IL-1R1 signaling in TBI: assessing chronic impacts and neuroinflammatory dynamics in a mouse model of mild closed-head injury.

Neuroinflammation contributes to secondary injury cascades following traumatic brain injury (TBI), with alternating waves of inflammation and resolution. Interleukin-1 (IL-1), a critical neuroinflammatory mediator originating from brain endothelial cells, microglia, astrocytes, and peripheral immune cells, is acutely overexpressed after TBI, propagating secondary injury and tissue damage. IL-1 affects blood-brain barrier permeability, immune cell activation, and neural plasticity. Despite the complexity of cytokine signaling post-TBI, we hypothesize that IL-1 signaling specifically regulates neuroinflammatory response components. Using a closed-head injury (CHI) TBI model, we investigated IL-1's role in the neuroinflammatory cascade with a new global knock-out (gKO) mouse model of the IL-1 receptor (IL-1R1), which efficiently eliminates all IL-1 signaling. We found that IL-1R1 gKO attenuated behavioral impairments 14 weeks post-injury and reduced reactive microglia and astrocyte staining in the neocortex, corpus callosum, and hippocampus. We then examined whether IL-1R1 loss altered acute neuroinflammatory dynamics, measuring gene expression changes in the neocortex at 3, 9, 24, and 72 h post-CHI using the NanoString Neuroinflammatory panel. Of 757 analyzed genes, IL-1R1 signaling showed temporal specificity in neuroinflammatory gene regulation, with major effects at 9 h post-CHI. IL-1R1 signaling specifically affected astrocyte-related genes, selectively upregulating chemokines like Ccl2, Ccl3, and Ccl4, while having limited impact on cytokine regulation, such as Tnfα. This study provides further insight into IL-1R1 function in amplifying the neuroinflammatory cascade following CHI in mice and demonstrates that suppression of IL-1R1 signaling offers long-term protective effects on brain health.

Disentangling controls on animal abundance: Prey availability, thermal habitat, and microhabitat structure.

The question of what controls animal abundance has always been fundamental to ecology, but given rapid environmental change, understanding the drivers and mechanisms governing abundance is more important than ever. Here, we determine how multidimensional environments and niches interact to determine population abundance along a tropical habitat gradient. Focusing on the endemic lizard Anolis bicaorum on the island of Utila (Honduras), we evaluate direct and indirect effects of three interacting niche axes on abundance: thermal habitat quality, structural habitat quality, and prey availability. We measured A. bicaorum abundance across a series of thirteen plots and used N-mixture models and path analysis to disentangle direct and indirect effects of these factors. Results showed that thermal habitat quality and prey biomass both had positive direct effects on anole abundance. However, thermal habitat quality also influenced prey biomass, leading to a strong indirect effect on abundance. Thermal habitat quality was primarily a function of canopy density, measured as leaf area index (LAI). Despite having little direct effect on abundance, LAI had a strong overall effect mediated by thermal quality and prey biomass. Our results demonstrate the role of multidimensional environments and niche interactions in determining animal abundance and highlight the need to consider interactions between thermal niches and trophic interactions to understand variation in abundance, rather than focusing solely on changes in the physical environment.

Inflammatory Regulation of CNS Barriers After Traumatic Brain Injury: A Tale Directed by Interleukin-1.

Several barriers separate the central nervous system (CNS) from the rest of the body. These barriers are essential for regulating the movement of fluid, ions, molecules, and immune cells into and out of the brain parenchyma. Each CNS barrier is unique and highly dynamic. Endothelial cells, epithelial cells, pericytes, astrocytes, and other cellular constituents each have intricate functions that are essential to sustain the brain's health. Along with damaging neurons, a traumatic brain injury (TBI) also directly insults the CNS barrier-forming cells. Disruption to the barriers first occurs by physical damage to the cells, called the primary injury. Subsequently, during the secondary injury cascade, a further array of molecular and biochemical changes occurs at the barriers. These changes are focused on rebuilding and remodeling, as well as movement of immune cells and waste into and out of the brain. Secondary injury cascades further damage the CNS barriers. Inflammation is central to healthy remodeling of CNS barriers. However, inflammation, as a secondary pathology, also plays a role in the chronic disruption of the barriers' functions after TBI. The goal of this paper is to review the different barriers of the brain, including (1) the blood-brain barrier, (2) the blood-cerebrospinal fluid barrier, (3) the meningeal barrier, (4) the blood-retina barrier, and (5) the brain-lesion border. We then detail the changes at these barriers due to both primary and secondary injury following TBI and indicate areas open for future research and discoveries. Finally, we describe the unique function of the pro-inflammatory cytokine interleukin-1 as a central actor in the inflammatory regulation of CNS barrier function and dysfunction after a TBI.

The effects of mild closed head injuries on tauopathy and cognitive deficits in rodents: Primary results in wild type and rTg4510 mice, and a systematic review.

In humans, the majority of sustained traumatic brain injuries (TBIs) are classified as 'mild' and most often a result of a closed head injury (CHI). The effects of a non-penetrating CHI are not benign and may lead to chronic pathology and behavioral dysfunction, which could be worsened by repeated head injury. Clinical-neuropathological correlation studies provide evidence that conversion of tau into abnormally phosphorylated proteotoxic intermediates (p-tau) could be part of the pathophysiology triggered by a single TBI and enhanced by repeated TBIs. However, the link between p-tau and CHI in rodents remains controversial. To address this question experimentally, we induced a single CHI or two CHIs to WT or rTg4510 mice. We found that 2× CHI increased tau phosphorylation in WT mice and rTg4510 mice. Behavioral characterization in WT mice found chronic deficits in the radial arm water maze in 2× CHI mice that had partially resolved in the 1× CHI mice. Moreover, using Manganese-Enhanced Magnetic Resonance Imaging with R1 mapping - a novel functional neuroimaging technique - we found greater deficits in the rTg4510 mice following 2× CHI compared to 1× CHI. To integrate our findings with prior work in the field, we conducted a systematic review of rodent mild repetitive CHI studies. Following Prisma guidelines, we identified 25 original peer-reviewed papers. Results from our experiments, as well as our systematic review, provide compelling evidence that tau phosphorylation is modified by experimental mild TBI studies; however, changes in p-tau levels are not universally reported. Together, our results provide evidence that repetitive TBIs can result in worse and more persistent neurological deficits compared to a single TBI, but the direct link between the worsened outcome and elevated p-tau could not be established.

Shifting the focus: A QI project to improve the management of delirium in patients with hip fracture.

INTRODUCTION: Delirium is common in the perioperative setting, particularly in those admitted with a neck of femur fracture. It is associated with poorer outcomes, including increasing mortality, morbidity and prolonged hospital stay. It is often poorly recognised and under diagnosed. SETTING: An urban district general hospital. INTERVENTION: A steering group was set up and used 'plan, do, study, act' methodology to develop a diagnostic pathway and educational programme for all staff working with patients admitted with neck of femur fracture. RESULTS: There was an increase in the multidisciplinary teams use of the 4AT delirium screening tool by 26% (p=0.0008). Staff surveys indicated an increase in the knowledge of delirium and confidence at explaining it to patients. DISCUSSION: By increasing staff confidence and use of recognised screening tools it is hoped that accurate diagnosis of this perioperative complication is improved, leading to improved management of these complex patients.

A systematic review of dose-volume predictors and constraints for late bowel toxicity following pelvic radiotherapy.

BACKGROUND: Advanced pelvic radiotherapy techniques aim to reduce late bowel toxicity which can severely impact the lives of pelvic cancer survivors. Although advanced techniques have been largely adopted worldwide, to achieve their aim, knowledge of which dose-volume parameters of which components of bowel predict late bowel toxicity is crucial to make best use of these techniques. The rectum is an extensively studied organ at risk (OAR), and dose-volume predictors of late toxicity for the rectum are established. However, for other components of bowel, there is a significant paucity of knowledge. The Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) reviews recommend dose-volume constraints for acute bowel toxicity for peritoneal cavity and bowel loops, although no constraints are recommended for late toxicity, despite its relevance to our increasing number of survivors. This systematic review aims to examine the published literature to seek dose-volume predictors and constraints of late bowel toxicity for OARs (apart from the rectum) for use in clinical practice. METHODS: A systematic literature search was performed using Medline, Embase, Cochrane Library, Web of Science, Cinahl and Pubmed. Studies were screened and included according to specific pre-defined criteria. Included studies were assessed for quality against QUANTEC-defined assessment criteria. RESULTS: 101 studies were screened to find 30 relevant studies. Eight studies related to whole bowel, 11 to small bowel, and 21 to large bowel (including 16 of the anal canal). The anal canal is an important OAR for the development of late toxicity, and we recommend an anal canal Dmean <40Gy as a constraint to reduce late incontinence. For other components of bowel (sigmoid, large bowel, intestinal cavity, bowel loops), although individual studies found statistically significant parameters and constraints these findings were not corroborated in other studies. CONCLUSIONS: The anal canal is an important OAR for the development of late bowel toxicity symptoms. Further validation of the constraints found for other components of bowel is needed. Studies that were more conclusive included those with patient-reported data, where individual symptom scores were assessed rather than an overall score, and those that followed statistical and endpoint criteria as defined by QUANTEC.

A Systematic Review of Closed Head Injury Models of Mild Traumatic Brain Injury in Mice and Rats.

Mild TBI (mTBI) is a significant health concern. Animal models of mTBI are essential for understanding mechanisms, and pathological outcomes, as well as to test therapeutic interventions. A variety of closed head models of mTBI that incorporate different aspects (i.e., biomechanics) of the mTBI have been reported. The aim of the current review was to compile a comprehensive list of the closed head mTBI rodent models, along with the common data elements, and outcomes, with the goal to summarize the current state of the field. Publications were identified from a search of PubMed and Web of Science and screened for eligibility following PRISMA guidelines. Articles were included that were closed head injuries in which the authors classified the injury as mild in rats or mice. Injury model and animal-specific common data elements, as well as behavioral and histological outcomes, were collected and compiled from a total of 402 articles. Our results outline the wide variety of methods used to model mTBI. We also discovered that female rodents and both young and aged animals are under-represented in experimental mTBI studies. Our findings will aid in providing context comparing the injury models and provide a starting point for the selection of the most appropriate model of mTBI to address a specific hypothesis. We believe this review will be a useful starting place for determining what has been done and what knowledge is missing in the field to reduce the burden of mTBI.

Chronic Intermittent Hypoxia Induces Robust Astrogliosis in an Alzheimer's Disease-Relevant Mouse Model.

Sleep disturbances are a common early symptom of neurodegenerative diseases, including Alzheimer's disease (AD) and other age-related dementias, and emerging evidence suggests that poor sleep may be an important contributor to development of amyloid pathology. Of the causes of sleep disturbances, it is estimated that 10-20% of adults in the United States have sleep-disordered breathing (SDB) disorder, with obstructive sleep apnea accounting for the majority of the SBD cases. The clinical and epidemiological data clearly support a link between sleep apnea and AD; yet, almost no experimental research is available exploring the mechanisms associated with this correlative link. Therefore, we exposed an AD-relevant mouse model (APP/PS1 KI) to chronic intermittent hypoxia (IH) (an experimental model of sleep apnea) to begin to describe one of the potential mechanisms by which SDB could increase the risk of dementia. Previous studies have found that astrogliosis is a contributor to neuropathology in models of chronic IH and AD; therefore, we hypothesized that a reactive astrocyte response might be a contributing mechanism in the neuroinflammation associated with sleep apnea. To test this hypothesis, 10-11-month-old wild-type (WT) and APP/PS1 KI mice were exposed to 10 hours of IH, daily for four weeks. At the end of four weeks brains were analyzed from amyloid burden and astrogliosis. No effect was found for chronic IH exposure on amyloid-beta levels or plaque load in the APP/PS1 KI mice. A significant increase in GFAP staining was found in the APP/PS1 KI mice following chronic IH exposure, but not in the WT mice. Profiling of genes associated with different phenotypes of astrocyte activation identified GFAP, CXCL10, and Ggta1 as significant responses activated in the APP/PS1 KI mice exposed to chronic IH.

Three-dimensional image-based high-dose-rate interstitial brachytherapy for vaginal cancer.

PURPOSE: To evaluate dosimetric and clinical outcomes of three-dimensional (3D) image-based high-dose-rate (HDR) interstitial brachytherapy (HDRB) in patients with vaginal cancers. METHODS AND MATERIALS: Thirty patients with vaginal cancers were treated with HDRB using Syed-Neblett template. CT scan was done after placement of needles for confirmation of placement and treatment planning. The target volume and organs at risk, including clinical target volume (CTV), rectum, bladder, and sigmoid colon, were contoured on CT scans. Twenty-eight (93.3%) patients received external beam radiation therapy at a median 45 (24.0-50.4)Gy in 12-28 fractions, followed by HDRB at 3.75-5.0Gy per fraction in five fractions. Total doses for CTV and organs at risk from external beam radiation therapy and HDRB were summated and normalized to a biologically equivalent dose of 2Gy per fraction. RESULTS: Seventeen patients (56.7%) with primary vaginal cancer and 13 patients (43.3%) with recurrent vaginal cancers were treated with 3D HDRB. The mean CTV was 39.3±25.7 cm(3), and the median tumor diameter was 3.3 (1.3-8.0)cm. The median biologically equivalent dose of 2Gy per fraction for 2cc of bladder, rectum, and sigmoid was 55.0, 56.3, 50.0Gy, respectively. The median D(90) for high-risk CTV was 74.3 (36.3-81.1)Gy. The mean volume receiving 100%, 150%, and 200% of prescribed dose was 90.7±10.0%, 41.3±14.6%, and 17.7±8.3%, respectively. With a median followup of 16.7 months, the respective 1-/2-year locoregional and overall survival rates were 84.4%/78.8% and 82.1%/70.2%, respectively. There were no Grade ≥3 gastrointestinal complications. Late complications of Grade 3 vaginal ulceration and Grade 4 vaginal necrosis were seen in two cases. CONCLUSIONS: Initial results of 3D HDRB using our fractionation schedule in the treatment of vaginal cancers showed good local response with acceptable morbidities.

Cysteine thioesters as myelin proteolipid protein analogues to examine the role of butyrylcholinesterase in myelin decompaction.

Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disorder involving demyelination, axonal transection, and neuronal loss in the brain. Recent studies have indicated that active MS lesions express elevated levels of butyrylcholinesterase (BuChE). BuChE can hydrolyze a wide variety of esters, including fatty acid esters of protein. Proteolipid protein (PLP), an important transmembrane protein component of myelin, has six cysteine residues acylated, via thioester linkages, with fatty acids, usually palmitic, that contribute to the stability of myelin. Experimental chemical deacylation of PLP has been shown to lead to decompaction of myelin. Because of elevated levels of BuChE in active MS lesions and its propensity to catalyze the hydrolysis of acylated protein, we hypothesized that this enzyme may contribute to deacylation of PLP in MS, leading to decompaction of myelin and contributing to demyelination. To test this hypothesis, a series of increasing chain length (C2-C16) acyl thioester derivatives of N-acetyl-l-cysteine methyl ester were synthesized and examined for hydrolysis by human cholinesterases. All N-acetyl-l-cysteine fatty acyl thioester derivatives were hydrolyzed by BuChE but not by the related enzyme acetylcholinesterase. In addition, it was observed that the affinity of BuChE for the compound increased the longer the fatty acid chain, with the highest affinity for cysteine bound to palmitic acid. This suggests that the elevated levels of BuChE observed in active MS lesions could be related to the decompaction of myelin characteristic of the disorder.