Exposure to Low-Intensity Blast Increases Clearance of Brain Amyloid Beta.

The long-term effects of exposure to blast overpressure are an important health concern in military personnel. Increase in amyloid beta (Aß) has been documented after non-blast traumatic brain injury (TBI) and may contribute to neuropathology and an increased risk for Alzheimer's disease. We have shown that Aß levels decrease following exposure to a low-intensity blast overpressure event. To further explore this observation, we examined the effects of a single 37 kPa (5.4 psi) blast exposure on brain Aß levels, production, and clearance mechanisms in the acute (24 h) and delayed (28 days) phases post-blast exposure in an experimental rat model. Aß and, notably, the highly neurotoxic detergent soluble Aß42 form, was reduced at 24 h but not 28 days after blast exposure. This reduction was not associated with changes in the levels of Aß oligomers, expression levels of amyloid precursor protein (APP), or increase in enzymes involved in the amyloidogenic cleavage of APP, the ß- and ϒ-secretases BACE1 and presenilin-1, respectively. The levels of ADAM17 α-secretase (also known as tumor necrosis factor α-converting enzyme) decreased, concomitant with the reduction in brain Aß. Additionally, significant increases in brain levels of the endothelial transporter, low-density related protein 1 (LRP1), and enhancement in co-localization of aquaporin-4 (AQP4) to perivascular astrocytic end-feet were observed 24 h after blast exposure. These findings suggest that exposure to low-intensity blast may enhance endothelial clearance of Aß by LRP1-mediated transcytosis and alter AQP4-aided glymphatic clearance. Collectively, the data demonstrate that low-intensity blast alters enzymatic, transvascular, and perivascular clearance of Aß.

The Neurovascular Unit as a Locus of Injury in Low-Level Blast-Induced Neurotrauma.

Blast-induced neurotrauma has received much attention over the past decade. Vascular injury occurs early following blast exposure. Indeed, in animal models that approximate human mild traumatic brain injury or subclinical blast exposure, vascular pathology can occur in the presence of a normal neuropil, suggesting that the vasculature is particularly vulnerable. Brain endothelial cells and their supporting glial and neuronal elements constitute a neurovascular unit (NVU). Blast injury disrupts gliovascular and neurovascular connections in addition to damaging endothelial cells, basal laminae, smooth muscle cells, and pericytes as well as causing extracellular matrix reorganization. Perivascular pathology becomes associated with phospho-tau accumulation and chronic perivascular inflammation. Disruption of the NVU should impact activity-dependent regulation of cerebral blood flow, blood-brain barrier permeability, and glymphatic flow. Here, we review work in an animal model of low-level blast injury that we have been studying for over a decade. We review work supporting the NVU as a locus of low-level blast injury. We integrate our findings with those from other laboratories studying similar models that collectively suggest that damage to astrocytes and other perivascular cells as well as chronic immune activation play a role in the persistent neurobehavioral changes that follow blast injury.

Metabotropic Glutamate Receptor 2 Expression Is Chronically Elevated in Male Rats With Post-Traumatic Stress Disorder Related Behavioral Traits Following Repetitive Low-Level Blast Exposure.

Many military veterans who experienced blast-related traumatic brain injuries in the conflicts in Iraq and Afghanistan currently suffer from chronic cognitive and mental health problems that include depression and post-traumatic stress disorder (PTSD). Male rats exposed to repetitive low-level blast develop cognitive and PTSD-related behavioral traits that are present for more than 1 year after exposure. We previously reported that a group II metabotropic receptor (mGluR2/3) antagonist reversed blast-induced behavioral traits. In this report, we explored mGluR2/3 expression following blast exposure in male rats. Western blotting revealed that mGluR2 protein (but not mGluR3) was increased in all brain regions studied (anterior cortex, hippocampus, and amygdala) at 43 or 52 weeks after blast exposure but not at 2 weeks or 6 weeks. mGluR2 RNA was elevated at 52 weeks while mGluR3 was not. Immunohistochemical staining revealed no changes in the principally presynaptic localization of mGluR2 by blast exposure. Administering the mGluR2/3 antagonist LY341495 after behavioral traits had emerged rapidly reversed blast-induced effects on novel object recognition and cued fear responses 10 months following blast exposure. These studies support alterations in mGluR2 receptors as a key pathophysiological event following blast exposure and provide further support for group II metabotropic receptors as therapeutic targets in the neurobehavioral effects that follow blast injury.

Late chronic local inflammation, synaptic alterations, vascular remodeling and arteriovenous malformations in the brains of male rats exposed to repetitive low-level blast overpressures.

In the course of military operations in modern war theaters, blast exposures are associated with the development of a variety of mental health disorders associated with a post-traumatic stress disorder-related features, including anxiety, impulsivity, insomnia, suicidality, depression, and cognitive decline. Several lines of evidence indicate that acute and chronic cerebral vascular alterations are involved in the development of these blast-induced neuropsychiatric changes. In the present study, we investigated late occurring neuropathological events associated with cerebrovascular alterations in a rat model of repetitive low-level blast-exposures (3 × 74.5 kPa). The observed events included hippocampal hypoperfusion associated with late-onset inflammation, vascular extracellular matrix degeneration, synaptic structural changes and neuronal loss. We also demonstrate that arteriovenous malformations in exposed animals are a direct consequence of blast-induced tissue tears. Overall, our results further identify the cerebral vasculature as a main target for blast-induced damage and support the urgent need to develop early therapeutic approaches for the prevention of blast-induced late-onset neurovascular degenerative processes.

(2R,6R)-Hydroxynorketamine Treatment of Rats Exposed to Repetitive Low-Level Blast Injury.

Many military veterans who experienced blast-related traumatic brain injuries (TBIs) in the conflicts in Iraq and Afghanistan suffer from chronic cognitive and mental health problems, including post-traumatic stress disorder (PTSD). Male rats subjected to repetitive low-level blast exposure develop chronic cognitive and PTSD-related traits that develop in a delayed manner. Ketamine has received attention as a treatment for refractory depression and PTSD. (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] is a ketamine metabolite that exerts rapid antidepressant actions. (2R,6R)-HNK has become of clinical interest because of its favorable side-effect profile, low abuse potential, and oral route of administration. We treated three cohorts of blast-exposed rats with (2R,6R)-HNK, beginning 7-11 months after blast exposure, a time when the behavioral phenotype is established. Each cohort consisted of groups (n = 10-13/group) as follows: 1) Sham-exposed treated with saline, 2) blast-exposed treated with saline, and 3) blast-exposed treated with a single dose of 20 mg/kg of (2R,6R)-HNK. (2R,6R)-HNK rescued blast-induced deficits in novel object recognition (NOR) and anxiety-related features in the elevated zero maze (EZM) in all three cohorts. Exaggerated acoustic startle was reversed in cohort 1, but not in cohort 3. (2R,6R)-HNK effects were still present in the EZM 12 days after administration in cohort 1 and 27 days after administration in NOR testing of cohorts 2 and 3. (2R,6R)-HNK may be beneficial for the neurobehavioral syndromes that follow blast exposure in military veterans. Additional studies will be needed to determine whether higher doses or more extended treatment regimens may be more effective.

BCI-838, an orally active mGluR2/3 receptor antagonist pro-drug, rescues learning behavior deficits in the PS19 MAPTP301S mouse model of tauopathy.

Tauopathies are a heterogeneous group of neurodegenerative disorders that are clinically and pathologically distinct from Alzheimer's disease (AD) having tau inclusions in neurons and/or glia as their most prominent neuropathological feature. BCI-838 (MGS00210) is a group II metabotropic glutamate receptor (mGluR2/3) antagonist pro-drug. Previously, we reported that orally administered BCI-838 improved learning behavior and reduced anxiety in Dutch (APPE693Q) transgenic mice, a model of the pathological accumulation of Aß oligomers found in AD. Herein, we investigated effects of BCI-838 on PS19 male mice that express the tauopathy mutation MAPTP301S associated with human frontotemporal lobar degeneration (FTLD). These mice develop an aging-related tauopathy without amyloid accumulation. Mice were divided into three experimental groups: (1) non-transgenic wild type mice treated with vehicle, (2) PS19 mice treated with vehicle and (3) PS19 mice treated with 5 mg/kg BCI-838. Groups of 10-13 mice were utilized. Vehicle or BCI-838 was administered by oral gavage for 4 weeks. Behavioral testing consisting of a novel object recognition task was conducted after drug administration. Two studies were performed beginning treatment of mice at 3 or 7 months of age. One month of BCI-838 treatment rescued deficits in recognition memory in PS19 mice whether treatment was begun at 3 or 7 months of age. These studies extend the potential utility of BCI-838 to neurodegenerative conditions that have tauopathy as their underlying basis. They also suggest an mGluR2/3 dependent mechanism as a basis for the behavioral deficits in PS19 mice.

Antiparasitic Activity of Hippeastrum Species and Synergistic Interaction between Montanine and Benznidazole against Trypanosoma cruzi.

BACKGROUND: Hippeastrum species have a wide range of biological properties. In Argentina, this genus comprises ten widely distributed species. PURPOSE: To evaluate the antiparasitic and anticholinesterase activities and chemical profiles of seven Argentinean Hippeastrum species and determine the synergism between the major isolated alkaloid-montanine-and benznidazole in anti-Trypanosoma cruzi activity. METHODS: The antiparasitic activity was evaluated through antiproliferative and viability assays against T. cruzi epimastigotes. Synergism assays were performed using the Chou-Talalay method. AChE and BuChE inhibitory activities were also assessed. The alkaloid composition was obtained using GC-MS analysis. RESULTS: All extracts showed strong growth inhibition of T. cruzi epimastigote proliferation. The extracts from H. aglaiae, H. aulicum, and H. hybrid stand out for their potent and total growth inhibition, which was comparable to benznidazole. The H. reticulatum extract showed strong Acetylcholinesterase (AChE) inhibitory activities, while five species showed moderate Butyrylcholinesterase (BuChE) inhibition. Fifteen alkaloids were identified by means of GC-MS. Regarding the synergism assessment, the highest synergistic effect was obtained from the combination of montanine and benznidazole. CONCLUSION: Hippeastrum species bulb extracts from Argentina were shown to be a good source of antiparasitic alkaloids and cholinesterase inhibitors. The synergism between montanine and benznidazole emerges as a potential combination for future studies to treat Chagas disease.

Progressive Transcriptional Changes in the Amygdala Implicate Neuroinflammation in the Effects of Repetitive Low-Level Blast Exposure in Male Rats.

Chronic mental health problems are common among military veterans who sustained blast-related traumatic brain injuries. The reasons for this association remain unexplained. Male rats exposed to repetitive low-level blast overpressure (BOP) exposures exhibit chronic cognitive and post-traumatic stress disorder (PTSD)-related traits that develop in a delayed fashion. We examined blast-induced alterations on the transcriptome in four brain areas (anterior cortex, hippocampus, amygdala, and cerebellum) across the time frame over which the PTSD-related behavioral phenotype develops. When analyzed at 6 weeks or 12 months after blast exposure, relatively few differentially expressed genes (DEGs) were found. However, longitudinal analysis of amygdala, hippocampus, and anterior cortex between 6 weeks and 12 months revealed blast-specific DEG patterns. Six DEGs (hyaluronan and proteoglycan link protein 1 [Hapln1], glutamate metabotropic receptor 2 [Grm2], purinergic receptor P2y12 [P2ry12], C-C chemokine receptor type 5 [Ccr5], phenazine biosynthesis-like protein domain containing 1 [Pbld1], and cadherin related 23 [Cdh23]) were found altered in all three brain regions in blast-exposed animals. Pathway enrichment analysis using all DEGs or those uniquely changed revealed different transcription patterns in blast versus sham. In particular, the amygdala in blast-exposed animals had a unique set of enriched pathways related to stress responses, oxidative phosphorylation, and mitochondrial dysfunction. Upstream analysis implicated tumor necrosis factor (TNF)α signaling in blast-related effects in amygdala and anterior cortex. Eukaryotic initiating factor eIF4E (EIF4e), an upstream regulator of P2ry12 and Ccr5, was predicted to be activated in the amygdala. Quantitative polymerase chain reaction (qPCR) validated longitudinal changes in two TNFα regulated genes (cathepsin B [Ctsb], Hapln1), P2ry12, and Grm2. These studies have implications for understanding how blast injury damages the brain and implicates inflammation as a potential therapeutic target.

Multimodal Assessment of Bottlenose Dolphin Auditory Nuclei Using 7-Tesla MRI, Immunohistochemistry and Stereology.

The importance of assessing neurochemical processes in the cetacean brain as a tool for monitoring their cognitive health and to indirectly model human neurodegenerative conditions is increasingly evident, although available data are largely semiquantitative. High-resolution MRI for post-mortem brains and stereology allow for quantitative assessments of the cetacean brain. In this study, we scanned two brains of bottlenose dolphins in a 7-Tesla (7T) MR scanner and assessed the connectivity of the inferior colliculi and ventral cochlear nuclei using diffusion tensor imaging (DTI). Serial thick sections were investigated stereologically in one of the dolphins to generate rigorous quantitative estimates of identifiable cell types according to their morphology and expression of molecular markers, yielding reliable cell counts with most coefficients of error <10%. Fibronectin immunoreactivity in the dolphin resembled the pattern in a human chronic traumatic encephalopathy brain, suggesting that neurochemical compensation for insults such as hypoxia may constitute a noxious response in humans, while being physiological in dolphins. These data contribute to a growing body of knowledge on the morphological and neurochemical properties of the dolphin brain and highlight a stereological and neuroimaging workflow that may enable quantitative and translational assessment of pathological processes in the dolphin brain in the future.

Cranioplasty with cryopreserved autologous bone in craniectomized patients due to brain trauma, a current and safe option: Experience of 97 cases.

BACKGROUND: Cranioplasty is the used method in neurosurgery for repairing cranial bone defects. In our environment, the most widely used material is cryopreserved autologous bone (ABCp). OBJECTIVE: A retrospective observational study was proposed in order to analyze complications in patients who underwent decompressive craniectomy for brain trauma, with subsequent cranioplasty with ABCp. METHOD: Patients who underwent cranioplasties with consecutive ABCp performed at our institution over a four-year period (2016-2019) with subsequent follow-up were included, collecting multiple variables in relation to the appearance of complications. RESULTS: 113 cranioplasties were performed, of which 85.8% (n = 97) were performed with ABCp. Mainly with frontotemporoparietal bone defect (94.84%) performed late (> 3 months) in 91.76%. The complication rate was 16.49%, the most significant being the infection of the surgical site (n = 8, 8.24%), the presence of intracranial hematoma (n = 3, 3.09%) and the reabsorption of the autologous bone (n = 2, 2.06%), meriting surgical management in nine of them (9.27%). CONCLUSIONS: ABCp is a valid and safe option, which meets the basic characteristics to consider it the ideal material, with an acceptable rate of complications, biocompatible, with osteogenic potential, adequate protection of the brain and decrease in surgery costs.

ANTECEDENTES: La craneoplastia es el método utilizado en neurocirugía para reparar los defectos óseos craneanos. En nuestro medio, el material utilizado mayormente es el hueso autólogo criopreservado (HACp). OBJETIVO: Realizamos un estudio retrospectivo observacional para analizar las complicaciones en pacientes sometidos a craniectomía descompresiva por trauma craneoencefálico y realización de craneoplastia con HACp. MÉTODO: Se incluyeron pacientes que fueron sometidos a craneoplastias con HACp consecutivas realizadas en un periodo de 4 años (2016-2019) con seguimiento posterior, recabando múltiples variables en relación con la aparición de complicaciones. RESULTADOS: Se realizaron 113 craneoplastias, de las cuales el 85.8% (n = 97) fueron realizadas con HACp, principalmente con defecto óseo frontotemporoparietal (94.84%), realizadas de forma tardía (> 3 meses) en el 91.76%. El índice de complicaciones fue del 16.49%, siendo las más significativas la infección del sitio quirúrgico (n = 8, 8.24%), la presencia de hematoma endocraneano (n = 3, 3.09%) y la reabsorción del hueso autólogo (n = 2, 2.06%), ameritando manejo quirúrgico en nueve ocasiones (9.27%). CONCLUSIONES: El HACp es una opción válida y segura, la cual cumple con las características para considerarlo el material ideal, con un aceptable índice de complicaciones, biocompatible, con potencial osteogénico, adecuada protección encefálica y disminución de los costos de la cirugía.

A comprehensive approach to complementary and alternative medicine usage among patients from a vascular department.

INTRODUCTION: Use of complementary and alternative medicine (CAM) therapies had been described in patients with disabling, chronic and painful conditions; these characteristics define the majority of vascular surgery (VS) entities. A lack of disclosure about CAM use from patients has been universally cited and may impact effective patient-doctor communication. Our primary objective was to describe CAM use, modalities, perceived benefits, safety, and associated factors among adult patients attending a VS outpatient clinic; we additionally explored patient's attitudes about CAM disclosure with their primary vascular surgeon. METHODS: This cross-sectional study invited 223 consecutive outpatients to an interview where the ICAM-Q (International Complementary and Alternative Medicine Questionnaire) and the PDRQ-9 (Patient-Doctor Relationship Questionnaire-9 items) were applied. In addition, sociodemographics, vascular disease and treatment-related information, comorbidity, and disease severity characteristics were obtained. Appropriated statistics was used; multiple logistic regression analysis identified factors associated to CAM use. All statistical tests were two-sided, and a p value ≤ 0.05 was considered significant. IRB approval was obtained. RESULTS: Patients recruited were primary females (69%) and had a median age of 65 years (54-75). Most frequent vascular diagnoses were chronic venous insufficiency (36.2%) and peripheral artery disease (26%). There were 104 (46.6%) patients who referred CAM use, primarily self-helped practices (96%), and use of herbal, vitamins, or homeopathic medicines (23.7%). Overall, the majority of the patients perceived CAM modalities helpful and 94.6% denied any adverse event. Female sex (OR: 1.768, 95% CI: 0.997-3.135, p = 0.051) and hospitalization during the previous year (OR: 3.173, 95% CI: 1.492-6.748, p = 0.003) were associated to CAM use. The majority of the patients (77%) agreed about CAM disclosure with their primary vascular surgeon; meanwhile, among CAM users, up to 54.9% did not disclose it, and their main reasons were "Doctor didn't ask" (32%) and "I consider it unnecessary" (16%). The patient-doctor relationship was rated by the patients with high scores. CONCLUSIONS: CAM use is frequent and perceived as safe and beneficial among VS outpatients; nonetheless, patients do not disclose CAM use with their primary vascular surgeons, and a wide range of reasons are given by the patients that prevent effective and open communication.

Transcranial Laser Therapy Does Not Improve Cognitive and Post-Traumatic Stress Disorder-Related Behavioral Traits in Rats Exposed to Repetitive Low-Level Blast Injury.

Many military veterans who experienced blast-related traumatic brain injuries (TBIs) in the conflicts in Iraq and Afghanistan suffer from chronic cognitive and mental health problems, including post-traumatic stress disorder (PTSD). Transcranial laser therapy (TLT) uses low-power lasers emitting light in the far- to near-infrared ranges. Beneficial effects of TLT have been reported in neurological and mental-health-related disorders in humans and animal models, including TBI. Rats exposed to repetitive low-level blast develop chronic cognitive and PTSD-related behavioral traits. We tested whether TLT treatment could reverse these traits. Rats received a 74.5-kPa blast or sham exposures delivered one per day for 3 consecutive days. Beginning at 34 weeks after blast exposure, the following groups of rats were treated with active or sham TLT: 1) Sham-exposed rats (n = 12) were treated with sham TLT; 2) blast-exposed rats (n = 13) were treated with sham TLT; and 3) blast-exposed rats (n = 14) were treated with active TLT. Rats received 5 min of TLT five times per week for 6 weeks (wavelength, 808 nm; power of irradiance, 240 mW). At the end of treatment, rats were tested in tasks found previously to be most informative (novel object recognition, novel object localization, contextual/cued fear conditioning, elevated zero maze, and light/dark emergence). TLT did not improve blast-related effects in any of these tests, and blast-exposed rats were worse after TLT in some anxiety-related measures. Based on these findings, TLT does not appear to be a promising treatment for the chronic cognitive and mental health problems that follow blast injury.

Low-level blast exposure induces chronic vascular remodeling, perivascular astrocytic degeneration and vascular-associated neuroinflammation.

Cerebral vascular injury as a consequence of blast-induced traumatic brain injury is primarily the result of blast wave-induced mechanical disruptions within the neurovascular unit. In rodent models of blast-induced traumatic brain injury, chronic vascular degenerative processes are associated with the development of an age-dependent post-traumatic stress disorder-like phenotype. To investigate the evolution of blast-induced chronic vascular degenerative changes, Long-Evans rats were blast-exposed (3 × 74.5 kPa) and their brains analyzed at different times post-exposure by X-ray microcomputed tomography, immunohistochemistry and electron microscopy. On microcomputed tomography scans, regional cerebral vascular attenuation or occlusion was observed as early as 48 h post-blast, and cerebral vascular disorganization was visible at 6 weeks and more accentuated at 13 months post-blast. Progression of the late-onset pathology was characterized by detachment of the endothelial and smooth muscle cellular elements from the neuropil due to degeneration and loss of arteriolar perivascular astrocytes. Development of this pathology was associated with vascular remodeling and neuroinflammation as increased levels of matrix metalloproteinases (MMP-2 and MMP-9), collagen type IV loss, and microglial activation were observed in the affected vasculature. Blast-induced chronic alterations within the neurovascular unit should affect cerebral blood circulation, glymphatic flow and intramural periarterial drainage, all of which may contribute to development of the blast-induced behavioral phenotype. Our results also identify astrocytic degeneration as a potential target for the development of therapies to treat blast-induced brain injury.

Complicaciones quirúrgicas del abordaje endoscópico endonasal transesfenoidal en macroadenomas hipofisarios no funcionantes: estudio de centro único.

ANTECEDENTES: Los abordajes quirúrgicos de la región selar han sido un reto para los neurocirujanos. Con la introducción de la técnica endoscópica se ha minimizado el trauma quirúrgico, pero esta técnica no se encuentra exenta de complicaciones. OBJETIVO: Describir nuestra experiencia institucional en pacientes sometidos a resección de macroadenomas hipofisarios por vía microquirúrgica endonasal transesfenoidal asistida por endoscopia con énfasis en las complicaciones resultantes. MÉTODO: Revisamos los expedientes electrónicos de 17 pacientes sometidos a dicho procedimiento de manera consecutiva entre 2017 y 2018, y recabamos variables como edad, sexo, clasificación imagenológica, tiempo de diagnóstico al momento de la cirugía, complicaciones posoperatorias y recurrencia. RESULTADOS: La edad promedio de los pacientes fue de 45.23 años y el 70.59% eran mujeres. Radiológicamente predominó el grado 2 Knosp (47.05%). La complicación principal fue diabetes insípida transitoria (23.52%), seguida por la fístula de líquido cefalorraquídeo (11.76%). CONCLUSIONES: El manejo microquirúrgico asistido por endoscopia ha demostrado ser un recurso valioso para tratar macroadenomas hipofisarios, pero presenta grados variables de complicaciones, por lo cual se requiere la adquisición de habilidades para el uso del endoscopio, la planeación preoperatoria adecuada y el manejo conjunto multidisciplinario con el fin de evitarlas. BACKGROUND: Surgical approaches to the sellar region have been a challenge for the neurosurgeon. With the introduction of the endoscopic technique, surgical trauma has been minimized, however it is not free of complications. OBJECTIVE: To describe our institutional experience in patients undergoing resection of pituitary macroadenomas by endoscopic-assisted microsurgical approach, with emphasis on the resulting complications. METHOD: We reviewed the electronic files of 17 patients who underwent this procedure consecutively between 2017 and 2018, collecting variables such as age, sex, imaging classification, time of diagnosis at the time of surgery, postoperative complications and recurrence. RESULTS: The average age of the patients was 45.23 years, with 70.59% women. Radiologically, grade 2 Knosp predominated (47.05%). The main complication was transient diabetes insipidus (23.52%) followed by cerebrospinal fluid fistula (11.76%). CONCLUSIONS: The endoscopic-assisted microsurgical approach has proven to be a valuable resource for treating pituitary macroadenomas, however it presents variable degrees of complications, which requires the acquisition of skills for the use of the endoscope, adequate preoperative planning, and multidisciplinary joint management in order to avoid them.

Repetitive Low-Level Blast Exposure Improves Behavioral Deficits and Chronically Lowers Aß42 in an Alzheimer Disease Transgenic Mouse Model.

Public awareness of traumatic brain injury (TBI) in the military increased recently because of the conflicts in Iraq and Afghanistan where blast injury was the most common mechanism of injury. Besides overt injuries, concerns also exist over the potential adverse consequences of subclinical blast exposures, which are common for many service members. A TBI is a risk factor for the later development of neurodegenerative diseases, including Alzheimer disease (AD)-like disorders. Studies of acute TBI in humans and animals have suggested that increased processing of the amyloid precursor protein (APP) toward the amyloid beta protein (Aß) may explain the epidemiological associations with AD. In a previous study, however, we found in both rat and mouse models of blast overpressure exposure that rather than increasing, rodent brain Aß42 levels were decreased after acute blast exposure. Here we subjected APP/presenilin 1 transgenic mice (APP/PS1 Tg) to an extended sequence of repetitive low-level blast exposures (34.5 kPa) administered three times per week over eight weeks. If initiated at 20 weeks of age, these repetitive exposures, which were designed to mimic human subclinical blast exposures, reduced anxiety and improved cognition as well as social interactions in APP/PS1 Tg mice, returning many behavioral parameters in APP/PS1 Tg mice to levels of non-transgenic wild type mice. Repetitive low-level blast exposure was less effective at improving behavioral deficits in APP/PS1 Tg mice when begun at 36 weeks of age. While amyloid plaque loads were unchanged, Aß 42 levels and Aß oligomers were reduced in the brain of mice exposed to repetitive low-level blast exposures initiated at 20 weeks of age, although levels did not directly correlate with behavioral parameters in individual animals. These results have implications for understanding the nature of blast effects on the brain and their relationship to human neurodegenerative diseases.

Surgical Management of a Type II Extracranial Internal Carotid Aneurysm near to the Skull Base.

True aneurysmal disease in the carotid arteries is very uncommon, but individuals with this pathology face the grave risk of thromboembolism, which may consequently lead to cerebrovascular accidents. Clinical knowledge remains relatively limited owing to its rarity. We present the case of a 41-year-old obese female with a type II right extracranial internal carotid artery aneurysm incidentally found during imaging work-up. She underwent open surgical reconstruction with an autologous interposition graft from the common carotid artery to the internal carotid artery at the base level of the skull. Her postoperative period was uneventful, and the patient was discharged on postoperative day five with aspirin. At 12 months of follow-up, the patient remained symptom-free without complications.

Unconventional animal models for traumatic brain injury and chronic traumatic encephalopathy.

Traumatic brain injury (TBI) is one of the main causes of death worldwide. It is a complex injury that influences cellular physiology, causes neuronal cell death, and affects molecular pathways in the brain. This in turn can result in sensory, motor, and behavioral alterations that deeply impact the quality of life. Repetitive mild TBI can progress into chronic traumatic encephalopathy (CTE), a neurodegenerative condition linked to severe behavioral changes. While current animal models of TBI and CTE such as rodents, are useful to explore affected pathways, clinical findings therein have rarely translated into clinical applications, possibly because of the many morphofunctional differences between the model animals and humans. It is therefore important to complement these studies with alternative animal models that may better replicate the individuality of human TBI. Comparative studies in animals with naturally evolved brain protection such as bighorn sheep, woodpeckers, and whales, may provide preventive applications in humans. The advantages of an in-depth study of these unconventional animals are threefold. First, to increase knowledge of the often-understudied species in question; second, to improve common animal models based on the study of their extreme counterparts; and finally, to tap into a source of biological inspiration for comparative studies and translational applications in humans.

Castration causes an increase in lysosomal size and upregulation of cathepsin D expression in principal cells along with increased secretion of procathepsin D and prosaposin oligomers in adult rat epididymis.

In the epididymis, lysosomal proteins of the epithelial cells are normally targeted from the Golgi apparatus to lysosomes for degradation, although their secretion into the epididymal lumen has been documented and associated with sperm maturation. In this study, cathepsin D (CatD) and prosaposin (PSAP) were examined in adult epididymis of control, and 2-day castrated rats without (Ct) and with testosterone replacement (Ct+T) to evaluate their expression and regulation within epididymal epithelial cells. By light microscope-immunocytochemistry, a quantitative increase in size of lysosomes in principal cells of Ct animals was noted from the distal initial segment to the proximal cauda. Androgen replacement did not restore the size of lysosomes to control levels. Western blot analysis revealed a significant increase in CatD expression in the epididymis of Ct animals, which suggested an upregulation of its expression in principal cells; androgens restored levels of CatD to that of controls. In contrast, PSAP expression in Ct animals was not altered from controls. Additionally, an increase in procathepsin D levels was noted from samples of the epididymal fluid of Ct compared to control animals, accompanied by an increased complex formation with PSAP. Moreover, an increased oligomerization of prosaposin was observed in the epididymal lumen of Ct rats, with changes reverted to controls in Ct+T animals. Taken together these data suggest castration causes an increased uptake of substrates that are acted upon by CatD in lysosomes of principal cells and in the lumen by procathepsin D. These substrates may be derived from apoptotic cells noted in the lumen of proximal regions and possibly by degenerating sperm in distal regions of the epididymis of Ct animals. Exploring the mechanisms by which lysosomal enzymes are synthesized and secreted by the epididymis may help resolve some of the issues originating from epididymal dysfunctions with relevance to sperm maturation.

Laterality and region-specific tau phosphorylation correlate with PTSD-related behavioral traits in rats exposed to repetitive low-level blast.

Military veterans who experience blast-related traumatic brain injuries often suffer from chronic cognitive and neurobehavioral syndromes. Reports of abnormal tau processing following blast injury have raised concerns that some cases may have a neurodegenerative basis. Rats exposed to repetitive low-level blast exhibit chronic neurobehavioral traits and accumulate tau phosphorylated at threonine 181 (Thr181). Using data previously reported in separate studies we tested the hypothesis that region-specific patterns of Thr181 phosphorylation correlate with behavioral measures also previously determined and reported in the same animals. Elevated p-tau Thr181 in anterior neocortical regions and right hippocampus correlated with anxiety as well as fear learning and novel object localization. There were no correlations with levels in amygdala or posterior neocortical regions. Particularly striking were asymmetrical effects on the right and left hippocampus. No systematic variation in head orientation toward the blast wave seems to explain the laterality. Levels did not correlate with behavioral measures of hyperarousal. Results were specific to Thr181 in that no correlations were observed for three other phospho-acceptor sites (threonine 231, serine 396, and serine 404). No consistent correlations were linked with total tau. These correlations are significant in suggesting that p-tau accumulation in anterior neocortical regions and the hippocampus may lead to disinhibited amygdala function without p-tau elevation in the amygdala itself. They also suggest an association linking blast injury with tauopathy, which has implications for understanding the relationship of chronic blast-related neurobehavioral syndromes in humans to neurodegenerative diseases.

Systemic lupus erythematosus diagnosis impacts clinical outcomes of arteriovenous fistulas in comparison to other end-stage renal disease etiologies.

OBJECTIVES: Arteriovenous fistulas primary patency at one-year occurs in 43-85% of the patients with end-stage renal disease. The diagnosis attributable to end-stage renal disease has been suggested to impact arteriovenous fistulas outcomes. The objective was to compare primary patency at one week, 1, 3, 6, and 12 months of follow-ups, among systemic lupus erythematosus patients and two control groups; additionally, we evaluated the impact of systemic lupus erythematosus to predict early patency loss. METHODS: A retrospective review of charts from arteriovenous fistulas created between 2008 and 2017 was performed. One-hundred thirty-four patients were identified and classified according to end-stage renal disease attributable diagnosis as: systemic lupus erythematosus cases (N = 14), control-group-1 (91 patients with primarily diabetes and hypertension), and control-group-2 (29 patients with idiopathic end-stage renal disease). A case-control matched design (1:2:1) was proposed. Logistic regression analysis and Kaplan-Meier curves were used. Institutional Review Board approval was obtained. RESULTS: More systemic lupus erythematosus patients lost primary patency at 3 (28.6%) and 12 months (71.4%) than patients from control-groups-1 (vs. 3.6% and 35.7%, respectively) and -2 (vs. 0% and 14.3%, respectively), (p ≤ 0.011 for both). Days of primary patency survival were shorter in systemic lupus erythematosus patients (p = 0.003). Systemic lupus erythematosus diagnosis was the only factor associated with early patency loss, HR: 3.141, 95%CI: 1.161-8.493 (systemic lupus erythematosus diagnosis vs. control-group-1) and HR: 12.582, 95%CI: 1.582-100.035 (systemic lupus erythematosus diagnosis vs. control-group-2). CONCLUSIONS: Diagnosis attributable to end-stage renal disease has a major impact on arteriovenous fistula outcomes in patients. Systemic lupus erythematosus patients have an increased risk of arteriovenous fistulas patency loss within the first six months of follow-up. Patients with idiopathic end-stage renal disease had an excellent one year arteriovenous fistula patency survival.