverse effects, such as pain and diarrhea, in addition to flushing and lymphopenia. OBJECTIVE: Solid lipid nanoparticles (SLNs) with DMF were developed for subcutaneous administration. METHODS: DMF-incorporated SLNs and free DMF were tested in mice induced with experimental autoimmune encephalomyelitis (EAE). RESULTS: Preventive treatment of free or incorporated DMF were able to reduce the EAE clinical scores, increase the weight of the animals, reduce the lesion area (demyelination and infiltration), reduce microglial fluorescence intensity and reduce the number of microglial cells and astrocytes, when compared to untreated EAE animals. Groups that received DMF had reduced numbers of T cells, B cells and natural killer (NK) cells in the blood, when compared to the non-induced group. CONCLUSIONS: DMF incorporated in SLNs was as effective as free DMF in reducing the clinical scores of the animals, but with reduced administrations when given subcutaneously. In addition, SLN-DMF preventive treatment partially prevented a reduction in the percentages of T and B cells, in the blood, when compared to preventive treatment with free DMF (oral), which suggests reduction of lymphopenia.

Evaluation of the lights4violence program: reduction in machismo and acceptance of violence among adolescents in Europe.

BACKGROUND: Machismo and acceptance of violence (AV) against women are part of the social construction of hegemonic masculinity and are related to the risk of dating violence. This study aims to analyze the effectiveness of the Lights4Violence program in reducing machismo and AV in secondary school students from different European cities. METHODS: Quasi-experimental longitudinal study using a convenience sample of 1,146 high school students from different European cities (12-17 years old) including 575 intervention group students (59.1% girls) and 571 control group students (62.7% girls). We performed linear regression models to identify the effect of the intervention, modelling the difference in means in machismo and AV (dependent variables) between wave-2 and wave-1. RESULTS: An interaction was identified between the group variable and the empathy variable. In wave-2, girls with high empathy at baseline in the intervention group obtained lower mean AV scores (ß: -0.131; p = 0.004). However, the boys in the intervention group (reference: control group) with low empathy at baseline registered a significant increase in the mean values of machismo (ß: 0.247; p < 0.001). CONCLUSION: The importance of empathy is shown in the effectiveness of interventions to reduce machismo and AV in adolescents. While the Lights4Violence program focuses on promoting healthy relationships, there were some controversial results. It is possible that some children, especially those with less empathy, may have felt "challenged" during the intervention and/or assessment. This suggests the need for the development of interventions that also consider psychological processes and integrate the promotion of positive expressions of masculinity.

Altered astrocytic function in experimental neuroinflammation and multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that affects about 2.5 million people worldwide. In MS, the patients' immune system starts to attack the myelin sheath, leading to demyelination, neurodegeneration, and, ultimately, loss of vital neurological functions such as walking. There is currently no cure for MS and the available treatments only slow the initial phases of the disease. The later-disease mechanisms are poorly understood and do not directly correlate with the activity of immune system cells, the main target of the available treatments. Instead, evidence suggests that disease progression and disability are better correlated with the maintenance of a persistent low-grade inflammation inside the CNS, driven by local glial cells, like astrocytes and microglia. Depending on the context, astrocytes can (a) exacerbate inflammation or (b) promote immunosuppression and tissue repair. In this review, we will address the present knowledge that exists regarding the role of astrocytes in MS and experimental animal models of the disease.

Sexism and its associated factors among adolescents in Europe: Lights4Violence baseline results.

Despite the efforts of recent decades to reduce gender inequality, sexism is still prevalent among adolescents. The objective of this study was to identify the main socioeconomic characteristics, personal experiences, resources, and competencies associated with sexism in a sample of adolescents from different European countries. Baseline data from the Lights4Violence project included 1555 students ages 12-17 from secondary schools in six European countries (Spain, Italy, Romania, United Kingdom, Portugal, and Poland). Linear regression models were carried out, stratified by sex for benevolent (BS) and hostile (HS) dimensions of the Ambivalent Sexism Inventory. The average age of the sample was 14.3 years (SD = 1.5), 59.3% were girls. Boys scored higher on the measure of sexism (mean BS = 29.7; HS = 29.1) than girls (BS = 27.5, HS = 23.0; p < .001). Girls whose mothers had a university degree reported lower BS (ß = -0.113; p = .023) (reference: lower education). Girls who had experienced dating violence reported higher HS (ß = .080; p = .010) than those who had never been in an intimate relationship. For both sexes, high aggressiveness was associated with high levels of HS, and high aggressiveness was related to high levels of BS in boys. High assertiveness was associated with high levels of BS in both sexes and with high levels of HS in boys. A high level of problem-solving ability was associated with lower HS in both sexes. The study reinforces the need to invest in school programs aimed at preventing dating violence and promoting positive youth development.

Beliefs on Marital Violence Among Portuguese Adolescents: Monitoring Their Evolution and Relationship With Dating Violence.

In the last two decades, the problem of violence in the family sphere in particular and in intimate relationships in general has been on the agenda for Portuguese governmental and nongovernmental agencies. Several initiatives and campaigns have been launched, which are aimed at reducing occurrence of this violence, particularly among teenagers. This present study aims to assess the evolution in adolescents' attitudes and behaviors concerning intimate partner violence. We collected data from a sample of adolescents (n = 913) to compare with corresponding data collected 7 years ago by Neves and Nogueira (2010) in a sample that had identical sociodemographic characteristics (n = 899). Both cohorts resided in the same areas in the northeastern region of Portugal. The instruments used were the Scale of Beliefs about Marital Violence (ECVC) and the Marital Violence Inventory (IVC; Neves & Nogueira, 2010). The results indicate that although respondents tend to reject traditional beliefs on marital violence more now than in the past, especially male and older respondents, the percentage of dating violence reports has not decreased. Among girls, there was even an increase in perpetration of emotional and mild physical violence. We discuss possible reasons for this discrepancy between the evolution of attitudes and behaviors and make suggestions for improvement in the actions implemented among teenagers to increase their effectiveness.

Integrin α E ß 7 (CD103) expression in bronchoalveolar lymphocytes of patients with hypersensitivity pneumonitis.

PURPOSE: CD4+/CD8+ ratio in bronchoalveolar lavage fluid (BALF) often retrieves contradictory findings when used for diagnosis of sarcoidosis and hypersensitivity pneumonitis (HP), so CD103+ has been investigated as a possible differential marker. We aimed to compare CD103+ expression in BALF T-lymphocytes between patients with HP, sarcoidosis and other interstitial lung diseases (ILD). METHODS: An observational study carried out over a 2-year period included consecutive patients with suspected ILD who underwent BALF as part of their initial diagnostic work-up; CD103+ expression on BALF T-lymphocytes was evaluated. After a final diagnosis established according to international criteria, three patient subgroups-HP, ILD (which included idiopathic interstitial pneumonia and connective tissue disease-associated lung disorders) and sarcoidosis-were considered for further analysis. RESULTS: A total of 77 subjects were enrolled, 20 with HP, 16 with other ILD and 41 with sarcoidosis. A significantly higher number of CD4+ CD103+ and CD8+ CD103+ lymphocytes were found in HP patients. Among patients with sarcoidosis, 12 (29.3 %) presented a BALF CD4+/CD8+ <3.5, all of them with histological confirmation. Compared to these patients, also statistically significant higher CD4+ CD103+ counts in HP patients were observed (p = 0.007). Among HP patients, although bird fanciers (n = 14) presented higher percentages of both CD4+ CD103+ and CD8+ CD103+ T-lymphocytes than those with work-related HP (n = 5), the differences did not reach statistical significance. CONCLUSIONS: Patients with HP present significantly higher counts of CD103+ T-lymphocytes in BALF, both in the CD4+ and CD8+ subsets, when compared to sarcoidosis, even with sarcoidosis subgroup presenting a BALF CD4+/CD8+ <3.5. The expression of CD103 may help in the interpretation of BALF data in these diffuse granulomatous lung disorders.

Occupational second-hand smoke exposure: A comparative shotgun proteomics study on nasal epithelia from healthy restaurant workers.

Non-smokers exposed to second-hand smoke (SHS) present risk of developing tobacco smoke-associated pathologies. To investigate the airway molecular response to SHS exposure that could be used in health risk assessment, comparative shotgun proteomics was performed on nasal epithelium from a group of healthy restaurant workers, non-smokers (never and former) exposed and not exposed to SHS in the workplace. HIF1α-glycolytic targets (GAPDH, TPI) and proteins related to xenobiotic metabolism, cell proliferation and differentiation leading to cancer (ADH1C, TUBB4B, EEF2) showed significant modulation in non-smokers exposed. In never smokers exposed, enrichment of glutathione metabolism pathway and EEF2-regulating protein synthesis in genotoxic response were increased, while in former smokers exposed, proteins (LYZ, ATP1A1, SERPINB3) associated with tissue damage/regeneration, apoptosis inhibition and inflammation that may lead to asthma, COPD or cancer, were upregulated. The identified proteins are potential response and susceptibility/risk biomarkers for SHS exposure.

Professionals' Perspectives on the Effects of the COVID-19 Pandemic among Child and Adolescent Victims of Domestic Violence Living in the Portuguese Residential Foster Care System.

The COVID-19 pandemic had several negative impacts on child and adolescent victims of domestic violence, especially on those who lived in the residential foster care system. The main goal of the present study was to understand these negative impacts through the perspectives of professionals in Portuguese residential foster care structures using both individual interviews and an online survey. One hundred and three professionals aged between 22 and 64 years (M = 38.39; SD = 8.34) participated in the online survey (86 females and 17 males). Of those, seven professionals, four females and three males aged between 29 and 49 years (M = 38.43, SD = 7.50), were also interviewed. According to the participants, the conditions imposed by the COVID-19 pandemic contributed adversely not only to the increase in domestic violence against children and adolescents but also to the aggravation of the conditions children and adolescents living in the Portuguese residential foster care system were exposed to, namely concerning family relationships, access to resources and services, and institutional dynamics. The results suggest the necessity to develop standard procedures to cope with pandemic situations in the residential foster care system.

Domestic Violence against LGBTI People: Perspectives of Portuguese Education Professionals.

Lesbian, gay, bisexual, trans and intersex (LGBTI) people are more likely to be exposed to domestic violence than the rest of the population. Using a descriptive qualitative methodology, 28 professionals from the educational sector, aged between 28 and 64 years old (M = 44.5), were interviewed to describe and understand their perspectives on the sector's ability to support, intervene and get involved with LGBTI people and, particularly, with victims or former victims of domestic violence. Through a thematic content analysis, three main themes emerged: (i) life trajectories of LGBTI people; (ii) domestic violence perpetrated against LGBTI people; and (iii) training of the educational sector to intervene with LGBTI people. The results show that Portuguese education professionals are not trained to recognize and intervene with LGBTI people and, in particular, with those who are victims of domestic violence, since they are unaware of the existence of protocols and/or guidelines for detecting and preventing risk situations among students. Furthermore, the curricular plan fails in the coverage of domestic violence and LGBTI-related topics, although the National Strategy for Citizenship Education has been implemented in Portugal since 2017. Findings suggest the need to invest in education professionals' training.

Use of Next-Generation Sequencing to Support the Diagnosis of Familial Interstitial Pneumonia.

Familial interstitial pneumonia (FIP) is defined as idiopathic interstitial lung disease (ILD) in two or more relatives. Genetic studies on familial ILD discovered variants in several genes or associations with genetic polymorphisms. The aim of this study was to describe the clinical features of patients with suspected FIP and to analyze the genetic variants detected through next-generation sequencing (NGS) genetic testing. A retrospective analysis was conducted in patients followed in an ILD outpatient clinic who had ILD and a family history of ILD in at least one first- or second-degree relative and who underwent NGS between 2017 and 2021. Only patients with at least one genetic variant were included. Genetic testing was performed on 20 patients; of these, 13 patients had a variant in at least one gene with a known association with familial ILD. Variants in genes implicated in telomere and surfactant homeostasis and MUC5B variants were detected. Most variants were classified with uncertain clinical significance. Probable usual interstitial pneumonia radiological and histological patterns were the most frequently identified. The most prevalent phenotype was idiopathic pulmonary fibrosis. Pulmonologists should be aware of familial forms of ILD and genetic diagnosis.

Astrocytes Undergo Metabolic Reprogramming in the Multiple Sclerosis Animal Model.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that presents a largely unknown etiopathology. The presence of reactive astrocytes in MS lesions has been described for a long time; however, the role that these cells play in the pathophysiology of MS is still not fully understood. Recently, we used an MS animal model to perform high-throughput sequencing of astrocytes' transcriptome during disease progression. Our data show that astrocytes isolated from the cerebellum (a brain region typically affected in MS) showed a strong alteration in the genes that encode for proteins related to several metabolic pathways. Specifically, we found a significant increase in glycogen degradation, glycolytic, and TCA cycle enzymes. Together with these alterations, we detected an upregulation of genes that characterize "astrocyte reactivity". Additionally, at each disease time point we also reconstructed the morphology of cerebellum astrocytes in non-induced controls and in EAE animals, near lesion regions and in the normal-appearing white mater (NAWM). We found that near lesions, astrocytes presented increased length and complexity compared to control astrocytes, while no significant alterations were observed in the NAWM. How these metabolic alterations are linked with disease progression is yet to be uncovered. Herein, we bring to the literature the hypothesis of performing metabolic reprogramming as a novel therapeutic approach in MS.

Differential Diagnosis or Etiology: A Case Report on Amyotrophic Lateral Sclerosis-like Neuropathy Associated with HIV Infection.

BACKGROUND: Retroviruses are described as a risk factor for chronic neuropathy. However, it is still unknown if they can work as amyotrophic lateral sclerosis triggers. Over the years, some cases of this association have been described with heterogenous disclosures. CASE REPRESENTATION: This study aimed to report a case of HIV and ALS-like neuropathy and briefly discuss peculiarities of clinical aspects, such as physiopathology and treatment options. The patient underwent neurological examination associated with blood tests, electromyography, analysis of cerebrospinal fluid, and imaging studies. DISCUSSION: A non-systematic review was performed in major databases regarding the topic. The case presented mixed upper and lower motor neuron signs and was framed as a probable case of ALS following the present criteria. CONCLUSION: After a short follow-up and viral load cleansing, neurological stabilization was achieved.

Attitudes of Portuguese Judges and Victim Support Professionals Toward Intimate Partner Homicide Committed by Women.

This investigation analyzed the attitudes of Portuguese judges and victim support professionals toward intimate partner homicide committed by women. By administering an online survey disseminated by the Portuguese Superior Council for the Magistracy and the Commission for Citizenship and Gender Equality, we found that both groups of professionals are not always aligned in their attitudes toward domestic violence and intimate partner homicide, which could jeopardize the articulation between both sectors needed for an effective preventive intervention. However, most professionals of both groups tend to disagree that women provoke their aggressors or lie about their condition as victims of domestic violence and agree that there is a need for increased security and prevention of intimate partner homicides against female and male victims when reporting domestic violence.

Lipocalin-2 does not influence EAE clinical score but it increases inflammation in central nervous system.

The contribution of lipocalin-2 (LCN2) to multiple sclerosis (MS) is controversial. Herein, we induced experimental autoimmune encephalomyelitis (EAE) in LCN2-null and wild-type (Wt) mice. While we did not find differences between genotypes regarding clinical score, LCN2-null EAE mice presented decreased expression of interferon gamma and diminished demyelination in the cerebellum. Both genotypes presented similar alterations in the thymocyte and splenocyte populations. In MS patients, higher LCN2 CSF levels at diagnosis could be associated with faster disease progression, however further studies are needed to confirm these results, since this association was lost after controlling for the patients age, presence of oligoclonal bands and gender. Overall, our results support a harmful role for LCN2 in the disease context.

Profiling Microglia in a Mouse Model of Machado-Joseph Disease.

Microglia have been increasingly implicated in neurodegenerative diseases (NDs), and specific disease associated microglia (DAM) profiles have been defined for several of these NDs. Yet, the microglial profile in Machado-Joseph disease (MJD) remains unexplored. Here, we characterized the profile of microglia in the CMVMJD135 mouse model of MJD. This characterization was performed using primary microglial cultures and microglial cells obtained from disease-relevant brain regions of neonatal and adult CMVMJD135 mice, respectively. Machine learning models were implemented to identify potential clusters of microglia based on their morphological features, and an RNA-sequencing analysis was performed to identify molecular perturbations and potential therapeutic targets. Our findings reveal morphological alterations that point to an increased activation state of microglia in CMVMJD135 mice and a disease-specific transcriptional profile of MJD microglia, encompassing a total of 101 differentially expressed genes, with enrichment in molecular pathways related to oxidative stress, immune response, cell proliferation, cell death, and lipid metabolism. Overall, these results allowed us to define the cellular and molecular profile of MJD-associated microglia and to identify genes and pathways that might represent potential therapeutic targets for this disorder.

Epidemiology of interstitial lung diseases and their progressive-fibrosing behaviour in six European countries.

The PERSEIDS study aimed to estimate incidence/prevalence of interstitial lung diseases (ILDs), fibrosing interstitial lung diseases (F-ILDs), idiopathic pulmonary fibrosis (IPF), systemic sclerosis-associated ILD (SSc-ILD), other non-IPF F-ILDs and their progressive-fibrosing (PF) forms in six European countries, as current data are scarce. This retrospective, two-phase study used aggregate data (2014-2018). In Phase 1, incident/prevalent cases of ILDs above were identified from clinical databases through an algorithm based on codes/keywords, and incidence/prevalence was estimated. For non-IPF F-ILDs, the relative percentage of subtypes was also determined. In Phase 2, a subset of non-IPF F-ILD cases was manually reviewed to determine the percentage of PF behaviour and usual interstitial pneumonia-like (UIP-like) pattern. A weighted mean percentage of progression was calculated for each country and used to extrapolate incidence/prevalence of progressive-fibrosing ILDs (PF-ILDs). In 2018, incidence/105 person-years ranged between 9.4 and 83.6 (ILDs), 7.7 and 76.2 (F-ILDs), 0.4 and 10.3 (IPF), 6.6 and 71.7 (non-IPF F-ILDs), and 0.3 and 1.5 (SSc-ILD); and prevalence/105 persons ranged between 33.6 and 247.4 (ILDs), 26.7 and 236.8 (F-ILDs), 2.8 and 31.0 (IPF), 22.3 and 205.8 (non-IPF F-ILDs), and 1.4 and 10.1 (SSc-ILD). Among non-IPF F-ILDs, sarcoidosis was the most frequent subtype. PF behaviour and UIP-like pattern were present in a third of non-IPF F-ILD cases each and hypersensitivity pneumonitis showed the highest percentage of progressive behaviour. Incidence of PF-ILDs ranged between 2.1 and 14.5/105 person-years, and prevalence between 6.9 and 78.0/105 persons. To our knowledge, PERSEIDS is the first study assessing incidence, prevalence and rate of progression of ILDs across several European countries. Still below the threshold for orphan diseases, the estimates obtained were higher and more variable than reported in previous studies, but differences in study design/population must be considered.

CNS-Draining Meningeal Lymphatic Vasculature: Roles, Conundrums and Future Challenges.

A genuine and functional lymphatic vascular system is found in the meninges that sheath the central nervous system (CNS). This unexpected (re)discovery led to a reevaluation of CNS fluid and solute drainage mechanisms, neuroimmune interactions and the involvement of meningeal lymphatics in the initiation and progression of neurological disorders. In this manuscript, we provide an overview of the development, morphology and unique functional features of meningeal lymphatics. An outline of the different factors that affect meningeal lymphatic function, such as growth factor signaling and aging, and their impact on the continuous drainage of brain-derived molecules and meningeal immune cells into the cervical lymph nodes is also provided. We also highlight the most recent discoveries about the roles of the CNS-draining lymphatic vasculature in different pathologies that have a strong neuroinflammatory component, including brain trauma, tumors, and aging-associated neurodegenerative diseases like Alzheimer's and Parkinson's. Lastly, we provide a critical appraisal of the conundrums, challenges and exciting questions involving the meningeal lymphatic system that ought to be investigated in years to come.

Association Between Iron-Related Protein Lipocalin 2 and Cognitive Impairment in Cerebrospinal Fluid and Serum.

A worldwide increase in longevity is bringing novel challenges to public health and health care professionals. Cognitive impairment in the elderly may compromise living conditions and precede Alzheimer's disease (AD), the most prevalent form of dementia. Therefore, finding molecular markers associated with cognitive impairment is of crucial importance. Lipocalin 2 (LCN2), an iron-related protein, has been suggested as a potential marker for mild cognitive impairment (MCI) and AD. This study aimed at investigating the association between LCN2 measured in serum and cerebrospinal fluid (CSF) with cognitive impairment. A cross-sectional design based on two aging cohorts was used: individuals diagnosed with subjective cognitive complaints (SCC), MCI, and AD from a Swedish memory clinic-based cohort, and individuals diagnosed with SCC and AD from a Portuguese cohort. Binary logistic [for the outcome cognitive impairment (MCI + AD) in the Swedish cohort and AD in the Portuguese cohort] and multinomial logistic (for the outcomes MCI and AD) regression analyses were used. No associations were found in both cohorts when controlling for sex, education, and age. This explanatory study suggests that the association between serum and CSF LCN2 concentrations with cognitive impairment reported in the literature must be further analyzed for confounders.