In vivo detection of cortical optical changes associated with seizure activity with optical coherence tomography.

The most common technology for seizure detection is with electroencephalography (EEG), which has low spatial resolution and minimal depth discrimination. Optical techniques using near-infrared (NIR) light have been used to improve upon EEG technology and previous research has suggested that optical changes, specifically changes in near-infrared optical scattering, may precede EEG seizure onset in in vivo models. Optical coherence tomography (OCT) is a high resolution, minimally invasive imaging technique, which can produce depth resolved cross-sectional images. In this study, OCT was used to detect changes in optical properties of cortical tissue in vivo in mice before and during the induction of generalized seizure activity. We demonstrated that a significant decrease (P < 0.001) in backscattered intensity during seizure progression can be detected before the onset of observable manifestations of generalized (stage-5) seizures. These results indicate the feasibility of minimally-invasive optical detection of seizures with OCT

Transparent nanocrystalline yttria-stabilized-zirconia calvarium prosthesis

UnlabelledLaser-based diagnostics and therapeutics show promise for many neurological disorders. However, the poor transparency of cranial bone (calvaria) limits the spatial resolution and interaction depth that can be achieved, thus constraining opportunity in this regard. Herein, we report preliminary results from efforts seeking to address this limitation through use of novel transparent cranial implants made from nanocrystalline yttria-stabilized zirconia (nc-YSZ). Using optical coherence tomography (OCT) imaging of underlying brain in an acute murine model, we show that signal strength is improved when imaging through nc-YSZ implants relative to native cranium. As such, this provides initial evidence supporting the feasibility of nc-YSZ as a transparent cranial implant material. Furthermore, it represents a crucial first step towards realization of an innovative new concept we are developing, which seeks to eventually provide a clinically-viable means for optically accessing the brain, on-demand, over large areas, and on a chronically-recurring basis, without need for repeated craniectomies.From the clinical editorIn this study, transparent nanocrystalline yttria-stabilized-zirconia is used as an experimental "cranium prosthesis" material, enabling the replacement of segments of cranial bone with a material that allows for optical access to the brain on a recurrent basis using optical imaging methods such as OCT

One- and two-stage surgical revision of peri-prosthetic joint infection of the hip: a pooled individual participant data analysis of 44 cohort studies.

One-stage and two-stage revision strategies are the two main options for treating established chronic peri-prosthetic joint infection (PJI) of the hip; however, there is uncertainty regarding which is the best treatment option. We aimed to compare the risk of re-infection between the two revision strategies using pooled individual participant data (IPD). Observational cohort studies with PJI of the hip treated exclusively by one- or two-stage revision and reporting re-infection outcomes were retrieved by searching MEDLINE, EMBASE, Web of Science, The Cochrane Library, and the WHO International Clinical Trials Registry Platform; as well as email contact with investigators. We analysed IPD of 1856 participants with PJI of the hip from 44 cohorts across four continents. The primary outcome was re-infection (recurrence of infection by the same organism(s) and/or re-infection with a new organism(s)). Hazard ratios (HRs) for re-infection were calculated using Cox proportional frailty hazards models. After a median follow-up of 3.7 years, 222 re-infections were recorded. Re-infection rates per 1000 person-years of follow-up were 16.8 (95% CI 13.6-20.7) and 32.3 (95% CI 27.3-38.3) for one-stage and two-stage strategies respectively. The age- and sex-adjusted HR of re-infection for two-stage revision was 1.70 (0.58-5.00) when compared with one-stage revision. The association remained consistently absent after further adjustment for potential confounders. The HRs did not vary importantly in clinically relevant subgroups. Analysis of pooled individual patient data suggest that a one-stage revision strategy may be as effective as a two-stage revision strategy in treating PJI of the hip

Identifying Potential Biomarkers of Posttraumatic Epilepsy

Posttraumatic epilepsy (PTE) is a long-term negative consequence of traumatic brain injury (TBI) in which recurrent spontaneous seizures occur after the initial head injury. PTE develops over an undefined period where circuitry reorganization in the brain causes permanent hyperexcitability. Unfortunately, current existing antiepileptogenic drugs (AEDs) have all failed at treating PTE, and thus, there is a critical need to identify biomarkers of PTE to ultimately develop new therapeutic strategies. The pathophysiology by which trauma leads to spontaneous seizures is unknown and clinically relevant models of PTE are key to understanding the molecular and cellular mechanisms underlying the development of PTE. Current animal studies of PTE are limited and comprehensive in vivo electrophysiological approaches remain absent. In the present study, I aimed to identify optical and electrographic biomarkers of PTE with correlation to hippocampal histopathology at 14, 30, 60, and 90 days post injury (dpi). Here, adult male CD1 wildtype (WT) and aquaporin-4 knockout (AQP4 KO) mice were subjected to a moderate-severe TBI in the right frontal cortex using the well-established controlled cortical impact (CCI) injury model. Additionally, mice underwent optical coherence tomography (OCT) imaging, in vivo video-electroencephalographic (vEEG) recordings, and immunohistochemistry and Western blot analysis for the key epileptogenic astrocytic channels AQP4 and Kir4.1. The main findings from these studies are: 1) successful implementation of CCI-based PTE in mice with chronic vEEG generated, for the first time,17% and 27% of WT and AQP4 KO mice with PTE, respectively (the highest yield of PTE reported); 2) AQP4 KO mice had a greater incidence of spontaneous seizures and PTE compared with WT mice; 3) AQP4 KO mice had longer spontaneous seizure duration compared with WT mice; 4) EEG power patterns are different between mice with and without PTE; and 5) AQP4, but not Kir4.1, is significantly upregulated in the frontal cortex and hippocampus of mice with PTE. Collectively, these findings identified specific PTE EEG phenotypes that may be modulated by AQP4 and carry significant implications for epileptogenesis after TBI which may serve as the first steps to developing surrogate biomarkers for PTE

Identifying Potential Biomarkers of Posttraumatic Epilepsy

Posttraumatic epilepsy (PTE) is a long-term negative consequence of traumatic brain injury (TBI) in which recurrent spontaneous seizures occur after the initial head injury. PTE develops over an undefined period where circuitry reorganization in the brain causes permanent hyperexcitability. Unfortunately, current existing antiepileptogenic drugs (AEDs) have all failed at treating PTE, and thus, there is a critical need to identify biomarkers of PTE to ultimately develop new therapeutic strategies. The pathophysiology by which trauma leads to spontaneous seizures is unknown and clinically relevant models of PTE are key to understanding the molecular and cellular mechanisms underlying the development of PTE. Current animal studies of PTE are limited and comprehensive in vivo electrophysiological approaches remain absent. In the present study, I aimed to identify optical and electrographic biomarkers of PTE with correlation to hippocampal histopathology at 14, 30, 60, and 90 days post injury (dpi). Here, adult male CD1 wildtype (WT) and aquaporin-4 knockout (AQP4 KO) mice were subjected to a moderate-severe TBI in the right frontal cortex using the well-established controlled cortical impact (CCI) injury model. Additionally, mice underwent optical coherence tomography (OCT) imaging, in vivo video-electroencephalographic (vEEG) recordings, and immunohistochemistry and Western blot analysis for the key epileptogenic astrocytic channels AQP4 and Kir4.1. The main findings from these studies are: 1) successful implementation of CCI-based PTE in mice with chronic vEEG generated, for the first time,17% and 27% of WT and AQP4 KO mice with PTE, respectively (the highest yield of PTE reported); 2) AQP4 KO mice had a greater incidence of spontaneous seizures and PTE compared with WT mice; 3) AQP4 KO mice had longer spontaneous seizure duration compared with WT mice; 4) EEG power patterns are different between mice with and without PTE; and 5) AQP4, but not Kir4.1, is significantly upregulated in the frontal cortex and hippocampus of mice with PTE. Collectively, these findings identified specific PTE EEG phenotypes that may be modulated by AQP4 and carry significant implications for epileptogenesis after TBI which may serve as the first steps to developing surrogate biomarkers for PTE

Cerebrovascular phenotypes in mouse models of Alzheimer’s disease

Alzheimer's disease (AD) is a devastating neurological degenerative disorder and is the most common cause of dementia in the elderly. Clinically, AD manifests with memory and cognitive decline associated with deposition of hallmark amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs). Although the mechanisms underlying AD remains unclear, two hypotheses have been proposed. The established amyloid hypothesis states that Aβ accumulation is the basis of AD and leads to formation of NFTs. In contrast, the two-hit vascular hypothesis suggests that early vascular damage leads to increased accumulation of Aβ deposits in the brain. Multiple studies have reported significant morphological changes of the cerebrovasculature which can result in severe functional deficits. In this review, we delve into known structural and functional vascular alterations in various mouse models of AD and the cellular and molecular constituents that influence these changes to further disease progression. Many studies shed light on the direct impact of Aβ on the cerebrovasculature and how it is disrupted during the progression of AD. However, more research directed towards an improved understanding of how the cerebrovasculature is modified over the time course of AD is needed prior to developing future interventional strategies

The Role of Astrocytic Aquaporin-4 in Synaptic Plasticity and Learning and Memory

Aquaporin-4 (AQP4) is the predominant water channel expressed by astrocytes in the central nervous system. AQP4 is widely expressed throughout the brain, especially at the blood-brain barrier where AQP4 is highly polarized to astrocytic foot processes in contact with blood vessels. The bidirectional water transport function of AQP4 suggests its role in cerebral water balance in the CNS. The regulation of AQP4 has been extensively investigated in various neuropathological conditions such as cerebral edema, epilepsy, and ischemia, however, the functional role of AQP4 in synaptic plasticity, learning, and memory is only beginning to be elucidated. In this review, we explore the current literature on AQP4 and its influence on LTP and LTD in the hippocampus as well as the potential relationship between AQP4 in learning and memory. We begin by discussing recent in vitro and in vivo studies using AQP4 knockout (KO) and wild-type mice, in particular, the impairment of LTP and LTD observed in the hippocampus. Early evidence using AQP4 KO mice have suggested that impaired LTP and LTD is BDNF dependent. Others have indicated a possible link between defective LTP and the downregulation of glutamate transporter-1 which is rescued by chronic treatment of β-lactam antibiotic ceftriaxone. Furthermore, behavioral studies may shed some light into the functional role of AQP4 in learning and memory. AQP4 KO mice performances utilizing Morris water maze, object placement tests, and contextual fear conditioning proposed a specific role of AQP4 in memory consolidation. All together, these studies highlight the potential influence AQP4 may have on long term synaptic plasticity and memory

Biological functions of the Olig gene family in brain cancer and therapeutic targeting.

Th

CKII Site in Epstein-Barr Virus Nuclear Protein 2 Controls Binding to hSNF5/Ini1 and Is Important for Growth Transformation

Substitution mutagenesis of EBNA2 shows that its interaction with hSNF5/Ini1 involves two sites (286IPP and DQQ313), and a mutation at a CKII phosphorylation site (SS469) is essential for the interaction. An alanine substitution (SS469AA) prevents binding to EBNA2 and diminishes the growth-promotion potential of EBNA2 in the transcomplementation assay