Funding Mine Risk Education: Saving Lives Around the Globe

Mine risk education is an important tool in preventing mine-related injuries and deaths. The U.S. State Department has provided funding to many mine risk education programs in several different countries, giving mine-affected communities the knowledge necessary to live their daily lives with more caution and less fear

The U.S. Humanitarian Mine Action Program: Helping Countries “Get on Their Feet”

Since 1988, the U.S. Humanitarian Mine Action Program (formerly the U.S. Humanitarian Demining Program) has been involved in mine action efforts around the globe. While much has been written about the U.S. Humanitarian Mine Action Program over the past few years, it is useful to review the program’s fundamentals if only to remind ourselves of its policy and procedural aspects

Mine Action in Egypt: The Landmine Struggle Center and Arabic Mine Action Campaign

Egypt’s land is plagued with almost 20 million mines/UXO dating back to WWII. The government does not want to remove them without help from those who planted them. In response, the Landmine Struggle Center and Arabic Mine Action Campaign were formed to help those who are affected

Cerebral Organoids and Antisense Oligonucleotide Therapeutics: Challenges and Opportunities

The advent of stem cell-derived cerebral organoids has already advanced our understanding of disease mechanisms in neurological diseases. Despite this, many remain without effective treatments, resulting in significant personal and societal health burden. Antisense oligonucleotides (ASOs) are one of the most widely used approaches for targeting RNA and modifying gene expression, with significant advancements in clinical trials for epilepsy, neuromuscular disorders and other neurological conditions. ASOs have further potential to address the unmet need in other neurological diseases for novel therapies which directly target the causative genes, allowing precision treatment. Induced pluripotent stem cell (iPSC) derived cerebral organoids represent an ideal platform in which to evaluate novel ASO therapies. In patient-derived organoids, disease-causing mutations can be studied in the native genetic milieu, opening the door to test personalized ASO therapies and n-of-1 approaches. In addition, CRISPR-Cas9 can be used to generate isogenic iPSCs to assess the effects of ASOs, by either creating disease-specific mutations or correcting available disease iPSC lines. Currently, ASO therapies face a number of challenges to wider translation, including insufficient uptake by distinct and preferential cell types in central nervous system and inability to cross the blood brain barrier necessitating intrathecal administration. Cerebral organoids provide a practical model to address and improve these limitations. In this review we will address the current use of organoids to test ASO therapies, opportunities for future applications and challenges including those inherent to cerebral organoids, issues with organoid transfection and choice of appropriate read-outs

Glial dysfunction and its contribution to the pathogenesis of the neuronal ceroid lipofuscinoses

While significant efforts have been made in developing pre-clinical treatments for the neuronal ceroid lipofuscinoses (NCLs), many challenges still remain to bring children with NCLs a cure. Devising effective therapeutic strategies for the NCLs will require a better understanding of pathophysiology, but little is known about the mechanisms by which loss of lysosomal proteins causes such devastating neurodegeneration. Research into glial cells including astrocytes, microglia, and oligodendrocytes have revealed many of their critical functions in brain homeostasis and potential contributions to neurodegenerative diseases. Genetically modified mouse models have served as a useful platform to define the disease progression in the central nervous system across NCL subtypes, revealing a wide range of glial responses to disease. The emerging evidence of glial dysfunction questions the traditional neuron-centric view of NCLs, and would suggest that directly targeting glia in addition to neurons could lead to better therapeutic outcomes. This review summarizes the most up-to-date understanding of glial pathologies and their contribution to the pathogenesis of NCLs, and highlights some of the associated challenges that require further research

Glial Dysfunction and Its Contribution to the Pathogenesis of the Neuronal Ceroid Lipofuscinoses

While significant efforts have been made in developing pre-clinical treatments for the neuronal ceroid lipofuscinoses (NCLs), many challenges still remain to bring children with NCLs a cure. Devising effective therapeutic strategies for the NCLs will require a better understanding of pathophysiology, but little is known about the mechanisms by which loss of lysosomal proteins causes such devastating neurodegeneration. Research into glial cells including astrocytes, microglia, and oligodendrocytes have revealed many of their critical functions in brain homeostasis and potential contributions to neurodegenerative diseases. Genetically modified mouse models have served as a useful platform to define the disease progression in the central nervous system across NCL subtypes, revealing a wide range of glial responses to disease. The emerging evidence of glial dysfunction questions the traditional “neuron-centric” view of NCLs, and would suggest that directly targeting glia in addition to neurons could lead to better therapeutic outcomes. This review summarizes the most up-to-date understanding of glial pathologies and their contribution to the pathogenesis of NCLs, and highlights some of the associated challenges that require further research

PolyQ length-dependent metabolic alterations and DNA damage drive human astrocyte dysfunction in Huntington's disease

Huntington's Disease (HD) is a neurodegenerative disease caused by a polyglutamine (polyQ) expansion in the Huntingtin gene. Astrocyte dysfunction is known to contribute to HD pathology, however our understanding of the molecular pathways involved is limited. Transcriptomic analysis of patient-derived PSC (pluripotent stem cells) astrocyte lines revealed that astrocytes with similar polyQ lengths shared a large number of differentially expressed genes (DEGs). Notably, weighted correlation network analysis (WGCNA) modules from iPSC derived astrocytes showed significant overlap with WGCNA modules from two post-mortem HD cohorts. Further experiments revealed two key elements of astrocyte dysfunction. Firstly, expression of genes linked to astrocyte reactivity, as well as metabolic changes were polyQ length-dependent. Hypermetabolism was observed in shorter polyQ length astrocytes compared to controls, whereas metabolic activity and release of metabolites were significantly reduced in astrocytes with increasing polyQ lengths. Secondly, all HD astrocytes showed increased DNA damage, DNA damage response and upregulation of mismatch repair genes and proteins. Together our study shows for the first time polyQ-dependent phenotypes and functional changes in HD astrocytes providing evidence that increased DNA damage and DNA damage response could contribute to HD astrocyte dysfunction

Mislocalization of Nucleocytoplasmic Transport Proteins in Human Huntington’s Disease PSC-Derived Striatal Neurons

Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene (HTT). Disease progression is characterized by the loss of vulnerable neuronal populations within the striatum. A consistent phenotype across HD models is disruption of nucleocytoplasmic transport and nuclear pore complex (NPC) function. Here we demonstrate that high content imaging is a suitable method for detecting mislocalization of lamin-B1, RAN and RANGAP1 in striatal neuronal cultures thus allowing a robust, unbiased, highly powered approach to assay nuclear pore deficits. Furthermore, nuclear pore deficits extended to the selectively vulnerable DARPP32 + subpopulation neurons, but not to astrocytes. Striatal neuron cultures are further affected by changes in gene and protein expression of RAN, RANGAP1 and lamin-B1. Lowering total HTT using HTT-targeted anti-sense oligonucleotides partially restored gene expression, as well as subtly reducing mislocalization of proteins involved in nucleocytoplasmic transport. This suggests that mislocalization of RAN, RANGAP1 and lamin-B1 cannot be normalized by simply reducing expression of CAG-expanded HTT in the absence of healthy HTT protein

Soluble CD14: Genomewide Association Analysis and Relationship to Cardiovascular Risk and Mortality in Older Adults

CD14 is a glycosylphosphotidylinositol-(GPI)-anchored membrane glycoprotein expressed on neutrophils and monocytes/macrophages that also circulates as a soluble form (sCD14). Despite the well-recognized role of CD14 in inflammation, relatively little is known about the genetic determinants of sCD14 or the relationship of sCD14 to vascular- and aging-related phenotypes

Stigmatisering binnen de ggz:Onderzoek onder cliënten en hulpverleners

Achtergrond: Mensen met ernstige psychische aandoeningen ervaren naast belemmeringen in het sociaal en maatschappelijk functioneren ook de negatieve gevolgen van vooroordelen en stigmatisering. Ook binnen de ggz, inclusief verslavingszorg, komt stigmatisering voor. Doel: Beschrijven van het vóórkomen en de uitingsvormen van stigmatisering door hulpverleners, vanuit het perspectief van cliënten en hulpverleners. Methode: Digitale enquêtes onder leden van het panel Psychisch Gezien (n = 628) en onder hulpverleners (n = 471). Resultaten: Meer dan de helft (54%) van de panelleden had in de afgelopen twee jaar te maken gehad met stigmatisering door ggz-hulpverleners. Zij ervoeren dit vooral door een afstandelijke houding (22%) en door het taalgebruik van hulpverleners (20%). Twee vijfde (40%) van de hulpverleners gaf aan dat stigmatisering regelmatig of vaak voorkwam bij het eigen team. Zowel cliënten als hulpverleners benadrukten het belang van normalisering van psychische problemen, terughoudend gebruik van psychiatrische labels en herstelgericht werken om stigma te verminderen. Conclusie: Stigmatisering door ggz-hulpverleners komt op veel manieren tot uiting, waardoor het een complex en niet-eenduidig probleem is. Hoewel er geen ‘one-size-fits-all’-oplossing is, is normalisering van psychische problemen een belangrijk aanknopingspunt