Molecular dissection of HERV-W dependent microglial- and astroglial cell polarization.

The endogenous retrovirus type W (HERV-W) is a human-specific entity, which was initially discovered in multiple sclerosis (MS) patient derived cells. We initially found that the HERV-W envelope (ENV) protein negatively affects oligodendrogenesis and controls microglial cell polarization towards a myelinated axon associated and damaging phenotype. Such first functional assessments were conducted ex vivo, given the human-specific origin of HERV-W. Recent experimental evidence gathered on a novel transgenic mouse model, mimicking activation and expression of the HERV-W ENV protein, revealed that all glial cell types are impacted and that cellular fates, differentiation, and functions were changed. In order to identify HERV-W-specific signatures in glial cells, the current study analyzed the transcriptome of ENV protein stimulated microglial- and astroglial cells and compared the transcriptomic signatures to lipopolysaccharide (LPS) stimulated cells, owing to the fact that both ligands can activate toll-like receptor-4 (TLR-4). Additionally, a comparison between published disease associated glial signatures and the transcriptome of HERV-W ENV stimulated glial cells was conducted. We, therefore, provide here for the first time a detailed molecular description of specific HERV-W ENV evoked effects on those glial cell populations that are involved in smoldering neuroinflammatory processes relevant for progression of neurodegenerative diseases.

A Novel Ex Vivo Model to Study Therapeutic Treatments for Myelin Repair following Ischemic Damage.

Stroke is a major reason for persistent disability due to insufficient treatment strategies beyond reperfusion, leading to oligodendrocyte death and axon demyelination, persistent inflammation and astrogliosis in peri-infarct areas. After injury, oligodendroglial precursor cells (OPCs) have been shown to compensate for myelin loss and prevent axonal loss through the replacement of lost oligodendrocytes, an inefficient process leaving axons chronically demyelinated. Phenotypic screening approaches in demyelinating paradigms revealed substances that promote myelin repair. We established an ex vivo adult organotypic coronal slice culture (OCSC) system to study repair after stroke in a resource-efficient way. Post-photothrombotic OCSCs can be manipulated for 8 d by exposure to pharmacologically active substances testing remyelination activity. OCSCs were isolated from a NG2-CreERT2-td-Tomato knock-in transgenic mouse line to analyze oligodendroglial fate/differentiation and kinetics. Parbendazole boosted differentiation of NG2+ cells and stabilized oligodendroglial fate reflected by altered expression of associated markers PDGFR-α, CC1, BCAS1 and Sox10 and GFAP. In vitro scratch assay and chemical ischemia confirmed the observed effects upon parbendazole treatment. Adult OCSCs represent a fast, reproducible, and quantifiable model to study OPC differentiation competence after stroke. Pharmacological stimulation by means of parbendazole promoted OPC differentiation.

Teriflunomide as a therapeutic means for myelin repair.

BACKGROUND: Promotion of myelin repair in the context of demyelinating diseases such as multiple sclerosis (MS) still represents a clinical unmet need, given that this disease is not only characterized by autoimmune activities but also by impaired regeneration processes. Hence, this relates to replacement of lost oligodendrocytes and myelin sheaths-the primary targets of autoimmune attacks. Endogenous remyelination is mainly mediated via activation and differentiation of resident oligodendroglial precursor cells (OPCs), whereas its efficiency remains limited and declines with disease progression and aging. Teriflunomide has been approved as a first-line treatment for relapsing remitting MS. Beyond its role in acting via inhibition of de novo pyrimidine synthesis leading to a cytostatic effect on proliferating lymphocyte subsets, this study aims to uncover its potential to foster myelin repair. METHODS: Within the cuprizone mediated de-/remyelination model teriflunomide dependent effects on oligodendroglial homeostasis and maturation, related to cellular processes important for myelin repair were analyzed in vivo. Teriflunomide administration was performed either as pulse or continuously and markers specific for oligodendroglial maturation and mitochondrial integrity were examined by means of gene expression and immunohistochemical analyses. In addition, axon myelination was determined using electron microscopy. RESULTS: Both pulse and constant teriflunomide treatment efficiently boosted myelin repair activities in this model, leading to accelerated generation of oligodendrocytes and restoration of myelin sheaths. Moreover, teriflunomide restored mitochondrial integrity within oligodendroglial cells. CONCLUSIONS: The link between de novo pyrimidine synthesis inhibition, oligodendroglial rescue, and maintenance of mitochondrial homeostasis appears as a key for successful myelin repair and hence for protection of axons from degeneration.

"It's the poverty"-Stakeholder perspectives on barriers to secondary education in rural Burkina Faso.

Universal primary and secondary education is a key target of the Sustainable Development Goals. While substantial gains have been made at the primary school level, progress towards universal secondary education has slowed, particularly in sub-Saharan Africa. In this study, we aimed to determine perceived barriers of secondary schooling in rural Burkina Faso, where secondary school completion is among the lowest globally (<10%). We conducted a two-stage qualitative study using semi-structured interviews (N = 49). In the first stage, we sampled enrolled students (n = 10), out-of-school adolescents (n = 9), parents of enrolled students (n = 5), parents of out-of-school adolescents (n = 5) and teachers (n = 10) from a random sample of five secondary schools. In a second stage, we interviewed key informants knowledgeable of the school context using snowball sampling (n = 10). Systematic analysis of the pooled sample was based on a reading of interview transcripts and coding of the narratives in NVivo12 using the diathesis-stress model. Recurring themes were classified using a priori developed categories of hypothesized barriers to secondary schooling. Major reported barriers included school-related expenses and the lack of school infrastructure and resources. Insufficient and heterogeneous French language skills (the official language of instruction in Burkina Faso) were seen as a major barrier to secondary schooling. Forced marriages, adolescent pregnancies, and the low perceived economic benefits of investing in secondary schooling were reported as key barriers among young women. Our results guide future interventions and policy aimed at achieving universal secondary education and gender equity in the region.

Health and economic benefits of secondary education in the context of poverty: Evidence from Burkina Faso.

Even though formal education is considered a key determinant of individual well-being globally, enrollment in secondary schooling remains low in many low- and middle-income countries, suggesting that the perceived returns to such schooling may be low. We jointly estimate survival and monetary benefits of secondary schooling using detailed demographic and surveillance data from the Boucle du Mouhoun region, Burkina Faso, where national upper secondary schooling completion rates are among the lowest globally (<10%). We first explore surveillance data from the Nouna Health and Demographic Surveillance System from 1992 to 2016 to determine long-term differences in survival outcomes between secondary and higher and primary schooling using Cox proportional hazards models. To estimate average increases in asset holdings associated with secondary schooling, we use regionally representative data from the Burkina Faso Demographic Health Surveys (2003, 2010, 2014, 2017-18; N = 3,924). Survival was tracked for 14,892 individuals. Each year of schooling was associated with a mortality reduction of up to 16% (95% CI 0.75-0.94), implying an additional 1.9 years of life expectancy for men and 5.1 years for women for secondary schooling compared to individuals completing only primary school. Relative to individuals with primary education, individuals with secondary or higher education held 26% more assets (SE 0.02; CI 0.22-0.30). Economic returns for women were 3% points higher than male returns with 10% (SE 0.03; CI 0.04-0.16) vs. 7% (SE 0.02; CI 0.02-0.012) and in rural areas 20% points higher than in urban areas with 30% (SE 0.06; CI 0.19-0.41) vs. 4% (SE 0.01; CI 0.02-0.07). Our results suggest that secondary education is associated with substantial health and economic benefits in the study area and should therefore be considered by researchers, governments, and other major stakeholders to create for example school promotion programs.

TLR4 Associated Signaling Disrupters as a New Means to Overcome HERV-W Envelope-Mediated Myelination Deficits.

Myelin repair in the adult central nervous system (CNS) is driven by successful differentiation of resident oligodendroglial precursor cells (OPCs) and thus constitutes a neurodegenerative process capable to compensate for functional deficits upon loss of oligodendrocytes and myelin sheaths as it is observed in multiple sclerosis (MS). The human endogenous retrovirus type W (HERV-W) represents an MS-specific pathogenic entity, and its envelope (ENV) protein was previously identified as a negative regulator of OPC maturation-hence, it is of relevance in the context of diminished myelin repair. We here focused on the activity of the ENV protein and investigated how it can be neutralized for improved remyelination. ENV-mediated activation of toll like receptor 4 (TLR4) increases inducible nitric oxide synthase (iNOS) expression, prompts nitrosative stress, and results in myelin-associated deficits, such as decreased levels of oligodendroglial maturation marker expression and morphological alterations. The intervention of TLR4 surface expression represents a potential means to rescue such ENV-dependent deficits. To this end, the rescue capacity of specific substances, either modulating V-ATPase activity or myeloid differentiation 2 (MD2)-mediated TLR4 glycosylation status, such as compound 20 (C20), L48H437, or folimycin, was analyzed, as these processes were demonstrated to be relevant for TLR4 surface expression. We found that pharmacological treatment can rescue the maturation arrest of oligodendroglial cells and their myelination capacity and can prevent iNOS induction in the presence of the ENV protein. In addition, downregulation of TLR4 surface expression was observed. Furthermore, mitochondrial integrity crucial for oligodendroglial cell differentiation was affected in the presence of ENV and ameliorated upon pharmacological treatment. Our study, therefore, provides novel insights into possible means to overcome myelination deficits associated with HERV-W ENV-mediated myelin deficits.

A retrospective assessment of different endodontic treatment protocols.

BACKGROUND: The aim of this study was to assess the clinical impact of non-surgical root canal treatments (NSRCT) performed with different treatment protocols on the probability of tooth survival without untoward events and to identify predictors influencing the outcome. METHODS: During the period from July 1999 to October 2016, 5,858 patients were identified in which 9,967 NSRCTs were performed. The treatments were followed up and divided into three groups. In Group 1 root canal treatment was performed with hand instruments, in Group 2 with multiple file rotary instruments and passive ultrasonic irrigation (PUI), and Group 3 was treated with Reciproc instruments and PUI. Untoward events were defined as orthograde retreatment, apicoectomy or extraction of the tooth after initial treatment. Weibull regression was used to analyse the data. RESULTS: A total of 9,938 cases could be included into the analyses. The results showed 5-years predicted survival rates without untoward events of 73.9% (95% CI [71.7%-76.1%]), 75.1% (95% CI [71.7%-78.0%]) and 78.4% (95% CI [75.1%-81.4%]) for study group 1 (N = 5,580), 2 (N = 1,700) and 3 (N = 2,658), respectively. The differences between Group 1 and 3 were statistically significant (p < 0.006). Higher age of the patient (per year increase) and number of earlier NSRCTs (per unit increase) reduce the survival without untoward events statistically significant (both p < 0.02), while treatment of premolars had a statistically significant lower hazard ratio [0.89 (95% CI [0.79-0.99]; p = 0.030)] compared to treatment of molars and anterior teeth. A higher number of supportive periodontal treatments (per unit increase) improved tooth survival without untoward events highly significant (p < 0.0001). DISCUSSION: More recent endodontic treatment protocols involving reciprocating instruments and PUI appear to be associated with higher tooth survival rates without untoward events compared to hand instruments.

"Because at school, you can become somebody" - The perceived health and economic returns on secondary schooling in rural Burkina Faso.

BACKGROUND: The perceived returns on schooling are critical in schooling decision-making but are not well understood. This study examines the perceived returns on secondary schooling in Burkina Faso, where secondary school completion is among the lowest globally (<10%). METHODS: We conducted a two-staged qualitative study using semi-structured interviews (N = 49). In the first stage, we sampled students, dropouts, parents and teachers from a random sample of five schools (n = 39). In the second stage, we interviewed key informants knowledgeable of the school context using snowball sampling (n = 10). Systematic analysis was based on a grounded theory approach with a reading of transcripts, followed by coding of the narratives in NVivo 12. RESULTS: Respondents nearly universally perceived health benefits to schooling. In particular, key health benefits included improved sexual and reproductive health outcomes, hygiene knowledge and practices, as well as better interactions with the formal health system. Common economic returns on schooling included improved employment opportunities and the provision of support to family members, in addition to generally attaining success and recognition. Indirect and long-term health returns, however, were infrequently mentioned by respondents. CONCLUSIONS: While respondents reported nearly universally short-term health benefits to schooling, responses with regard to economic as well as indirect and long-term health benefits were more ambiguous. Future intervention studies on the perceived returns on formal education are needed to inform policy and reach education and health targets in the region.