AMPA receptors and seizures mediate hippocampal radial glia-like stem cell proliferation.

Neurogenesis is sustained throughout life in the mammalian brain, supporting hippocampus-dependent learning and memory. Its permanent alteration by status epilepticus (SE) is associated with learning and cognitive impairments. The mechanisms underlying the initiation of altered neurogenesis after SE are not understood. Glial fibrillary acidic protein-positive radial glia (RG)-like cells proliferate early after SE, but their proliferation dynamics and signaling are largely unclear. We have previously reported a polarized distribution of AMPA receptors (AMPARs) on RG-like cells in vivo and postulated that these may signal their proliferation. Here, we examined the acute effects of kainate on hippocampal precursor cells in vitro and in kainate-induced SE on proliferating and quiescent clones of 5-bromo-2-deoxyuridine prelabeled hippocampal precursors in vivo. In vitro, we found that 5 μM kainate shortened the cell cycle time of RG-like cells via AMPAR activation and accelerated cell cycle re-entry of their progeny. It also shifted their fate choice expanding the population of RG-like cells and reducing the population of downstream amplifying neural progenitors. Kainate enhanced the survival of all precursor cell subtypes. Pharmacologically, kainate's proliferative and survival effects were abolished by AMPAR blockade. Functional AMPAR expression was confirmed on RG-like cells in vitro. In agreement with these observations, kainate/seizures enhanced the proliferation and expansion predominantly of constitutively cycling RG-like cell clones in vivo. Our results identify AMPARs as key potential players in initiating the proliferation of dentate RG-like cells and unravel a possible receptor target for modifying the radial glia-like cell response to SE

Analysis of neuro-theatre utilisation and reasons for cancellation to improve efficiency and productivity

Aim: In neurosurgery, much emphasis has recently been placed on theatre cancellation and time utilization as a key hospital management performance indicator. We sought to evaluate our unit’s theatre throughput efficiency, and identify the causes of elective surgery cancellations. Methods: We retrospectively audited all scheduled elective neurosurgical procedures over a period of 9 months. Results: Mean theatre utilization time was 47.0%. The common causes of cancellations were lack of theatre time (32%), non-availability of beds in recovery room (18.6%), and insufficient preoperative patient preparation (5.5%). Discussion: Inefficiencies were noted in turnover of patients and inaccurate prediction of operative time. Our theatre utilization time is consistent with available literature, however cancellations of elective surgery waste valuable operative time and resources. Conclusions: A multi- dimensional approach must be taken to improve theatre utilization and reduce cancellation rates. A pre-assessment clinic has been introduced in order to reduce cancellation rates

Neurocutaneous melanosis presenting with hydrocephalus & malignant transformation: case base update

Introduction Neurocutaneous melanosis (NCM) is a sporadic condition characterized by congenital melanocytic nevi and melanocytic thickening of the leptomeninges. It is believed to result from congenital dysplasia of melanin producing-cells within the skin and leptomeninges. The management of cutaneous manifestations remains controversial, for neurological manifestations, outcome remains poor even with the use of radiotherapy and chemotherapy. Patients & Methods We describe the case of a 5-month old boy who presented with giant congenital melanocytic nevus and hydrocephalus. MR imaging and CSF immunohistochemistry confirmed leptomeningeal melanosis. We discuss the diagnosis, treatment and prognosis of this rare disorder in the light of recent published literature. Results Patient required placement of right sided ventriculoperitoneal shunt to control hydrocephalus. The patient tolerated the procedure well and was discharged home with normal neurological function. A presumptive diagnosis of NCM was made based on the MR characteristics, CSF cytology and clinical presentation. He received Trametinib, a MAPK/Erk kinase inhibitor for 7 months. At 30 months of age he developed left sided weakness and status epilepticus requiring paediatric intensive care unit admission and ventilator support. The patient eventually succumbed to malignant transformation of leptomeningeal disease Conclusion Cutaneous manifestations of NCM are usually congenital, and neurological manifestations develop early in life. Patients with large or multiple congenital nevi should therefore be investigated early to facilitate treatment. MR imaging is the investigation of choice which can further assist in performing biopsy. Symptomatic NCM is refractory to radiotherapy and chemotherapy and has a poor prognosis. A multidisciplinary approach is necessary in the management of NCM patients

Microglial VPAC1R mediates a novel mechanism of neuroimmune-modulation of hippocampal precursor cells via IL-4 release

Neurogenesis, the production of new neurons from neural stem/progenitor cells (NSPCs), occurs throughout adulthood in the dentate gyrus of the hippocampus, where it supports learning and memory. The innate and adaptive immune systems are increasingly recognized as important modulators of hippocampal neurogenesis under both physiological and pathological conditions. However, the mechanisms by which the immune system regulates hippocampal neurogenesis are incompletely understood. In particular, the role of microglia, the brains resident immune cell is complex, as they have been reported to both positively and negatively regulate neurogenesis. Interestingly, neuronal activity can also regulate the function of the immune system. Here, we show that depleting microglia from hippocampal cultures reduces NSPC survival and proliferation. Furthermore, addition of purified hippocampal microglia, or their conditioned media, is trophic and proliferative to NSPCs. VIP, a neuropeptide released by dentate gyrus interneurons, enhances the proliferative and pro-neurogenic effect of microglia via the VPAC1 receptor. This VIP-induced enhancement is mediated by IL-4 release, which directly targets NSPCs. This demonstrates a potential neuro-immuno-neurogenic pathway, disruption of which may have significant implications in conditions where combined cognitive impairments, interneuron loss, and immune system activation occurs, such as temporal lobe epilepsy and Alzheimer's disease

Analysis of neuro-theatre utilisation and reasons for cancellation to improve efficiency and productivity

Aim: In neurosurgery, much emphasis has recently been placed on theatre cancellation and time utilization as a key hospital management performance indicator. We sought to evaluate our unit’s theatre throughput efficiency, and identify the causes of elective surgery cancellations. Methods: We retrospectively audited all scheduled elective neurosurgical procedures over a period of 9 months. Results: Mean theatre utilization time was 47.0%. The common causes of cancellations were lack of theatre time (32%), non-availability of beds in recovery room (18.6%), and insufficient preoperative patient preparation (5.5%). Discussion: Inefficiencies were noted in turnover of patients and inaccurate prediction of operative time. Our theatre utilization time is consistent with available literature, however cancellations of elective surgery waste valuable operative time and resources. Conclusions: A multi- dimensional approach must be taken to improve theatre utilization and reduce cancellation rates. A pre-assessment clinic has been introduced in order to reduce cancellation rates

The efficacy of endoscopic third ventriculostomy in children 1 year of age or younger: A systematic review and meta-analysis

Purpose Hydrocephalus is a major cause of morbidity in the pediatric population, with potentially severe consequences if left untreated. Two viable strategies for management of non-communicating hydrocephalus are endoscopic third ventriculostomy (ETV) and ventriculoperitoneal shunting. However, there is uncertainty over the safety and efficacy of ETV in younger infants aged 1 year or below. In this systematic review, we aim to elucidate the success rate and procedural risks of ETV in this age group. Methods A multi-database (PubMed, Embase, Web of Science) literature search between January 1990 and April 2018 was performed in accordance with PRISMA guidelines. Eligible studies were included if they (i) examined non-communicating hydrocephalus; (ii) quantified the success/failure rates of ETV; and (iii) assessed outcomes in children 1 year of age or younger. Results A total of 19 articles with 399 patients were eligible for inclusion. Mean age at procedure was 4.2 months (range 34 weeks gestation to 12 months), with 116 females and 143 males. Commonest underlying aetiology was congenital aqueductal stenosis (AS) (60.4%). Remaining causes included post-haemorrhagic, post-infection, Chiari malformations, malignancies and others. Overall and AS mean success rates were 51.6% and 56.5% respectively. Overall complication rate was 10.0%, consisting mainly of CSF leak, infection, and haemorrhage. Younger age was significantly associated with poorer ETV success rate when divided into <6 months and 6–12 months of age (44.4 vs 66.7%; p = 0.0007). Underlying pathology had no significant association with ETV outcome when divided into AS and other pathologies (p = 0.53). Conclusions Age is significantly associated with ETV success rates. Pathology-dependent effects were not found in this age group. Despite a lower ETV success rate at younger ages (44.4 vs 66.7%), it offers a comparable safety profile that is independent of age. ETV remains a viable treatment option for non-communicating hydrocephalus for infants aged 1 year or younger

Sonic Hedgehog Signaling Promotes Peri-Lesion Cell Proliferation and Functional Improvement after Cortical Contusion Injury

Traumatic brain injury (TBI) is a leading cause of death and disability globally. No drug treatments are available, so interest has turned to endogenous neural stem cells (NSCs) as alternative strategies for treatment. We hypothesized that regulation of cell proliferation through modulation of the sonic hedgehog pathway, a key NSC regulatory pathway, could lead to functional improvement. We assessed sonic hedgehog (Shh) protein levels in the cerebrospinal fluid (CSF) of patients with TBI. Using the cortical contusion injury (CCI) model in rodents, we used pharmacological modulators of Shh signaling to assess cell proliferation within the injured cortex using the marker 5-Ethynyl-2’-deoxyuridine (EdU); 50mg/mL. The phenotype of proliferating cells was determined and quantified. Motor function was assessed using the rotarod test. In patients with TBI there is a reduction of Shh protein in CSF compared with control patients. In rodents, following a severe CCI, quiescent cells become activated. Pharmacologically modulating the Shh signaling pathway leads to changes in the number of newly proliferating injury-induced cells. Upregulation of Shh signaling with Smoothened agonist (SAG) results in an increase of newly proliferating cells expressing glial fibrillary acidic protein (GFAP), whereas the Shh signaling inhibitor cyclopamine leads to a reduction. Some cells expressed doublecortin (DCX) but did not mature into neurons. The SAG-induced increase in proliferation is associated with improved recovery of motor function. Localized restoration of Shh in the injured rodent brain, via increased Shh signaling, has the potential to sustain endogenous cell proliferation and the mitigation of TBI-induced motor deficits albeit without the neuronal differentiation

Large-scale compartment fires to develop a self-extinction design framework for mass timber—Part 1: Literature review and methodology

Fire safety remains a major challenge for engineered timber buildings. Their combustible nature challenges the design principles of compartmentation and structural integrity beyond burnout, which are inherent to the fire resistance framework. Therefore, self-extinction is critical for the fire-safe design of timber buildings. This paper is the first of a three-part series that seeks to establish the fundamental principles underpinning a design framework for self-extinction of engineered timber. The paper comprises: a literature review introducing the body of work developed at material and compartment scales; and the design of a large-scale testing methodology which isolates the fundamental phenomena to enable the development and validation of the required design framework. Research at the material scale has consolidated engineering principles to quantify self-extinction using external heat flux as a surrogate of the critical mass loss rate, and mass transfer or Damköhler numbers. At the compartment scale, further interdependent, complex phenomena influencing self-extinction occurrence have been demonstrated. Time-dependent phenomena include encapsulation failure, fall-off of charred lamellae and the burning of the movable fuel load, while thermal feedback is time-independent. The design of the testing methodology is described in reference to these fundamental phenomena