Homozygosity for the C9orf72 GGGGCC repeat expansion in frontotemporal dementia

An expanded hexanucleotide repeat in the C9orf72 gene is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). We now report the first description of a homozygous patient and compare it to a series of heterozygous cases. The patient developed early-onset frontotemporal dementia without additional features. Neuropathological analysis showed c9FTD/ALS characteristics, with abundant p62-positive inclusions in the frontal and temporal cortices, hippocampus and cerebellum, as well as less abundant TDP-43-positive inclusions. Overall, the clinical and pathological features were severe, but did not fall outside the usual disease spectrum. Quantification of C9orf72 transcript levels in post-mortem brain demonstrated expression of all known C9orf72 transcript variants, but at a reduced level. The pathogenic mechanisms by which the hexanucleotide repeat expansion causes disease are unclear and both gain- and loss-of-function mechanisms may play a role. Our data support a gain-of-function mechanism as pure homozygous loss of function would be expected to lead to a more severe, or completely different clinical phenotype to the one described here, which falls within the usual range. Our findings have implications for genetic counselling, highlighting the need to use genetic tests that distinguish C9orf72 homozygosity

Between care and control : the uses and abuses of humanitarianism in contemporary migration debates

The coexistence of punitive forms of border control and a commitment to humanitarianism in liberal states – the liberal paradox – has long been a vexed issue in migration theory and policy. Despite the hegemonoic focus on deterring and detaining irregular migrants at the border, states acknowledge their commitment to compassion by resettling refugees and providing financial assistance to humanitarian organizations. This thesis considers how the tensions between these two approaches is enacted in contemporary migration debates in order to better understand how this paradox persists. Specifically, it uses a discourse analysis approach to consider government elite and policymaker responses to two migration crises in 2015; the large scale drownings in the Mediterranean in April, and the stranded boats carrying Rohingya migrants in the Bay of Bengal in May. The thesis asks to what extent is humanitarianism deployed as a tool by states for legitimating border controls? It identifies key rhetorical techniques that elites and policymakers use to defend their commitment to punitive forms of migration control, and demonstrates that ‘humanitarian’ policy solutions to migration crises primarily serve to reinforce states security interests.Arts, Faculty ofPolitical Science, Department ofGraduat

Using resources: conceptualizing the mediation and reflective use of tools and signs

The idea that culture comprises resources that are used has become a popular means to re-conceptualize the culture—agency antinomy. However, the theorization of using resources is fragmented. The present article reviews several attempts to theorize resources, arguing that there has been too much focus upon the resources themselves, while the notion of use has been neglected. Focusing upon mode of use, as opposed to the resources used, the article underscores the importance of distinguishing between tools, which are used to act upon the world, and signs, which are used to act upon the mind. The article also argues for a distinction between non-reflective use, or mediation, and reflective use of resources. Future research should focus upon the transformation of tools into signs and the transformation of mediation into reflective use. The article concludes by discussing problematic issues that remain in conceptualizing the use of resources

It is time for us all to embrace person-centred language for people in prison and people who were formerly in prison

The use of person-centred language is well accepted regarding substance use and infectious disease healthcare and research, and appropriate acronyms have become commonplace, e.g., “people who inject drugs (PWID) ”has mostly replaced phrases like “injecting drugs users ”. However, the use of the term’s ‘prisoner’ or ‘prisoners’ remains common. Although less common, terms such as ‘offenders’ and ‘inmates’ are also still used on occasion. This persists despite calls from people with lived experience of incarceration, and fellow academics, to stop using these terms. Given the considerable overlap between substance use, infectious diseases, and incarceration, in this commentary we discuss how they interact, including the stigma that is common to each. We propose that using person-centred language (i.e., people in prison or people formerly in prison) needs to become the default language used when presenting research related to people in prison or people formerly in prison. This is a much- needed step in efforts to overcome the continued stigma that people in prison face while incarcerated from prison officers and other employees, including healthcare providers. Likewise, overcoming stigma, including legalised discrimination, that follows people who were formerly in prison upon gaining their freedom is critical, as this impacts their health and related social determinants, including employment and housing

Nanofiber-Based Delivery of Therapeutic Peptides to the Brain

The delivery of therapeutic peptides and proteins to the central nervous system is the biggest challenge when developing effective neuropharmaceuticals. The central issue is that the blood-brain barrier is impermeable to most molecules. Here we demonstrate the concept of employing an amphiphilic derivative of a peptide to deliver the peptide into the brain. The key to success is that the amphiphilic peptide should by design self-assemble into nanofibers wherein the active peptide epitope is tightly wrapped around the nanofiber core. The nanofiber form appears to protect the amphiphilic peptide from degradation while in the plasma, and the amphiphilic nature of the peptide promotes its transport across the blood-brain barrier. Therapeutic brain levels of the amphiphilic peptide are achieved with this strategy, compared with the absence of detectable peptide in the brain and the consequent lack of a therapeutic response when the underivatized peptide is administered