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Glia in the central nervous system engulf neuron fragments to remodel synapses and recycle photoreceptor outer segments. Whether glia passively clear shed neuronal debris or actively prune neuron fragments is unknown. How pruning of single-neuron endings impacts animal behavior is also unclear. Here, we report our discovery of glia-directed neuron pruning in Caenorhabditis elegans. Adult C. elegans AMsh glia engulf sensory endings of the AFD thermosensory neuron by repurposing components of the conserved apoptotic corpse phagocytosis machinery. The phosphatidylserine (PS) flippase TAT-1/ATP8A functions with glial PS-receptor PSR-1/PSR and PAT-2/α-integrin to initiate engulfment. This activates glial CED-10/Rac1 GTPase through the ternary GEF complex of CED-2/CrkII, CED-5/DOCK180, CED-12/ELMO. Execution of phagocytosis uses the actin-remodeler WSP-1/nWASp. This process dynamically tracks AFD activity and is regulated by temperature, the AFD sensory input. Importantly, glial CED-10 levels regulate engulfment rates downstream of neuron activity, and engulfment-defective mutants exhibit altered AFD-ending shape and thermosensory behavior. Our findings reveal a molecular pathway underlying glia-dependent engulfment in a peripheral sense-organ and demonstrate that glia actively engulf neuron fragments, with profound consequences on neuron shape and animal sensory behavior. Neurons are tree-shaped cells that receive information through endings connected to neighbouring cells or the environment. Controlling the size, number and location of these endings is necessary to ensure that circuits of neurons get precisely the right amount of input from their surroundings. Glial cells form a large portion of the nervous system, and they are tasked with supporting, cleaning and protecting neurons. In humans, part of their duties is to ‘eat’ (or prune) unnecessary neuron endings. In fact, this role is so important that defects in glial pruning are associated with conditions such as Alzheimer’s disease. Yet it is still unknown how pruning takes place, and in particular whether it is the neuron or the glial cell that initiates the process. To investigate this question, Raiders et al. enlisted the common laboratory animal Caenorhabditis elegans , a tiny worm with a simple nervous system where each neuron has been meticulously mapped out. First, the experiments showed that glial cells in C. elegans actually prune the endings of sensory neurons. Focusing on a single glia-neuron pair then revealed that the glial cell could trim the endings of a living neuron by redeploying the same molecular machinery it uses to clear dead cell debris. Compared to this debris-clearing activity, however, the glial cell takes a more nuanced approach to pruning: specifically, it can adjust the amount of trimming based on the activity load of the neuron. When Raiders et al. disrupted the glial pruning for a single temperature-sensing neuron, the worm lost its normal temperature preferences; this demonstrated how the pruning activity of a single glial cell can be linked to behavior. Taken together the experiments showcase how C. elegans can be used to study glial pruning. Further work using this model could help to understand how disease emerges when glial cells cannot perform their role, and to spot the genetic factors that put certain individuals at increased risk for neurological and sensory disorders.

How did the individual human being become the focus of the contemporary discourse on security? What was the role of the United Nations in securing the individual? What are the payoffs and costs of this extension of the concept? Neil MacFarlane and Yuen Foong Khong tackle these questions by analyzing historical and contemporary debates about what is to be secured. From Westphalia through the 19th century, the state's claim to be the object of security was sustainable because it offered its subjects some measure of protection. The state's ability to provide security for its citizens came under heavy strain in the 20th century as a result of technological, strategic, and ideological innovations. By the end of World War II, efforts to reclaim the security rights of individuals gathered pace, as seen in the Universal Declaration of Human Rights and a host of United Nations covenants and conventions. MacFarlane and Khong highlight the UN's work in promoting human security ideas since the 1940s, giving special emphasis to its role in extending the notion of security to include development, economic, environmental, and other issues in the 1990s.

IntroductionSodium selenate is a potential disease-modifying treatment for Alzheimer’s disease (AD) which reduces hyperphosphorylated tau through activation of the protein phosphatase 2A enzyme. We have shown sodium selenate to be safe and well tolerated in a 24-week, phase 2a double-blind placebo-controlled randomised controlled trial (RCT), also reporting sodium selenate reduced neurodegeneration on diffusion-weighted MRI. This study assessed the safety and tolerability of chronic sodium selenate treatment (up to 23 months) in patients with AD who had been enrolled in the RCT. Cognitive measures served as secondary outcomes of potential disease-modification.MethodsAn open-label extension study of sodium selenate (10 mg three times a day) in patients with AD who had completed the previous RCT. Twenty-eight patients were enrolled. Patients were regularly monitored for safety, adverse events (AEs) and protocol compliance. Cognitive tests were administered for measures of disease progression.ResultsSixteen patients were discontinued by the sponsor, and 12 discontinued for other reasons. Treatment duration ranged from 6 to 23 months. The majority of AEs were mild (83%), and 33% were treatment-related. Common treatment-related AEs were alopecia (21%) and nail disorder (32%), which both resolved either prior to or following cessation of treatment. Two serious AEs occurred, which were not treatment-related. Alzheimer’s Disease Assessment Scale—Cognitive Subscale 11 score increased 1.8 points over 12 months.DiscussionChronic sodium selenate treatment is safe and well tolerated in patients with AD. Cognitive measures suggest a slowing of disease progression though this could not be confirmed as the study was not controlled. Further research into sodium selenate as a treatment for AD is warranted.

[1], entitled “Differences in Staff-Assessed Pain Behaviors among Newly Admitted Nursing Home Residents by Level of Cognitive Impairment,” published in the journal Dementia and Geriatric Cognitive Disorders. [...]the need to use validated facial cues in pain assessment tools [e.g., Pain Assessment Checklist for Seniors with Limited Ability to Communicate (PACSLAC-II), PainChek® (formerly known as the electronic Pain Assessment Tool “ePAT”)] for this population [7-9]. [...]we commend the data reported by Morrison et al. in their article and appreciate any additional clinical or demographic information (e.g., pain behaviors by ethnicity; orofacial pain data) related to this important topic.

Most patients with dementia have behavioural and psychological symptoms. The first-line treatments for these symptoms are not drugs, but behavioural and psychological interventions Antipsychotic drugs are widely prescribed for people living with dementia. This is despite a high adverse effect burden and limited evidence of efficacy Most behavioural and psychological symptoms will subside spontaneously within six months. Trials of deprescribing are therefore recommended Behaviours should be seen as symptoms that have an underlying cause. Treatment should target these causes, rather than the resultant behaviours.

Dementia is now the leading cause of admission to residential aged care facilities (RACF) in the developed world (Van Rensbergen and Nawrot, 2010), with prevalence rates among residents estimated to be approximately 70% (Zimmerman et al., 2014). In addition, dementia is now the 4th leading cause of death in high-income countries with this expected to rise to the 3rd leading cause of death by 2030 (World health Organization, 2015). Despite the prevalence of the condition, the amount of teaching time devoted to dementia in medical school curricula remains low and does not adequately prepare graduates for their work as doctors (Tullo and Allan, 2011; Tullo and Gordon, 2013). As a consequence, many general practitioners feel their level of confidence in managing behavioral and psychological symptoms of dementia (BPSD) is very low (Buhagiar et al., 2011).

(NPS MedicineWise has several resources covering medicines in dementia.) In my role undertaking residential medication management reviews for people suffering from dementia in residential care, I am continually recommending that, where possible, olanzapine should be avoided in older people for the specific indication of treating BPSD, due to the high risk of anticholinergic adverse effects and sedation. The deprescribing algorithm which appeared in the article was reproduced with permission from Canadian Clinical Practice Guidelines.3 While correctly suggesting the use of alternative antipsychotics in accordance with existing evidence-based guidelines, the algorithm is not without its flaws. A study found that olanzapine (5 or 10 mg) was significantly more effective than placebo in reducing agitation, aggression and hallucinations in a six-week study in 206 nursing home residents with Alzheimer’s disease.4 The 5 mg dose had the greatest effect, followed by the 10 mg dose, while 15 mg was no more effective than placebo.

Background There are no approved oral disease‐modifying small molecule therapies for treatment of early Alzheimer’s disease (AD). Blarcamesine is an orally bioavailable small molecule that enhances autophagy through SIGMAR1 activation and restoration of cellular homeostasis in early AD. Method The ATTENTION‐AD study was an up to 144‐week open‐label extension study subsequent the 48‐Week Phase IIb/III double‐blind placebo‐controlled ANAVEX®2‐73‐AD‐004 study, to evaluate the safety and efficacy of oral once daily blarcamesine in 508 participants with early AD. Delayed‐start analysis was performed to assess the effect of early treatment initiation up to 192 Weeks. Result The ATTENTION‐AD trial confirmed the good efficacy and safety profile of once daily oral blarcamesine and also demonstrated the manageable nature of the most frequent treatment emergent adverse event (TEAE) (dizziness) observed in the preceding ANAVEX®2‐73‐AD‐004 trial, which was generally transient in duration (approx. 7‐11 days) and mild or moderate in severity (Grade 1 or 2). The titration schedule was adjusted to a slightly longer titration period in the ATTENTION‐AD trial, from previous 2‐3 weeks to 10 weeks. A markedly lower frequency of the TEAE of dizziness in the respective maintenance phase was observed: from previously 25.2% in the ANAVEX®2‐73‐AD‐004 trial to 9.6% in the ATTENTION‐AD trial, demonstrating the manageable nature of this TEAE. No severe or life‐threatening adverse events were attributed to blarcamesine. No Amyloid Related Imaging Abnormalities (ARIA) adverse events were identified. There were no deaths related to blarcamesine. Efficacy of the cognitive and functional endpoints in the delayed‐start analysis of treatment resulted in significant outcomes, ADAS‐Cog13 (LS mean difference ‐3.83, P = 0.0165) and ADCS‐ADL (LS mean difference +4.30, P = 0.0206) at Week 192, reflecting importance of early treatment initiation with oral blarcamesine. Conclusion Blarcamesine significantly reduced clinical decline showing meaningful benefit for early Alzheimer’s disease patients. Blarcamesine exhibited a favorable safety profile with no treatment‐related deaths and demonstrated no associated neuroimaging adverse events with continued treatment over 4 years. Altogether, these results indicate that blarcamesine may be an effective, safe, and novel scalable oral treatment for early AD.

Insufficient supply of selenium to antioxidant enzymes in the brain may contribute to Alzheimer's disease (AD) pathophysiology; therefore, oral supplementation may potentially slow neurodegeneration. We examined selenium and selenoproteins in serum and cerebrospinal fluid (CSF) from a dual-dose 24-week randomized controlled trial of sodium selenate in AD patients, to assess tolerability, and efficacy of selenate in modulating selenium concentration in the central nervous system (CNS). A pilot study of 40 AD cases was randomized to placebo, nutritional (0.32 mg sodium selenate, 3 times daily), or supranutritional (10 mg, 3 times daily) groups. We measured total selenium, selenoproteins, and inorganic selenium levels, in serum and CSF, and compared against cognitive outcomes. Supranutritional selenium supplementation was well tolerated and yielded a significant (p < 0.001) but variable (95% CI = 13.4–24.8 μg/L) increase in CSF selenium, distributed across selenoproteins and inorganic species. Reclassifying subjects as either responsive or non-responsive based on elevation in CSF selenium concentrations revealed that responsive group did not deteriorate in Mini-Mental Status Examination (MMSE) as non-responsive group (p = 0.03). Pooled analysis of all samples revealed that CSF selenium could predict change in MMSE performance (Spearman's rho = 0.403; p = 0.023). High-dose sodium selenate supplementation is well tolerated and can modulate CNS selenium concentration, although individual variation in selenium metabolism must be considered to optimize potential benefits in AD. The Vel002 study is listed on the Australian and New Zealand Clinical Trials Registry (http://www.anzctr.org.au/), ID: ACTRN12611001200976.

There are no approved oral disease-modifying small molecule therapies for treatment of early Alzheimer's disease (AD). Blarcamesine is an orally bioavailable small molecule that enhances autophagy through SIGMAR1 activation and restoration of cellular homeostasis in early AD. The ATTENTION-AD study was an up to 144-week open-label extension study subsequent the 48-Week Phase IIb/III double-blind placebo-controlled ANAVEX 2-73-AD-004 study, to evaluate the safety and efficacy of oral once daily blarcamesine in 508 participants with early AD. Delayed-start analysis was performed to assess the effect of early treatment initiation up to 192 Weeks. The ATTENTION-AD trial confirmed the good efficacy and safety profile of once daily oral blarcamesine and also demonstrated the manageable nature of the most frequent treatment emergent adverse event (TEAE) (dizziness) observed in the preceding ANAVEX 2-73-AD-004 trial, which was generally transient in duration (approx. 7-11 days) and mild or moderate in severity (Grade 1 or 2). The titration schedule was adjusted to a slightly longer titration period in the ATTENTION-AD trial, from previous 2-3 weeks to 10 weeks. A markedly lower frequency of the TEAE of dizziness in the respective maintenance phase was observed: from previously 25.2% in the ANAVEX 2-73-AD-004 trial to 9.6% in the ATTENTION-AD trial, demonstrating the manageable nature of this TEAE. No severe or life-threatening adverse events were attributed to blarcamesine. No Amyloid Related Imaging Abnormalities (ARIA) adverse events were identified. There were no deaths related to blarcamesine. Efficacy of the cognitive and functional endpoints in the delayed-start analysis of treatment resulted in significant outcomes, ADAS-Cog13 (LS mean difference -3.83, P = 0.0165) and ADCS-ADL (LS mean difference +4.30, P = 0.0206) at Week 192, reflecting importance of early treatment initiation with oral blarcamesine. Blarcamesine significantly reduced clinical decline showing meaningful benefit for early Alzheimer's disease patients. Blarcamesine exhibited a favorable safety profile with no treatment-related deaths and demonstrated no associated neuroimaging adverse events with continued treatment over 4 years. Altogether, these results indicate that blarcamesine may be an effective, safe, and novel scalable oral treatment for early AD.