9,017 results
Search Results
52. The age factor in optic nerve regeneration: intrinsic and extrinsic barriers hinder successful recovery in the short-living killifish
- Author
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Sophie Vanhunsel, Steven Bergmans, An Beckers, Isabelle Etienne, Tine Van Bergen, Lies De Groef, and Lieve Moons
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Original Paper ,Aging ,African turquoise killifish ,Age Factors ,axonal regeneration ,Optic Nerve ,Cell Biology ,central nervous system ,Original Papers ,optic nerve crush ,Nerve Regeneration ,short lifespan ,Fundulidae ,Animals - Abstract
As the mammalian central nervous system matures, its regenerative ability decreases, leading to incomplete or non‐recovery from the neurodegenerative diseases and central nervous system insults that we are increasingly facing in our aging world population. Current neuroregenerative research is largely directed toward identifying the molecular and cellular players that underlie central nervous system repair, yet it repeatedly ignores the aging context in which many of these diseases appear. Using an optic nerve crush model in a novel biogerontology model, that is, the short‐living African turquoise killifish, the impact of aging on injury‐induced optic nerve repair was investigated. This work reveals an age‐related decline in axonal regeneration in female killifish, with different phases of the repair process being affected depending on the age. Interestingly, as in mammals, both a reduced intrinsic growth potential and a non‐supportive cellular environment seem to lie at the basis of this impairment. Overall, we introduce the killifish visual system and its age‐dependent regenerative ability as a model to identify new targets for neurorepair in non‐regenerating individuals, thereby also considering the effects of aging on neurorepair., In contrast to findings in zebrafish, this study reveals a striking age‐related decline in optic nerve regeneration in the short‐living killifish, with different phases of the repair process being affected depending on the age. Interestingly, while resembling zebrafish at young age, the regenerative ability is more mammalian‐like at old age. As in mammals, both a reduced intrinsic growth potential and a non‐supportive cellular environment seem to lie at the basis of impaired nerve regeneration.
- Published
- 2022
53. Electroencephalographic insights into the pathophysiological mechanisms of emergence delirium in children and corresponding clinical treatment strategies.
- Author
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Xin Gao, Zhichao Li, Jun Chai, Si Li, Xuanyuan Pan, Jie Liu, Linxing Li, Shangyuan Qin, Yihan Kang, and Youzhuang Zhu
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DELIRIUM ,ELECTROENCEPHALOGRAPHY ,INHALATION anesthetics ,CENTRAL nervous system ,DRUG therapy ,NEUROPHYSIOLOGY - Abstract
Emergence delirium is a common postoperative complication in patients undergoing general anesthesia, especially in children. In severe cases, it can cause unnecessary self-harm, affect postoperative recovery, lead to parental dissatisfaction, and increase medical costs. With the widespread use of inhalation anesthetic drugs (such as sevoflurane and desflurane), the incidence of emergence delirium in children is gradually increasing; however, its pathogenesis in children is complex and unclear. Several studies have shown that age, pain, and anesthetic drugs are strongly associated with the occurrence of emergence delirium. Alterations in central neurophysiology are essential intermediate processes in the development of emergence delirium. Compared to adults, the pediatric nervous system is not fully developed; therefore, the pediatric electroencephalogram may vary slightly by age. Moreover, pain and anesthetic drugs can cause changes in the excitability of the central nervous system, resulting in electroencephalographic changes. In this paper, we review the pathogenesis of and prevention strategies for emergence delirium in children from the perspective of brain electrophysiology--especially for commonly used pharmacological treatments--to provide the basis for understanding the development of emergence delirium as well as its prevention and treatment, and to suggest future research direction. [ABSTRACT FROM AUTHOR]
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- 2024
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54. Case report: Overlap syndrome of neuromyelitis optica spectrum disorder with anti-Argonaute antibodies.
- Author
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Pei Liu, Xuemei Lin, and Songdi Wu
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NEUROMYELITIS optica ,SYMPTOMS ,TRANSVERSE myelitis ,PROGNOSIS ,CENTRAL nervous system ,IMMUNOGLOBULINS - Abstract
Aquaporin-4 antibodies (AQP4-Abs) are a diagnostic marker for patients with a demyelinating disease called neuromyelitis optica spectrum disorder (NMOSD). Anti-Argonaute antibodies (AGO-Abs) present as potential biomarkers of the overlap syndrome between NMOSD and other autoimmune diseases. In this paper, we present the case of an adult woman with numbness, tingling, and burning sensations in her arms and subsequent bilateral internuclear ophthalmoplegia. Brain–cervical–thoracic magnetic resonance imaging (MRI) showed T2 hyperintensities in the dorsal brainstem and around the midbrain aqueduct and longitudinally transverse myelitis with homogeneous enhancement on gadolinium-enhanced MRI. The contemporaneous detection of AQP4- and AGO-Abs led to a definite diagnosis of overlap syndrome of NMOSD with AGO-Abs. The patient was treated with immunosuppressive agents, including corticosteroids and immunoglobulins, and achieved remission. This case highlights a novel phenotype of NMOSD with AGO-Abs overlap syndrome, which presents with relapsing brainstem syndrome and longitudinally extensive myelitis with acute severe neurological involvement. The promising prognosis of the disease could serve as a distinct clinical profile. Broad screening for antibodies against central nervous system autoimmune antigens is recommended in suspected patients with limited or atypical clinical manifestations. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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55. New Heterostilbene and Triazole Oximes as Potential CNS-Active and Cholinesterase-Targeted Therapeutics.
- Author
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Mlakić, Milena, Čadež, Tena, Šinko, Goran, Škorić, Irena, and Kovarik, Zrinka
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OXIMES ,OXIME derivatives ,BLOOD-brain barrier ,PARKINSON'S disease ,TRIAZOLES ,ORGANOPHOSPHORUS compounds ,CENTRAL nervous system - Abstract
New furan, thiophene, and triazole oximes were synthesized through several-step reaction paths to investigate their potential for the development of central nervous systems (CNS)-active and cholinesterase-targeted therapeutics in organophosphorus compound (OP) poisonings. Treating patients with acute OP poisoning is still a challenge despite the development of a large number of oxime compounds that should have the capacity to reactivate acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The activity of these two enzymes, crucial for neurotransmission, is blocked by OP, which has the consequence of disturbing normal cholinergic nerve signal transduction in the peripheral and CNS, leading to a cholinergic crisis. The oximes in use have one or two pyridinium rings and cross the brain–blood barrier poorly due to the quaternary nitrogen. Following our recent study on 2-thienostilbene oximes, in this paper, we described the synthesis of 63 heterostilbene derivatives, of which 26 oximes were tested as inhibitors and reactivators of AChE and BChE inhibited by OP nerve agents–sarin and cyclosarin. While the majority of oximes were potent inhibitors of both enzymes in the micromolar range, we identified several oximes as BChE or AChE selective inhibitors with the potential for drug development. Furthermore, the oximes were poor reactivators of AChE; four heterocyclic derivatives reactivated cyclosarin-inhibited BChE up to 70%, and cis,trans-5 [2-((Z)-2-(5-((E)-(hydroxyimino)methyl)thiophen-2-yl)vinyl)benzonitrile] had a reactivation efficacy comparable to the standard oxime HI-6. In silico analysis and molecular docking studies, including molecular dynamics simulation, connected kinetic data to the structural features of these oximes and confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on inhibition and reactivation and their ADMET properties regarding lipophilicity, CNS activity, and hepatotoxicity, these compounds could be considered for further development of CNS-active reactivators in OP poisoning as well as cholinesterase-targeted therapeutics in neurodegenerative diseases such as Alzheimer's and Parkinson's. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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56. Optical Devices for the Diagnosis and Management of Spinal Cord Injuries: A Review.
- Author
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Sharma, Sonika, Kalyani, Neeti, Dutta, Taposhree, Velázquez-González, Jesús Salvador, Llamas-Garro, Ignacio, Ung, Bora, Bas, Joan, Dubey, Rakesh, and Mishra, Satyendra K.
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SPINAL cord injuries ,OPTICAL devices ,CENTRAL nervous system ,DIAGNOSIS ,SPINAL cord - Abstract
Throughout the central nervous system, the spinal cord plays a very important role, namely, transmitting sensory and motor information inwardly so that it can be processed by the brain. There are many different ways this structure can be damaged, such as through traumatic injury or surgery, such as scoliosis correction, for instance. Consequently, damage may be caused to the nervous system as a result of this. There is no doubt that optical devices such as microscopes and cameras can have a significant impact on research, diagnosis, and treatment planning for patients with spinal cord injuries (SCIs). Additionally, these technologies contribute a great deal to our understanding of these injuries, and they are also essential in enhancing the quality of life of individuals with spinal cord injuries. Through increasingly powerful, accurate, and minimally invasive technologies that have been developed over the last decade or so, several new optical devices have been introduced that are capable of improving the accuracy of SCI diagnosis and treatment and promoting a better quality of life after surgery. We aim in this paper to present a timely overview of the various research fields that have been conducted on optical devices that can be used to diagnose spinal cord injuries as well as to manage the associated health complications that affected individuals may experience. [ABSTRACT FROM AUTHOR]
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- 2024
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57. The Landscape of Pediatric High-Grade Gliomas: The Virtues and Pitfalls of Pre-Clinical Models.
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Furst, Liam M., Roussel, Enola M., Leung, Ryan F., George, Ankita M., Best, Sarah A., Whittle, James R., Firestein, Ron, Faux, Maree C., and Eisenstat, David D.
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ANIMAL models in research ,CANCER cell culture ,GLIOMAS ,BRAIN tumors ,GENE expression profiling ,CENTRAL nervous system - Abstract
Simple Summary: Pediatric high-grade gliomas are aggressive and deadly brain tumors that arise in children and are notoriously difficult to cure. Researchers require accurate methods, or "model systems," to better understand these tumors. Model systems include culturing cancer cells in a dish, observing how cancer cells grow in an animal brain, and growing cells in self-organizing 3D cultures called organoids, which more accurately resemble the brain. In this paper, we describe the molecular changes that these cancers acquire that cause them to be so aggressive, the development of past and present model systems, highlight the newest model systems being developed, and offer suggestions regarding how these model systems can be used in the future to develop better therapies for patients. Further, we outline the benefits and limitations of each model system to better guide researchers in the design of their experiments. Developing a variety of model systems that adequately and faithfully represent how tumors exist, progress, recur, and respond to treatment in a patient is absolutely essential to the eventual development of effective therapeutics. Therefore, investing in the continued development of these model systems is paramount to improving patient outcomes. Pediatric high-grade gliomas (pHGG) are malignant and usually fatal central nervous system (CNS) WHO Grade 4 tumors. The majority of pHGG consist of diffuse midline gliomas (DMG), H3.3 or H3.1 K27 altered, or diffuse hemispheric gliomas (DHG) (H3.3 G34-mutant). Due to diffuse tumor infiltration of eloquent brain areas, especially for DMG, surgery has often been limited and chemotherapy has not been effective, leaving fractionated radiation to the involved field as the current standard of care. pHGG has only been classified as molecularly distinct from adult HGG since 2012 through Next-Generation sequencing approaches, which have shown pHGG to be epigenetically regulated and specific tumor sub-types to be representative of dysregulated differentiating cells. To translate discovery research into novel therapies, improved pre-clinical models that more adequately represent the tumor biology of pHGG are required. This review will summarize the molecular characteristics of different pHGG sub-types, with a specific focus on histone K27M mutations and the dysregulated gene expression profiles arising from these mutations. Current and emerging pre-clinical models for pHGG will be discussed, including commonly used patient-derived cell lines and in vivo modeling techniques, encompassing patient-derived xenograft murine models and genetically engineered mouse models (GEMMs). Lastly, emerging techniques to model CNS tumors within a human brain environment using brain organoids through co-culture will be explored. As models that more reliably represent pHGG continue to be developed, targetable biological and genetic vulnerabilities in the disease will be more rapidly identified, leading to better treatments and improved clinical outcomes. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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58. Exosomes in the Diagnosis of Neuropsychiatric Diseases: A Review.
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Wu, Song, Shang, Xinmiao, Guo, Meng, Su, Lei, and Wang, Jun
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EXOSOMES ,DIAGNOSIS ,EXTRACELLULAR vesicles ,LINCRNA ,CENTRAL nervous system - Abstract
Simple Summary: The diagnostic value of exosomes has been well recognized by researchers. The use of exosomal biomarkers as an adjunct diagnosis method not only improves diagnostic accuracy but can also be used for early diagnosis and disease progression differentiation, thus supporting personalized clinical treatment strategies for patients with neuropsychiatric disorders. In this paper, we summarize potential exosomal biomarkers in the diagnosis of neuropsychiatric diseases. Exosomes are 30–150 nm small extracellular vesicles (sEVs) which are highly stable and encapsulated by a phospholipid bilayer. Exosomes contain proteins, lipids, RNAs (mRNAs, microRNAs/miRNAs, long non-coding RNAs/lncRNAs), and DNA of their parent cell. In pathological conditions, the composition of exosomes is altered, making exosomes a potential source of biomarkers for disease diagnosis. Exosomes can cross the blood–brain barrier (BBB), which is an advantage for using exosomes in the diagnosis of central nervous system (CNS) diseases. Neuropsychiatric diseases belong to the CNS diseases, and many potential diagnostic markers have been identified for neuropsychiatric diseases. Here, we review the potential diagnostic markers of exosomes in neuropsychiatric diseases and discuss the potential application of exosomal biomarkers in the early and accurate diagnosis of these diseases. Additionally, we outline the limitations and future directions of exosomes in the diagnosis of neuropsychiatric diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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59. The Emerging Role of Microglial Hv1 as a Target for Immunomodulation in Myelin Repair.
- Author
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Yingxin Tang, Xuan Wu, Jiarui Li, Yuanwei Li, Xiaoxiao Xu, Gaigai Li, Ping Zhang, Chuan Qin, Long-Jun Wu, Zhouping Tang, and Dai-Shi Tian
- Subjects
MICROGLIA ,IMMUNOREGULATION ,CENTRAL nervous system - Abstract
In the central nervous system (CNS), the myelin sheath ensures efficient interconnection between neurons and contributes to the regulation of the proper function of neuronal networks. The maintenance of myelin and the well-organized subtle process of myelin plasticity requires cooperation among myelin-forming cells, glial cells, and neural networks. The process of cooperation is fragile, and the balance is highly susceptible to disruption by microenvironment influences. Reactive microglia play a critical and complicated role in the demyelination and remyelination process. Recent studies have shown that the voltage-gated proton channel Hv1 is selectively expressed in microglia in CNS, which regulates intracellular pH and is involved in the production of reactive oxygen species, underlying multifaceted roles in maintaining microglia function. This paper begins by examining the molecular mechanisms of demyelination and emphasizes the crucial role of the microenvironment in demyelination. It focuses specifically on the role of Hv1 in myelin repair and its therapeutic potential in CNS demyelinating diseases. [ABSTRACT FROM AUTHOR]
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- 2024
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60. Multifunctional roles of γ-enolase in the central nervous system: more than a neuronal marker.
- Author
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Horvat, Selena, Kos, Janko, and Pišlar, Anja
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CENTRAL nervous system ,ALZHEIMER'S disease ,SCAFFOLD proteins ,NEURONS ,NEUROLOGICAL disorders - Abstract
Enolase, a multifunctional protein with diverse isoforms, has generally been recognized for its primary roles in glycolysis and gluconeogenesis. The shift in isoform expression from α-enolase to neuron-specific γ-enolase extends beyond its enzymatic role. Enolase is essential for neuronal survival, differentiation, and the maturation of neurons and glial cells in the central nervous system. Neuron-specific γ-enolase is a critical biomarker for neurodegenerative pathologies and neurological conditions, not only indicating disease but also participating in nerve cell formation and neuroprotection and exhibiting neurotrophic-like properties. These properties are precisely regulated by cysteine peptidase cathepsin X and scaffold protein γ
1 -syntrophin. Our findings suggest that γ-enolase, specifically its C-terminal part, may offer neuroprotective benefits against neurotoxicity seen in Alzheimer's and Parkinson's disease. Furthermore, although the therapeutic potential of γ-enolase seems promising, the effectiveness of enolase inhibitors is under debate. This paper reviews the research on the roles of γ-enolase in the central nervous system, especially in pathophysiological events and the regulation of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]- Published
- 2024
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61. Emerging insights into cuproptosis and copper metabolism: implications for age-related diseases and potential therapeutic strategies.
- Author
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Haohui Fan, Kun Wang, Xiaofang Zhao, Bei Song, Tianci Yao, Ting Liu, Guangyu Gao, Weilin Lu, and Chengyun Liu
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COPPER metabolism ,PROTEINS ,MUSCULOSKELETAL system ,GLUTATHIONE ,MITOCHONDRIA ,APOPTOSIS ,COPPER ,RETINAL degeneration ,OXIDATIVE stress ,CENTRAL nervous system ,PARKINSON'S disease ,NEURODEGENERATION ,ATHEROSCLEROSIS ,REACTIVE oxygen species ,AMYOTROPHIC lateral sclerosis ,AGING ,GENETIC mutation ,INFLAMMATION ,DIGESTIVE organs ,STROKE ,TRICARBOXYLIC acids ,CARDIOVASCULAR system ,PLANT proteins ,DIABETES ,SARCOPENIA - Abstract
The expanding geriatric population, whose predisposition toward disabling morbidities and age-related diseases (ARD) is well-documented, has become a paramount social issue, exerting an onerous burden on both the healthcare industry and wider society. ARD manifest as the progressive deterioration of bodily tissues and organs, eventually resulting in the failure of these vital components. At present, no efficacious measures exist to hinder the onset of ARD. Copper, an essential trace element, is involved in a wide range of physiological processes across different cell types. In recent research, a novel variant of copper-dependent cell death, termed cuproptosis, has been identified. This mode of cellular demise stands apart from previously recognized types of cell death. Cuproptosis occurs when copper binds with acyl-CoA synthetase in the tricarboxylic acid (TCA) cycle, resulting in protein aggregation and protein toxicity stress, ultimately leading to cell death. In this paper, we provide a concise overview of the current understanding concerning the metabolism of copper, copper-related diseases, the hallmarks of copper toxicity, and the mechanisms that regulate copper toxicity. Additionally, we discuss the implications of cuproptosis mutations in the development of ARD, as well as the potential for targeting cuproptosis as a treatment for ARD. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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62. A Difficult Case of Ventriculitis in a 40-Year-Old Woman with Acute Myeloid Leukemia.
- Author
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Rubino, Raffaella, Trizzino, Marcello, Pipitò, Luca, Sucato, Giuseppe, Santoro, Marco, Maugeri, Rosario, Iacopino, Domenico Gerardo, Giammanco, Giovanni Maurizio, Siragusa, Sergio, and Cascio, Antonio
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ACUTE myeloid leukemia ,KLEBSIELLA infections ,ENTEROCOCCAL infections ,CENTRAL nervous system infections ,ENTEROCOCCUS faecium ,CENTRAL nervous system ,GRAM-positive bacteria - Abstract
Ventriculitis and nosocomial meningitis caused by carbapenem-resistant Gram-negative and vancomycin-resistant Gram-positive bacteria represent a growing treatment challenge. A case of ventriculitis and bacteremia caused by carbapenem-resistant, KPC-producing Klebsiella pneumoniae and vancomycin-resistant Enterococcus faecium in a young woman with acute leukemia who was successfully treated with meropenem/vaborbactam (MVB), rifampicin, and linezolid is described in this paper. This case report emphasizes the importance of a multidisciplinary strategy, including infectious focus control, for the treatment of device-associated central nervous system (CNS) infections from multidrug-resistant bacteria. Considering the novel resistance patterns, more research on drug penetration into the central nervous system, as well as on the necessity of association therapies, is needed. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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63. HIV-Associated Neurocognitive Disorder: A Look into Cellular and Molecular Pathology.
- Author
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Thompson, Landon John-Patrick, Genovese, Jessica, Hong, Zhenzi, Singh, Meera Vir, and Singh, Vir Bahadur
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NEUROBEHAVIORAL disorders ,CELLULAR pathology ,BLOOD-brain barrier ,TAT protein ,HIV-1 glycoprotein 120 ,MOLECULAR pathology ,CENTRAL nervous system - Abstract
Despite combined antiretroviral therapy (cART) limiting HIV replication to undetectable levels in the blood, people living with HIV continue to experience HIV-associated neurocognitive disorder (HAND). HAND is associated with neurocognitive impairment, including motor impairment, and memory loss. HIV has been detected in the brain within 8 days of estimated exposure and the mechanisms for this early entry are being actively studied. Once having entered into the central nervous system (CNS), HIV degrades the blood–brain barrier through the production of its gp120 and Tat proteins. These proteins are directly toxic to endothelial cells and neurons, and propagate inflammatory cytokines by the activation of immune cells and dysregulation of tight junction proteins. The BBB breakdown is associated with the progression of neurocognitive disease. One of the main hurdles for treatment for HAND is the latent pool of cells, which are insensitive to cART and prolong inflammation by harboring the provirus in long-lived cells that can reactivate, causing damage. Multiple strategies are being studied to combat the latent pool and HAND; however, clinically, these approaches have been insufficient and require further revisions. The goal of this paper is to aggregate the known mechanisms and challenges associated with HAND. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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64. Combined treatment with C16 peptide and angiopoietin-1 confers neuroprotection and reduces inflammation in 3-nitropropionic acid-induced dystonia mice
- Author
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Hua-Ying Cai, Xiao-Xiao Fu, Shu Han, and Hong Jiang
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Ang-1 ,Central Nervous System ,Male ,Aging ,medicine.medical_treatment ,Central nervous system ,Excitotoxicity ,Anti-Inflammatory Agents ,dystonia model ,Striatum ,Endothelial Growth Factors ,Pharmacology ,medicine.disease_cause ,Neuroprotection ,Capillary Permeability ,Random Allocation ,improving micro-environment ,Basal ganglia ,medicine ,Angiopoietin-1 ,Animals ,C16 ,Neuroinflammation ,Dystonia ,Inflammation ,Neurons ,3-Nitropropionic acid ,business.industry ,Growth factor ,Brain ,Cell Biology ,medicine.disease ,Nitro Compounds ,Corpus Striatum ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Drug Therapy, Combination ,Propionates ,business ,Peptides ,Research Paper - Abstract
Dystonia is a disorder associated with abnormalities in many brain regions including the basal ganglia and cerebellum. The toxin 3-Nitropropionic acid (3-NP) can induce neuropathologies in the mice striatum and nigra substance, including excitotoxicity, neuroinflammation, and extensive neuronal atrophy, characterized by progressive motor dysfunction, dystonia, and memory loss, mimicking those observed in humans. We established a mouse model of dystonia by administering 3-NP. Given the reported neuroprotective effects of the endothelial growth factor angiopoietin-1 (Ang-1) and the anti-inflammatory integrin αvβ3 binding peptide C16, we performed this study to evaluate their combined effects on 3-NP striatal toxicity and their therapeutic potential with multiple methods using an in vivo mouse model. Sixty mice were equally and randomly divided into three groups: control, 3-NP treatment, and 3-NP+C16+Ang-1 treatment. Behavioral and electrophysiological tests were conducted and the effect of the combined C16+Ang-1 treatment on neural function recovery was determined. We found that C16+Ang-1 treatment alleviated 3-NP-induced behavioral, biochemical, and cellular alterations in the central nervous system and promoted function recovery by restoring vascular permeability and reducing inflammation in the micro-environment. In conclusion, our results confirmed the neuroprotective effect of combined C16+Ang-1 treatment and suggest their potential as a complementary therapeutic against 3-NP-induced dystonia.
- Published
- 2021
65. Inhibiting microglia proliferation after spinal cord injury improves recovery in mice and nonhuman primates
- Author
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Claire M. Bringuier, Jean-Christophe Perez, Emilie Aloy, Gaëtan Poulen, Nicolas Lonjon, Christophe Goze-Bac, Maida Cardoso, Yannick Nicolas Gerber, Hassan Boukhaddaoui, Florence E. Perrin, Emaëlle V.F. Artus, Nadine Mestre-Francés, Mécanismes moléculaires dans les démences neurodégénératives (MMDN), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire Charles Coulomb (L2C), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Perrin, Florence, Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Regional Imaging Platform, Montpellier Ressources Imagerie (MRI), BioCampus, Montpellier, France, Institut Universitaire de France (IUF), and Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.)
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Male ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,[SDV]Life Sciences [q-bio] ,primates ,Medicine (miscellaneous) ,microglia ,Gene Expression ,Transcriptome ,Mice ,0302 clinical medicine ,Oral administration ,Receptor ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Spinal cord injury ,ComputingMilieux_MISCELLANEOUS ,0303 health sciences ,Microglia ,rodent ,medicine.anatomical_structure ,Receptors, Granulocyte-Macrophage Colony-Stimulating Factor ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,medicine.symptom ,Cheirogaleidae ,Spinal cord pathology ,Research Paper ,proliferation ,Neurogenesis ,Central nervous system ,Mice, Transgenic ,Anisoles ,Lesion ,03 medical and health sciences ,Downregulation and upregulation ,medicine ,Animals ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Neuroinflammation ,Spinal Cord Injuries ,030304 developmental biology ,Cell Proliferation ,Inflammation ,business.industry ,Recovery of Function ,Functional recovery ,medicine.disease ,spinal cord injury ,Mice, Inbred C57BL ,Disease Models, Animal ,Pyrimidines ,Neuroinflammatory Diseases ,Cancer research ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
No curative treatment is available for any deficits induced by spinal cord injury (SCI). Following injury, microglia undergo highly diverse activation processes, including proliferation, and play a critical role on functional recovery.In a translational objective, we investigated whether a transient pharmacological reduction of microglia proliferation after injury is beneficial for functional recovery after SCI in mice and nonhuman primates. The colony stimulating factor-1 receptor (CSF1R) regulates proliferation, differentiation, and survival of microglia, we thus used an oral administration of GW2580, a CSF1R inhibitor.First, transient post-injury GW2580 administration in mice improves motor function recovery, promotes tissues preservation and/or reorganization (identified by coherent anti-stokes Raman scattering microscopy), and modulates glial reactivity.Second, post-injury GW2580-treatment in nonhuman primates reduces microglia proliferation, improves functional motor function recovery, and promotes tissue protection. Notably, three months after lesion microglia reactivity returned to baseline value.Finally, to initiate the investigation on molecular mechanisms induced by a transient post-SCI GW2580-treatment, we used microglia-specific transcriptomic analysis in mice. Notably, we detected a downregulation in the expression of inflammatory-associated genes and we identified genes that were up-regulated by SCI and further downregulated by the treatment.Thus, a transient oral GW2580 treatment post-injury may provide a promising therapeutic strategy for SCI patients and may also be extended to other central nervous system disorders displaying microglia activation.
- Published
- 2021
66. Mitochondrial DNA Heteroplasmy as an Informational Reservoir Dynamically Linked to Metabolic and Immunological Processes Associated with COVID-19 Neurological Disorders
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George B. Stefano and Richard M. Kream
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Mitochondrial DNA ,Cell type ,Somatic cell ,Mitochondrion ,Biology ,Heteroplasmy ,DNA, Mitochondrial ,Genome ,Cellular and Molecular Neuroscience ,Immune system ,Animals ,Humans ,Immune response ,Genetics ,Review Paper ,Gut microbiome ,SARS-CoV-2 ,Immunity ,COVID-19 ,Cell Biology ,General Medicine ,Mitochondria ,Nuclear DNA ,Central nervous system ,Nervous System Diseases - Abstract
Mitochondrial DNA (mtDNA) heteroplasmy is the dynamically determined co-expression of wild type (WT) inherited polymorphisms and collective time-dependent somatic mutations within individual mtDNA genomes. The temporal expression and distribution of cell-specific and tissue-specific mtDNA heteroplasmy in healthy individuals may be functionally associated with intracellular mitochondrial signaling pathways and nuclear DNA gene expression. The maintenance of endogenously regulated tissue-specific copy numbers of heteroplasmic mtDNA may represent a sensitive biomarker of homeostasis of mitochondrial dynamics, metabolic integrity, and immune competence. Myeloid cells, monocytes, macrophages, and antigen-presenting dendritic cells undergo programmed changes in mitochondrial metabolism according to innate and adaptive immunological processes. In the central nervous system (CNS), the polarization of activated microglial cells is dependent on strategically programmed changes in mitochondrial function. Therefore, variations in heteroplasmic mtDNA copy numbers may have functional consequences in metabolically competent mitochondria in innate and adaptive immune processes involving the CNS. Recently, altered mitochondrial function has been demonstrated in the progression of coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Accordingly, our review is organized to present convergent lines of empirical evidence that potentially link expression of mtDNA heteroplasmy by functionally interactive CNS cell types to the extent and severity of acute and chronic post-COVID-19 neurological disorders.
- Published
- 2021
67. Proliferation rate and differentiation potential are independent during the transition from neurogenesis to gliogenesis in the mouse embryonic spinal cord
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Leonora Olivos-Cisneros, Gabriel Gutiérrez-Ospina, and Jesús Ramírez-Santos
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Spinal cord ,Neurogenesis ,General Neuroscience ,Central nervous system ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Cell cycle ,Biology ,Cell fate determination ,Embryonic stem cell ,Neural stem cell ,Cell biology ,medicine.anatomical_structure ,Neurosphere culture ,Neurosphere ,medicine ,Gliogenesis ,RC321-571 ,Research Paper - Abstract
Neural stem cells (NSC) restrict their differentiation potential as the central nervous system develops. Experimental evidence suggests that the mechanisms governing the transition from the neurogenic to the gliogenic phase irreversibly affect the ability of NSC to generate neurons. Cell cycle regulation has been associated with cell fate in different models. In this work, we assessed the temporal correlation between the loss of the neurogenic potential and cell cycle lengthening of NSC obtained from embryonic mouse spinal cords, during the transition of the neurogenic to the gliogenic phase, using neurospheres. We also used the cell cycle inhibitor Olomoucine to increase cell cycle length by decreasing the proliferation rate. Our results show that neurospheres obtained from a neurogenic stage give rise mostly to neurons, whereas those obtained from later stages produce preferentially glial cells. During the transition from neurogenesis to gliogenesis, the proliferation rate dropped, and the cell cycle length increased 1.5 folds, as monitored by DNA BrdU incorporation. Interestingly, Olomoucine-treated neurogenic-neurospheres display a reduced proliferation rate and preserve their neurogenic potential. Our results suggest that the mechanisms that restrict the differentiation potential of NSC are independent of the proliferation control., Highlights • Neurosphere cultured, spinal cord NSC preserve their differentiation potential. • Neurogenic NSC divide faster than those giving rise to glial cells. • Cell cycle inhibitors increase in NSC transitioning from the neurogenic to the gliogenic phase. • Artificial cell cycle lengthening does not affect the differentiation potential of neurogenic NSC.
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- 2021
68. Spinal cord fMRI with MB‐SWIFT for assessing epidural spinal cord stimulation in rats
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Shalom Michaeli, Igor Lavrov, Jaakko Paasonen, Lauri J. Lehto, Antonietta Canna, Olli Gröhn, Hanne Laakso, Silvia Mangia, Raimo A. Salo, Tampere University, and Kanta-Häme Central Hospital Hämeenlinna
- Subjects
Central nervous system ,Pilot Projects ,Stimulation ,Spinal cord stimulation ,epidural stimulation ,030218 nuclear medicine & medical imaging ,zero echo time ,03 medical and health sciences ,0302 clinical medicine ,Animals ,Medicine ,Radiology, Nuclear Medicine and imaging ,Spinal cord injury ,Research Articles—Preclinical and Clinical Imaging ,Spinal Cord Stimulation ,Full Paper ,MB‐SWIFT ,business.industry ,fMRI ,Respiratory motion ,Chronic pain ,3126 Surgery, anesthesiology, intensive care, radiology ,Spinal cord ,medicine.disease ,Magnetic Resonance Imaging ,Rats ,medicine.anatomical_structure ,Spinal Cord ,nervous system ,High bandwidth ,Artifacts ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Purpose: Electrical epidural spinal cord stimulation (SCS) is used as a treatment for chronic pain as well as to partially restore motor function after a spinal cord injury. Monitoring the spinal cord activity during SCS with fMRI could provide important and objective measures of integrative responses to treatment. Unfortunately, spinal cord fMRI is severely challenged by motion and susceptibility artifacts induced by the implanted electrode and bones. This pilot study introduces multi-band sweep imaging with Fourier transformation (MB-SWIFT) technique for spinal cord fMRI during SCS in rats. Given the close to zero acquisition delay and high bandwidth in 3 dimensions, MB-SWIFT is demonstrated to be highly tolerant to motion and susceptibility-induced artifacts and thus holds promise for fMRI during SCS. Methods: MB-SWIFT with 0.78 × 0.78 × 1.50 mm3 spatial resolution and 3-s temporal resolution was used at 9.4 Tesla in rats undergoing epidural SCS at different frequencies. Its performance was compared with spin echo EPI. The origin of the functional contrast was also explored using suppression bands. Results: MB-SWIFT was tolerant to electrode-induced artifacts and respiratory motion, leading to substantially higher fMRI sensitivity than spin echo fMRI. Clear stimulation frequency-dependent responses to SCS were detected in the rat spinal cord close to the stimulation site. The origin of MB-SWIFT fMRI signals was consistent with dominant inflow effects. Conclusion: fMRI of the rat spinal cord during SCS can be consistently achieved with MB-SWIFT, thus providing a valuable experimental framework for assessing the effects of SCS on the central nervous system. publishedVersion
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- 2021
69. Neutrophil extracellular traps, released from neutrophil, promote microglia inflammation and contribute to poor outcome in subarachnoid hemorrhage
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Chen Gao, Zhuang Jianfeng, Cao Shenglong, Zhou Shengjun, Chen Huaijun, Zhou Hang, Li Jianru, Guo Yinghan, Yu Xiaobo, Gu Chi, Yan Feng, Fu Xiongjie, Cai Lingxin, Zeng Hanhai, Peng Yucong, Qin Bin, Tan Xiaoxiao, and Li Jingbo
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Adult ,Male ,Aging ,Subarachnoid hemorrhage ,subarachnoid hemorrhage ,Neutrophils ,Central nervous system ,neutrophil extracellular traps ,microglia ,Inflammation ,CD16 ,Extracellular Traps ,Proinflammatory cytokine ,medicine ,Humans ,Neuroinflammation ,Aged ,Aged, 80 and over ,Microglia ,business.industry ,neutrophil ,Cell Biology ,Neutrophil extracellular traps ,Middle Aged ,medicine.disease ,medicine.anatomical_structure ,Phenotype ,Immunology ,Female ,medicine.symptom ,business ,Research Paper - Abstract
Evidence indicates that neutrophil has promoted inflammation in several central nervous system diseases. However, whether the peripheral blood levels of neutrophils are associated with the functional outcome after subarachnoid hemorrhage and its potential mechanism remain unclear. In this study, we showed that neutrophil levels in peripheral blood were higher in patients with subarachnoid hemorrhage (P < 0.001) than in healthy subjects. Neutrophil levels were positively associated with Hunt and Hess grade (P < 0.001) and modified Rankin Scale scores at 3 months after SAH (P = 0.008). In terms of the mechanism, neutrophil extracellular traps markedly increased the proinflammatory subtype transition of microglia. After treatment with DNAse I, the proinflammatory subtype transition of microglia involving CD16 positive and IL-1β positive microglia was limited (P < 0.05). This mechanism was also verified in vitro. These results indicate that the existence of neutrophil extracellular traps, released from neutrophils after subarachnoid hemorrhage, can shift microglia toward a more proinflammatory phenotype and contribute to neuroinflammation and poor outcome in subarachnoid hemorrhage.
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- 2021
70. CELL CHANGES IN THE CENTRAL NERVOUS SYSTEM UNDER VARIOUS NATURAL AND EXPERIMENTAL CONDITIONS. THIRD PAPER: FUNCTIONAL ACTIVITY
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Joseph A. Dye
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Cerebellum ,Pathology ,medicine.medical_specialty ,Cell ,Central nervous system ,Cervical cord ,Biology ,symbols.namesake ,medicine.anatomical_structure ,Endocrinology ,Internal medicine ,Nerve cells ,Chromatolysis ,medicine ,Nissl body ,symbols ,Functional activity - Abstract
1. Varying degrees of functional activity and fatigue were induced in white rats by prolonged swimming. 2. Microscopical examination of Nissl preparations from the cerebellum, cervical cord, and spinal ganglia revealed mild but demonstrable nerve-cell alterations. 3. These were strikingly similar in character to those previously observed in parathyroid tetany dogs and cretin lambs. 4. Chromatolysis is considered as a general reaction of nerve cells, which invariably occurs whenever the normal functional equilibrium of these units is disturbed. 5. This reaction varies in its intensity with the severity of the opposing influence, and to this extent only can it be spoken of as specific.
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- 1927
71. CELL CHANGES IN THE CENTRAL NERVOUS SYSTEM UNDER VARIOUS NATURAL AND EXPERIMENTAL CONDITIONS. FIRST PAPER: PARATHYROID TETANY
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Joseph A. Dye
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Nervous system ,Cerebellum ,Karyolysis ,Pathology ,medicine.medical_specialty ,Tetany ,Central nervous system ,Karyorrhexis ,Biology ,Pons ,symbols.namesake ,medicine.anatomical_structure ,medicine ,Nissl body ,symbols ,medicine.symptom - Abstract
1. Complete thyroparathyroidectomy was performed on thirteen dogs, with the result that all except one developed typical tetany in some degree within one to fourteen days. The one not showing these symptoms was killed on the twenty-second day after the operation, to be used as an operated control. The tissue from three normal dogs supplied the necessary control material. 2. The symptoms of parathyroid tetany suggest an acute affection of the nervous system, especially of the nerve centres. This fact is strongly supported by microscopic alterations found in the nerve cells, the degree of which corresponds very closely to the acuteness of the attacks. These pictures point to a condition of general toxaemia. 3. Not all cells of a single animal or even of a single nerve-nucleus are affected to the same extent, so that for the same animal various steps in the reaction can be recognised. The alterations cannot be considered as the result of activity alone, but are interpreted as being produced by the same agent or agents which act as stimuli upon the neuromuscular mechanism. 4. A careful study of the nerve cells from Nissl preparations has been made, taking representative sections from the spinal cord, medulla oblongata, cerebellum, pons, mid-brain, thalamus, and cruciate gyrus. 5. The nerve cells of dog C, the operated control, are well within the normal. In the remaining twelve animals definite although varying degrees of alterations were found in these elements. In general, one might say that these changes are proportional to the acuteness of the tetanic affection. The milder grades of tetany, although extending over several days, are less drastic in their effects as measured by nerve-cell reaction than more acute attacks of a few hours' duration. 6. Sufficiently graduated stages are represented to warrant an account of the course of the affection. Early in the chromatolytic reaction, as measured by the severity of the symptoms, there is a stage of absolute hyperchromatosis with shrinkage of the cells, after which the amount of stainable material gradually diminishes through fragmentation and dissolution. This begins in the perinuclear region and spreads towards the periphery until a stage is reached in which normal staining Nissl substance can no longer be demonstrated. 7. The nucleus, on the other hand, seems to maintain its integrity to a greater extent. Except that it is slightly swollen and clouded, it appears to be normal. Complete degeneration of the cells, with karyorrhexis or karyolysis, was not seen; and in very few cells, if any, did it appear that the alterations were beyond repair had it been possible to restore the normal condition of the animal. 8. Shifting of the nucleus toward the periphery, although occasionally seen, occurred no more frequently in the experimental than in the control tissues. Vacuolisation of the cytoplasm commonly accompanied the most acute affection, particularly in the Purkinje cells and granule cells of the cerebrum. This was often associated with perivascular and pericellular œdema. 9. The associated hyperpyrexia was roughly proportional to the severity of the tetanic spasms, and followed rather than preceded the latter. This increase in body temperature is sufficient by itself to produce changes in the nerve cells, and undoubtedly exaggerates the condition of general poisoning. But this alone cannot account for the nerve-cell alterations, since these occur in milder form in animals whose temperature remains about normal. 10. This work offers insufficient proof of the conclusion that there is an increase in the number of glia cells, or that the processes can be seen for greater distances from the cell-bodies. Little importance is attached to these findings of other observers.
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- 1927
72. Acute disseminated encephalomyelitis and routine childhood vaccinations – a self-controlled case series
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Hazel J Clothier, Jim Buttery, Mee Lee Easton, Nigel W Crawford, T. J. Martin, R. Samuel, and M. Fahey
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Pediatrics ,medicine.medical_specialty ,Victoria ,030231 tropical medicine ,Immunology ,Central nervous system ,03 medical and health sciences ,0302 clinical medicine ,Pediatric hospital ,Humans ,Immunology and Allergy ,Medicine ,030212 general & internal medicine ,Child ,Demyelinating Disorder ,Adverse effect ,Pharmacology ,Preschool child ,Vaccines ,business.industry ,Incidence ,Encephalomyelitis, Acute Disseminated ,Vaccination ,Infant ,medicine.disease ,medicine.anatomical_structure ,Immunization ,Child, Preschool ,Acute disseminated encephalomyelitis ,business ,Research Paper - Abstract
Acute disseminated encephalomyelitis (ADEM) is an autoimmune, central nervous system demyelinating disorder that follows antecedent immunologic challenges, such as infection or vaccination. This study aimed to investigate the potential association between routine childhood vaccinations and ADEM. Children under 7 years of age admitted to the two tertiary level pediatric hospitals in Victoria, Australia with ADEM from 2000–2015 had their clinical information linked to vaccination records from the Australian Childhood Immunization Register. Chart review was undertaken utilizing the Brighton Collaboration ADEM criteria. The self-controlled case-series (SCCS) methodology was employed to determine the relative incidences of ADEM post-vaccination in two risk intervals: 5–28 days and 2–42 days. Forty-six cases were eligible for SCCS analysis with a median age of 3.2 years. Of the forty-six cases, three were vaccine proximate cases and received vaccinations 23, 25 and 28 days before ADEM onset. Two vaccine proximate cases received their 4-year-old scheduled vaccinations (MMR and DTPa-IPV) and one vaccine proximate case the 1-year old scheduled vaccinations (MMR and Hib-MenC). The relative incidence of ADEM during the narrow and broad risk intervals were 1.041 (95% CI 0.323–3.356, p = 0.946) and 0.585 (95% CI 0.182–1.886, p = 0.370) respectively. Sensitivity analyses did not yield any substantial deviations. These results do not provide evidence of an association between vaccinations routinely provided to children aged under 7 years in Australia and the incidence of ADEM. However, these results should be interpreted with caution as the number of ADEM cases identified was limited and further research is warranted.
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- 2021
73. OnabotulinumtoxinA affects cortical recovery period but not occurrence or propagation of cortical spreading depression in rats with compromised blood–brain barrier
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Rami Burstein, Aaron J. Schain, Yadira Flores-Montanez, Brian B. Cai, Amy Brideau-Andersen, Mitchell F. Brin, Catherine Rhéaume, Ron S. Broide, Sait Ashina, Agustin Melo-Carrillo, and Andrew M. Strassman
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Central nervous system ,Trigeminovascular ,Stimulus (physiology) ,Blood–brain barrier ,Rats, Sprague-Dawley ,medicine ,Animals ,Botulinum Toxins, Type A ,Migraine ,Botox ,business.industry ,Cortical Spreading Depression ,Headache ,Nociceptors ,Trigeminal ,medicine.disease ,Rats ,Cortex (botany) ,Anesthesiology and Pain Medicine ,medicine.anatomical_structure ,Neurology ,Blood-Brain Barrier ,Cortical spreading depression ,Scalp ,Calcitonin gene-related peptide ,Nociceptor ,Neurology (clinical) ,business ,Aura ,Neuroscience ,Research Paper - Abstract
Suture-line injections of onabotulinumtoxinA alter a neuronal function along a central nervous system pathway involved in the pathophysiology of migraine that is secondary to appearance of SNAP25 in dural nerve fibers., OnabotulinumtoxinA (BoNT-A) is an Food and Drug Administration-approved, peripherally acting preventive migraine drug capable of inhibiting meningeal nociceptors. Expanding our view of how else this neurotoxin attenuates the activation of the meningeal nociceptors, we reasoned that if the stimulus that triggers the activation of the nociceptor is lessened, the magnitude and/or duration of the nociceptors' activation could diminish as well. In the current study, we further examine this possibility using electrocorticogram recording techniques, immunohistochemistry, and 2-photon microscopy. We report (1) that scalp (head) but not lumbar (back) injections of BoNT-A shorten the period of profound depression of spontaneous cortical activity that follows a pinprick-induced cortical spreading depression (CSD); (2) that neither scalp nor lumbar injections prevent the induction, occurrence, propagation, or spreading velocity of a single wave of CSD; (3) that cleaved SNAP25—one of the most convincing tools to determine the anatomical targeting of BoNT-A treatment—could easily be detected in pericranial muscles at the injection sites and in nerve fibers of the intracranial dura, but not within any cortical area affected by the CSD; (4) that the absence of cleaved SNAP25 within the cortex and pia is unrelated to whether the blood–brain barrier is intact or compromised; and (5) that BoNT-A does not alter vascular responses to CSD. To the best of our knowledge, this is the first report of peripherally applied BoNT-A's ability to alter a neuronal function along a central nervous system pathway involved in the pathophysiology of migraine.
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- 2021
74. Indoxyl sulfate caused behavioral abnormality and neurodegeneration in mice with unilateral nephrectomy
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Shih-Yi Lin, Su-Lan Liao, Jian-Ri Li, Cheng-Jui Lin, Jiaan-Der Wang, Yen-Chuan Ou, Chiao-Yin Sun, Chun-Jung Chen, and Ya-Yu Wang
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Male ,Aging ,Interleukin-1beta ,uremic toxin ,Anxiety ,Gut flora ,medicine.disease_cause ,Nephrectomy ,neuroinflammation ,Neural Stem Cells ,Neurotrophic factors ,Behavior, Animal ,biology ,Depression ,Neurodegeneration ,neurodegeneration ,Oxides ,medicine.anatomical_structure ,Injections, Intraperitoneal ,Research Paper ,Serotonin ,medicine.medical_specialty ,Cell Survival ,Neurogenesis ,Central nervous system ,Prefrontal Cortex ,Internal medicine ,medicine ,Animals ,Cognitive Dysfunction ,RNA, Messenger ,Renal Insufficiency, Chronic ,Neuroinflammation ,gut microbiota ,business.industry ,Brain-Derived Neurotrophic Factor ,Cell Biology ,medicine.disease ,Aryl hydrocarbon receptor ,biology.organism_classification ,Carbon ,Mice, Inbred C57BL ,Repressor Proteins ,Affect ,Oxidative Stress ,Endocrinology ,biology.protein ,Corticosterone ,business ,Indican ,Oxidative stress ,Kidney disease - Abstract
Chronic Kidney Disease (CKD) and neurodegenerative diseases are aging-related diseases. CKD with declined renal function is associated with an elevation of circulating indoxyl sulfate, a metabolite synthesized by gut microbes. We explored the roles of gut microbial metabolites in linking with Central Nervous System (CNS) diseases by administrating indoxyl sulfate intraperitoneally to male C57BL/6 mice with unilateral nephrectomy. Upon exposure, the accumulation of indoxyl sulfate was noted in the blood, prefrontal cortical tissues, and cerebrospinal fluid. Mice showed behavioral signs of mood disorders and neurodegeneration such as anxiety, depression, and cognitive impairment. Those behavioral changes were accompanied by disturbed neuronal survival, neural stem cell activity, expression of Brain-Derived Neurotrophic Factor, serotonin, corticosterone, and Repressor Element-1 Silencing Transcription Factor, and post-receptor intracellular signaling, as well as upregulated oxidative stress and neuroinflammation. Uremic toxin adsorbent AST-120 improved the above mentioned changes. Intriguingly, intracerebroventricular indoxyl sulfate administration only caused limited alterations in the normal mice and the alterations were reversed by aryl hydrocarbon receptor antagonism. The findings suggest pathogenic roles of indoxyl sulfate in the development of CNS diseases, and highlight gut microbiota as alternative targets for intervention with the aim of slowing down the progression of CKD and decreasing CNS complications.
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- 2021
75. Sex and age-related differences in cerebral blood flow investigated using pseudo-continuous arterial spin labeling magnetic resonance imaging
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Mustapha Bouhrara, Richard W Kim, Wenshu Qian, Joseph S R Alisch, Luigi Ferrucci, Richard G. Spencer, Abinand C. Rejimon, Susan M. Resnick, Nikkita Khattar, and Luis E. Cortina
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Adult ,Male ,Aging ,medicine.medical_specialty ,cerebral blood flow ,Central nervous system ,White matter ,Myelin ,Sex Factors ,Internal medicine ,medicine ,Humans ,Dementia ,Gray Matter ,Aged ,Aged, 80 and over ,medicine.diagnostic_test ,business.industry ,Age Factors ,Magnetic resonance imaging ,Cell Biology ,Middle Aged ,medicine.disease ,arterial spin labeling ,Magnetic Resonance Imaging ,White Matter ,Healthy Volunteers ,Oligodendrocyte ,medicine.anatomical_structure ,Cerebral blood flow ,Cerebrovascular Circulation ,Cardiology ,Female ,business ,Perfusion ,Research Paper ,MRI ,circulatory and respiratory physiology - Abstract
Adequate cerebral blood flow (CBF) is essential to a healthy central nervous system (CNS). Previous work suggests that CBF differs between men and women, and declines with age and certain pathologies, but a highly controlled systematic study across a wide age range, and incorporating white matter (WM) regions, has not been undertaken. Here, we investigate age- and sex-related differences in CBF in gray matter (GM) and WM regions in a cohort (N = 80) of cognitively unimpaired individuals over a wide age range. In agreement with literature, we find that GM regions exhibited lower CBF with age. In contrast, WM regions exhibited higher CBF with age in various cerebral regions. We attribute this new finding to increased oligodendrocyte metabolism to maintain myelin homeostasis in the setting of increased myelin turnover with age. Further, consistent with prior studies, we found that CBF was higher in women than in men in all brain structures investigated. Our work provides new insights into the effects of age and sex on CBF. In addition, our results provide reference CBF values for the standard ASL protocol recommended by the ISMRM Perfusion Study Group and the European ASL in Dementia consortium. Thus, these results provide a foundation for further investigations of CNS perfusion in a variety of settings, including aging, cerebrovascular diseases, and dementias.
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- 2021
76. Gene expression barcode values reveal a potential link between Parkinson’s disease and gastric cancer
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Shishun Zhao, Mingbo Tang, Chi Wang, and Suyan Tian
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Aging ,Parkinson's disease ,Degenerative Disorder ,Central nervous system ,barcode values ,Disease ,Biology ,Stomach Neoplasms ,Gene expression ,medicine ,Humans ,Gene ,Genetics ,gene expression profiles ,Stomach ,gastric cancer ,Gene Expression Profiling ,differentially expressed genes (DEGs) ,Cancer ,Computational Biology ,Parkinson Disease ,Cell Biology ,medicine.disease ,medicine.anatomical_structure ,Algorithms ,Research Paper - Abstract
Gastric cancer is a disease that develops from the lining of the stomach, whereas Parkinson's disease is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. Although these two diseases seem to be distinct from each other, increasing evidence suggests that they might be linked. To explore the linkage between these two diseases, differentially expressed genes between the diseased people and their normal controls were identified using the barcode algorithm. This algorithm transforms actual gene expression values into barcode values comprised of 1's (expressed genes) and 0's (silenced genes). Once the overlapped differentially expressed genes were identified, their biological relevance was investigated. Thus, using the gene expression profiles and bioinformatics methods, we demonstrate that Parkinson's disease and gastric cancer are indeed linked. This research may serve as a pilot study, and it will stimulate more research to investigate the relationship between gastric cancer and Parkinson's disease from the perspective of gene profiles and their functions.
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- 2021
77. Distinct amyloid-β and tau-associated microglia profiles in Alzheimer’s disease
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Nieske Brouwer, Thomas Möller, Jan Mulder, Maya E. Woodbury, Emma Gerrits, Peter Paul De Deyn, Knut Biber, Wilfred F. A. den Dunnen, Markus P. Kummer, Yannick Vermeiren, Erik Boddeke, Mirjam Lambourne, Susanne M. Kooistra, Bart J. L. Eggen, Molecular Neuroscience and Ageing Research (MOLAR), Translational Immunology Groningen (TRIGR), and Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)
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Male ,Pathology ,medicine.medical_specialty ,Amyloid ,Central nervous system ,Population ,tau Proteins ,Biology ,Pathology and Forensic Medicine ,s disease ,Amyloid-β ,Cellular and Molecular Neuroscience ,Alzheimer Disease ,Single-nucleus RNA sequencing ,mental disorders ,medicine ,Extracellular ,Humans ,Amyloid-β ,education ,Alzheimer’ ,Aged ,Aged, 80 and over ,education.field_of_study ,Original Paper ,Amyloid beta-Peptides ,Microglia ,Brain ,Phenotype ,Pathophysiology ,Nutritional Biology ,medicine.anatomical_structure ,nervous system ,Female ,Neurology (clinical) ,Human medicine ,Tau ,Alzheimer’s disease ,Homeostasis - Abstract
Alzheimer’s disease (AD) is the most prevalent form of dementia and is characterized by abnormal extracellular aggregates of amyloid-β and intraneuronal hyperphosphorylated tau tangles and neuropil threads. Microglia, the tissue-resident macrophages of the central nervous system (CNS), are important for CNS homeostasis and implicated in AD pathology. In amyloid mouse models, a phagocytic/activated microglia phenotype has been identified. How increasing levels of amyloid-β and tau pathology affect human microglia transcriptional profiles is unknown. Here, we performed snRNAseq on 482,472 nuclei from non-demented control brains and AD brains containing only amyloid-β plaques or both amyloid-β plaques and tau pathology. Within the microglia population, distinct expression profiles were identified of which two were AD pathology-associated. The phagocytic/activated AD1-microglia population abundance strongly correlated with tissue amyloid-β load and localized to amyloid-β plaques. The AD2-microglia abundance strongly correlated with tissue phospho-tau load and these microglia were more abundant in samples with overt tau pathology. This full characterization of human disease-associated microglia phenotypes provides new insights in the pathophysiological role of microglia in AD and offers new targets for microglia-state-specific therapeutic strategies. Supplementary Information The online version contains supplementary material available at 10.1007/s00401-021-02263-w.
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- 2021
78. Identification of distinct and age-dependent p16High microglia subtypes
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Boshi Wang, Nynke Talma, Emma Gerrits, Marco Demaria, Bart J. L. Eggen, Molecular Neuroscience and Ageing Research (MOLAR), Damage and Repair in Cancer Development and Cancer Treatment (DARE), and Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)
- Subjects
Senescence ,Aging ,senescence ,Central nervous system ,Inflammation ,p16 ,neuroscience ,Mice ,Cyclin-dependent kinase ,medicine ,cellular senescence ,Animals ,Humans ,Cyclin-Dependent Kinase Inhibitor p16 ,Original Paper ,biology ,Microglia ,Kinase ,Neurodegeneration ,Cell Biology ,medicine.disease ,Original Papers ,Cell biology ,Disease Models, Animal ,medicine.anatomical_structure ,biology.protein ,medicine.symptom ,Homeostasis - Abstract
Cells expressing high levels of the cyclin‐dependent kinase (CDK)4/6 inhibitor p16 (p16High) accumulate in aging tissues and promote multiple age‐related pathologies, including neurodegeneration. Here, we show that the number of p16High cells is significantly increased in the central nervous system (CNS) of 2‐year‐old mice. Bulk RNAseq indicated that genes expressed by p16High cells were associated with inflammation and phagocytosis. Single‐cell RNAseq of brain cells indicated p16High cells were primarily microglia, and their accumulation was confirmed in brains of aged humans. Interestingly, we identified two distinct subpopulations of p16High microglia in the mouse brain, with one being age‐associated and one present in young animals. Both p16High clusters significantly differed from previously described disease‐associated microglia and expressed only a partial senescence signature. Taken together, our study provides evidence for the existence of two p16‐expressing microglia populations, one accumulating with age and another already present in youth that could positively and negatively contribute to brain homeostasis, function, and disease., P16+ microglia increases in aging brains of mice and humans. P16+ cells are found in 597 different microglia populations, including two previously unknown clusters.
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- 2021
79. Inhibition of the cGAS‐STING pathway ameliorates the premature senescence hallmarks of Ataxia‐Telangiectasia brain organoids
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Cecilia Gómez-Inclán, Ernst J. Wolvetang, Hannah C Leeson, Harman Kaur Chaggar, Julio Aguado, Alan Mackay-Sim, and Mohammed R. Shaker
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Senescence ,Aging ,Central nervous system ,Inflammation ,Neuropathology ,Biology ,Ataxia‐Telangiectasia ,Ataxia Telangiectasia ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Organoid ,cellular senescence ,Humans ,Cells, Cultured ,030304 developmental biology ,Original Paper ,0303 health sciences ,cGAS‐STING signalling ,brain organoids ,Aspirin ,Dose-Response Relationship, Drug ,Neurodegeneration ,neurodegeneration ,Brain ,Membrane Proteins ,Cell Biology ,medicine.disease ,Original Papers ,Nucleotidyltransferases ,Cell biology ,Organoids ,medicine.anatomical_structure ,Astrocytes ,Ataxia-telangiectasia ,brain aging ,medicine.symptom ,030217 neurology & neurosurgery ,Astrocyte - Abstract
Ataxia‐telangiectasia (A‐T) is a genetic disorder caused by the lack of functional ATM kinase. A‐T is characterized by chronic inflammation, neurodegeneration and premature ageing features that are associated with increased genome instability, nuclear shape alterations, micronuclei accumulation, neuronal defects and premature entry into cellular senescence. The causal relationship between the detrimental inflammatory signature and the neurological deficiencies of A‐T remains elusive. Here, we utilize human pluripotent stem cell‐derived cortical brain organoids to study A‐T neuropathology. Mechanistically, we show that the cGAS‐STING pathway is required for the recognition of micronuclei and induction of a senescence‐associated secretory phenotype (SASP) in A‐T olfactory neurosphere‐derived cells and brain organoids. We further demonstrate that cGAS and STING inhibition effectively suppresses self‐DNA‐triggered SASP expression in A‐T brain organoids, inhibits astrocyte senescence and neurodegeneration, and ameliorates A‐T brain organoid neuropathology. Our study thus reveals that increased cGAS and STING activity is an important contributor to chronic inflammation and premature senescence in the central nervous system of A‐T and constitutes a novel therapeutic target for treating neuropathology in A‐T patients., Aguado et al. show that senescent astrocytes upregulate detrimental pro‐inflammatory SASP factors in a cGAS/STING‐dependant manner that promote accelerated ageing in brain organoids of ataxia‐telangiectasia. Pharmacological interventions in these organoids with cGAS and STING inhibitors reduce astrocyte senescence and the SASP, and consequently, improve neuronal activity and survival.
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- 2021
80. Use and validity of child neurodevelopment outcome measures in studies on prenatal exposure to psychotropic and analgesic medications – A systematic review.
- Author
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Hjorth, Sarah, Bromley, Rebecca, Ystrom, Eivind, Lupattelli, Angela, Spigset, Olav, and Nordeng, Hedvig
- Subjects
MATERNAL exposure ,MEDICAL personnel ,META-analysis ,MEDICATION safety ,SCIENTIFIC community ,CENTRAL nervous system ,PRENATAL exposure - Abstract
In recent years there has been increased attention to child neurodevelopment in studies on medication safety in pregnancy. Neurodevelopment is a multifactorial outcome that can be assessed by various assessors, using different measures. This has given rise to a debate on the validity of various measures of neurodevelopment. The aim of this review was twofold. Firstly we aimed to give an overview of studies on child neurodevelopment after prenatal exposure to central nervous system acting medications using psychotropics and analgesics as examples, giving special focus on the use and validity of outcome measures. Secondly, we aimed to give guidance on how to conduct and interpret medication safety studies with neurodevelopment outcomes. We conducted a systematic review in the MEDLINE, Embase, PsycINFO, Web of Science, Scopus, and Cochrane databases from inception to April 2019, including controlled studies on prenatal exposure to psychotropics or analgesics and child neurodevelopment, measured with standardised psychometric instruments or by diagnosis of neurodevelopmental disorder. The review management tool Covidence was used for data-extraction. Outcomes were grouped as motor skills, cognition, behaviour, emotionality, or “other”. We identified 110 eligible papers (psychotropics, 82 papers, analgesics, 29 papers). A variety of neurodevelopmental outcome measures were used, including 27 different psychometric instruments administered by health care professionals, 15 different instruments completed by parents, and 13 different diagnostic categories. In 23 papers, no comments were made on the validity of the outcome measure. In conclusion, establishing neurodevelopmental safety includes assessing a wide variety of outcomes important for the child’s daily functioning including motor skills, cognition, behaviour, and emotionality, with valid and reliable measures from infancy through to adolescence. Consensus is needed in the scientific community on how neurodevelopment should be assessed in medication safety in pregnancy studies. Review registration number: CRD42018086101 in the PROSPERO database. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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81. Microglia exosomal miRNA-137 attenuates ischemic brain injury through targeting Notch1
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Pei Siying, Zhang Dianquan, Kun-Ping Jia, Wen-Li Song, Hong Wang, Cai Guoliang, Guofeng Cai, Kai Liu, Sihui Guo, Zhe Zhuang, Cheng Cui, Sheng-Nan Xu, Xiu-Zhen Wang, and Manchao Sun
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Aging ,Central nervous system ,microglia ,Apoptosis ,Exosomes ,Exosome ,Neuroprotection ,Brain Ischemia ,Mice ,Downregulation and upregulation ,In vivo ,medicine ,exosome ,Animals ,Receptor, Notch1 ,Neurons ,Notch1 ,TUNEL assay ,Microglia ,business.industry ,Infarction, Middle Cerebral Artery ,Cell Biology ,Microvesicles ,Cell biology ,Disease Models, Animal ,MicroRNAs ,medicine.anatomical_structure ,Reperfusion Injury ,miRNA-137 ,business ,ischemic injury ,Research Paper - Abstract
Microglia are the resident immune cells in the central nervous system and play an essential role in brain homeostasis and neuroprotection in brain diseases. Exosomes are crucial in intercellular communication by transporting bioactive miRNAs. Thus, this study aimed to investigate the function of microglial exosome in the presence of ischemic injury and related mechanism. Oxygen-glucose deprivation (OGD)-treated neurons and transient middle cerebral artery occlusion (TMCAO)-treated mice were applied in this study. Western blotting, RT-PCR, RNA-seq, luciferase reporter assay, transmission electron microscope, nanoparticle tracking analysis, immunohistochemistry, TUNEL and LDH assays, and behavioral assay were applied in mechanistic and functional studies. The results demonstrated that exosomes derived from microglia in M2 phenotype (BV2-Exo) were internalized by neurons and attenuated neuronal apoptosis in response to ischemic injury in vitro and in vivo. BV2-Exo also decreased infarct volume and behavioral deficits in ischemic mice. Exosomal miRNA-137 was upregulated in BV2-Exo and participated in the partial neuroprotective effect of BV2-Exo. Furthermore, Notch1 was a directly targeting gene of exosomal miRNA-137. In conclusion, these results suggest that BV2-Exo alleviates ischemia-reperfusion brain injury through transporting exosomal miRNA-137. This study provides novel insight into microglial exosomes-based therapies for the treatment of ischemic brain injury.
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- 2021
82. Activation of carbonic anhydrases from human brain by amino alcohol oxime ethers: towards human carbonic anhydrase VII selective activators
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Alessio Nocentini, Elisabetta Orlandini, Elisa Nuti, Claudiu T. Supuran, Doretta Cuffaro, Susanna Nencetti, Lidia Ciccone, and Armando Rossello
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Gene isoform ,cognition ,metalloenzyme ,Central nervous system ,cns-disease ,Alcohol ,RM1-950 ,activation ,CNS-disease ,Metalloenzyme ,selectivity ,01 natural sciences ,Structure-Activity Relationship ,chemistry.chemical_compound ,Carbonic anhydrase ,Oximes ,Drug Discovery ,medicine ,Humans ,Carbonic Anhydrases ,Pharmacology ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,010405 organic chemistry ,Chemistry ,Brain ,General Medicine ,Human brain ,Metabolism ,Oxime ,Amino Alcohols ,0104 chemical sciences ,Isoenzymes ,010404 medicinal & biomolecular chemistry ,medicine.anatomical_structure ,Biochemistry ,biology.protein ,CARBONIC ANHYDRASE VII ,Therapeutics. Pharmacology ,Ethers ,Research Article ,Research Paper - Abstract
The synthesis and carbonic anhydrase (CA; EC 4.2.1.1) activating effects of a series of oxime ether-based amino alcohols towards four human (h) CA isoforms expressed in human brain, hCA I, II, IV and VII, are described. Most investigated amino alcohol derivatives induced a consistent activation of the tested CAs, with KAs spanning from a low micromolar to a medium nanomolar range. Specifically, hCA II and VII, putative main CA targets when central nervous system (CNS) diseases are concerned, were most efficiently activated by these oxime ether derivatives. Furthermore, a multitude of selective hCA VII activators were identified. As hCA VII is one of the key isoforms involved in brain metabolism and other brain functions, the identified potent and selective hCA VII activators may be considered of interest for investigations of various therapeutic applications or as lead compounds in search of even more potent and selective CA activators.
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- 2021
83. Substance use, unlike dolutegravir, is associated with mood symptoms in people living with HIV
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Wouter A. van der Heijden, Mike van Verseveld, Arnt F. A. Schellekens, Quirijn de Mast, Lisa Van de Wijer, André J. A. M. van der Ven, and Mihai G. Netea
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Male ,medicine.medical_specialty ,Social Psychology ,Pyridones ,Substance-Related Disorders ,Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13] ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,HIV Infections ,Anti-retroviral agents ,Impulsivity ,Piperazines ,Experimental Psychopathology and Treatment ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,All institutes and research themes of the Radboud University Medical Center ,Oxazines ,medicine ,Humans ,030212 general & internal medicine ,Psychiatry ,Side effects ,Depression (differential diagnoses) ,0303 health sciences ,Original Paper ,030306 microbiology ,business.industry ,Depression ,Public health ,Psychiatric assessment ,Public Health, Environmental and Occupational Health ,Health psychology ,Infectious Diseases ,Mood ,lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] ,chemistry ,Dolutegravir ,Central nervous system ,Anxiety ,Female ,Impulsive behavior ,medicine.symptom ,business ,Heterocyclic Compounds, 3-Ring - Abstract
Contradictory data have been reported concerning neuropsychiatric side effects of the first-line antiretroviral drug dolutegravir, which may be partly due to lack of control groups or psychiatric assessment tools. Using validated self-report questionnaires, we compared mood and anxiety (DASS-42), impulsivity (BIS-11), and substance use (MATE-Q) between dolutegravir-treated and dolutegravir-naive people living with HIV (PLHIV). We analyzed 194, mostly male, PLHIV on long-term treatment of whom 82/194 (42.3%) used dolutegravir for a median (IQR) of 280 (258) days. Overall, 51/194 (26.3%) participants reported DASS-42 scores above the normal cut-off, 27/194 (13.5%) were classified as highly impulsive, and 58/194 (29.9%) regularly used recreational drugs. Regular substance use was positively associated with depression (p = 0.012) and stress scores (p = 0.045). We observed no differences between dolutegravir-treated and dolutegravir-naive PLHIV. Our data show that depressed and anxious moods and impulsivity are common in PLHIV and associate with substance use and not with dolutegravir use.
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- 2021
84. Concurrent OCT and OCT angiography of retinal neurovascular degeneration in the 5XFAD Alzheimer’s disease mice
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Tae-Hoon Kim, Dieter Klatt, Taeyoon Son, and Xincheng Yao
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Paper ,Retinal degeneration ,retina ,Pathology ,medicine.medical_specialty ,Central nervous system ,Neuroscience (miscellaneous) ,chemistry.chemical_compound ,Optical coherence tomography ,medicine ,Radiology, Nuclear Medicine and imaging ,5XFAD ,Retina ,Radiological and Ultrasound Technology ,medicine.diagnostic_test ,business.industry ,Retinal ,neurovascular degeneration ,medicine.disease ,Neurovascular bundle ,Research Papers ,medicine.anatomical_structure ,OCT ,chemistry ,Angiography ,sense organs ,OCTA ,business ,Alzheimer’s disease ,Artery - Abstract
Significance: As one part of the central nervous system, the retina manifests neurovascular defects in Alzheimer’s disease (AD). Quantitative imaging of retinal neurovascular abnormalities may promise a new method for early diagnosis and treatment assessment of AD. Previous imaging studies of transgenic AD mouse models have been limited to the central part of the retina. Given that the pathological hallmarks of AD frequently appear in different peripheral quadrants, a comprehensive regional investigation is needed for a better understanding of the retinal degeneration associated with AD-like pathology. Aim: We aim to demonstrate concurrent optical coherence tomography (OCT) and OCT angiography (OCTA) of retinal neuronal and vascular abnormalities in the 5XFAD mouse model and to investigate region-specific retinal degeneration. Approach: A custom-built OCT system was used for retinal imaging. Retinal thickness, vessel width, and vessel density were quantitatively measured. The artery and vein (AV) were classified for differential AV analysis, and trilaminar vascular plexuses were segmented for depth-resolved density measurement. Results: It was observed that inner and outer retinal thicknesses were explicitly reduced in the dorsal and temporal quadrants, respectively, in 5XFAD mice. A significant arterial narrowing in 5XFAD mice was also observed. Moreover, overall capillary density consistently showed a decreasing trend in 5XFAD mice, but regional specificity was not identified. Conclusions: Quadrant- and layer-specific neurovascular degeneration was observed in 5XFAD mice. Concurrent OCT and OCTA promise a noninvasive method for quantitative monitoring of AD progression and treatment assessment.
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- 2021
85. Bacteria elevate extracellular adenosine to exploit host signaling for blood-brain barrier disruption
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Wenhua Huang, Qingyu Lv, Peng Liu, Ying Chen, Hua Jiang, Zunquan Zhao, Xueyi Shang, Decong Kong, Yuling Zheng, and Yongqiang Jiang
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Microbiology (medical) ,Nervous system ,Virulence Factors ,Immunology ,Streptococcus suis ,Virulence ,Infectious and parasitic diseases ,RC109-216 ,Blood–brain barrier ,Microbiology ,03 medical and health sciences ,Mice ,Bacterial Proteins ,medicine ,Extracellular ,Animals ,Humans ,Pathogen ,Cells, Cultured ,030304 developmental biology ,brain microvascular endothelial cell ,0303 health sciences ,biology ,030306 microbiology ,streptococcus suis ,Brain ,meningitis ,blood-brain barrier ,biology.organism_classification ,central nervous system ,Adenosine receptor ,Adenosine ,Cell biology ,Mice, Inbred C57BL ,Infectious Diseases ,medicine.anatomical_structure ,adenosine ,Bacterial Translocation ,Host-Pathogen Interactions ,Parasitology ,Female ,streptococcus agalactiae ,medicine.drug ,Signal Transduction ,Research Article ,Research Paper - Abstract
Bacterial meningitis remains a substantial cause of mortality worldwide and survivors may have severe lifelong disability. Although we know that meningeal bacterial pathogens must cross blood-central nervous system (CNS) barriers, the mechanisms which facilitate the virulence of these pathogens are poorly understood. Here, we show that adenosine from a surface enzyme (Ssads) of Streptococcus suis facilitates this pathogen’s entry into mouse brains. Monolayer translocation assays (from the human cerebrovascular endothelium) and experiments using diverse inhibitors and agonists together demonstrate that activation of the A1 adenosine receptor signaling cascade in hosts, as well as attendant cytoskeleton remodeling, promote S. suis penetration across blood-CNS barriers. Importantly, our additional findings showing that Ssads orthologs from other bacterial species also promote their translocation across barriers suggest that exploitation of A1 AR signaling may be a general mechanism of bacterial virulence.
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- 2020
86. Gastrodin promotes CNS myelination via a lncRNA Gm7237/miR-142a/MRF pathway
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Lin Zhang, Yue Shu, Qianxing Wang, Tianyuan Luo, Qiang Zhang, Shouyang Yu, Jia Zou, Yu Zhang, Zhi Xiao, Liang Zhou, Tian Yu, Shang-Fu Xu, Mingda Wang, and Changyin Yu
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Central Nervous System ,CNS demyelination ,Central nervous system ,Biology ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Myelin ,0302 clinical medicine ,Glucosides ,In vivo ,microRNA ,medicine ,Animals ,Gastrodin ,Molecular Biology ,Gene ,Benzyl Alcohols ,Myelin Sheath ,030304 developmental biology ,0303 health sciences ,RNA ,Cell Biology ,Mice, Inbred C57BL ,MicroRNAs ,medicine.anatomical_structure ,Gene Expression Regulation ,chemistry ,030220 oncology & carcinogenesis ,RNA, Long Noncoding ,Neuroscience ,Transcription Factors ,Research Paper - Abstract
Treatment of central nervous system (CNS) demyelination is greatly hindered by lack of the knowledge regarding to underlying molecular mechanisms as well as therapeutic agents. Here, we report a novel small molecule agent, gastrodin (GAS), which can significantly promote CNS myelination in in vivo mice models. By using high-throughput sequencing analysis, we discover a key long non-coding RNA Gm7237 that can enhance CNS myelination and is up-regulated by GAS. Through using bioinformatic analysis and experimental validations, we further unravel that microRNA-142a (miR-142a) and its target myelin gene regulatory factor (MRF) is under the direct regulation by Gm7237. Finally, we demonstrate that Gm7237/miR-142a/MRF axis is the key pathway involved in CNS myelination mediated by GAS. Overall, our results provide not only a novel agent for therapeutic treatment of CNS demyelination but also a molecular basis responsible for GAS-promoted CNS myelination.
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- 2020
87. Lewy pathology of the esophagus correlates with the progression of Lewy body disease: a Japanese cohort study of autopsy cases
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Yasuhiro Sakashita, Masako Ikemura, Ito Kawakami, Renpei Sengoku, Mikihiro Yamazaki, Tomio Arai, Shinya Tanaka, Yuko Saito, Shinji Ito, Atsuko Motoda, Tomoyasu Matsubara, Zen-ichi Tanei, and Shigeo Murayama
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Adult ,Central Nervous System ,Lewy Body Disease ,Male ,Pathology ,medicine.medical_specialty ,Parkinson's disease ,Myenteric Plexus ,Autopsy ,Disease ,Pathology and Forensic Medicine ,Cohort Studies ,Cellular and Molecular Neuroscience ,Esophagus ,Japan ,Peripheral Nervous System ,medicine ,Prevalence ,Humans ,Pure autonomic failure ,Aged ,Biological Specimen Banks ,α-Synuclein ,Aged, 80 and over ,Plexus ,Original Paper ,Dementia with Lewy bodies ,business.industry ,Age Factors ,Middle Aged ,medicine.disease ,Immunohistochemistry ,medicine.anatomical_structure ,Peripheral nervous system ,Parkinson’s disease ,alpha-Synuclein ,Female ,Lewy Bodies ,Neurology (clinical) ,Enteric nervous system ,business - Abstract
Lewy body disease (LBD) is a spectrum of progressive neurodegenerative disorders characterized by the wide distribution of Lewy bodies and neurites in the central and peripheral nervous system (CNS, PNS). Clinical diagnoses include Parkinson’s disease (PD), dementia with Lewy bodies, or pure autonomic failure. All types of LBD are accompanied by non-motor symptoms (NMSs) including gastrointestinal dysfunctions such as constipation. Its relationship to Lewy body-related α-synucleinopathy (Lewy pathology) of the enteric nervous system (ENS) is attracting attention because it can precede the motor symptoms. To clarify the role of ENS Lewy pathology in disease progression, we performed a clinicopathological study using the Brain Bank for Aging Research in Japan. Five-hundred and eighteen cases were enrolled in the study. Lewy pathology of the CNS and PNS, including the lower esophagus as a representative of the ENS, was examined via autopsy findings. Results showed that one-third of older people (178 cases, 34%) exhibited Lewy pathology, of which 78 cases (43.8%) exhibited the pathology in the esophagus. In the esophageal wall, Auerbach’s plexus (41.6%) was most susceptible to the pathology, followed by the adventitia (33.1%) and Meissner’s plexus (14.6%). Lewy pathology of the esophagus was significantly associated with autonomic failures such as constipation (p
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- 2020
88. Towards Design and Implementation of an EEG-Based BCI TV Remote Control.
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Ali, Haider Abdullah, Ali, Liwa Abdullah, Vasilateanu, Andrei, Goga, Nicolae, and Popa, Ramona Cristina
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REMOTE control ,ELECTROENCEPHALOGRAPHY ,RASPBERRY Pi ,BIOMEDICAL engineering ,CENTRAL nervous system - Abstract
BCI is a rapidly growing field within biomedical engineering as it enables a direct connection between the central nervous system and an external device. BCI detects brain signals using biosensors (electrodes) installed on the head's scalp or implanted inside the brain. EEG is a non-invasive method for detecting and monitoring the brain's activity. Using EEG-based BCI in the medical field can significantly help disabled people to perform daily activities. In this context, it is very important to support and enable paralysed people to interact with multimedia devices like televisions by developing suitable solutions. This paper proposes an EEG mind-controlled TV remote control system prototype. The proposed prototype uses affordable hardware components to perform its task. A quantitative questionnaire has been conducted to identify the system's functional and non-functional requirements. The system can send four different signals to power on/off, change the channel, raise and reduce the volume of the TV. The system has been tested by 20 subjects. The testing results show that the accuracy of the system is 74.9%. Despite the system being able to control only four TV functions, the system is scalable, and more commands can be added in the future. Also, using Raspberry Pi in the system gives a great possibility to eliminate the computer and to use Raspberry Pi directly with the headset. This paper demonstrates the approach's feasibility and opens the route for enhancing the system and using EEG-based BCI with more and different devices. [ABSTRACT FROM AUTHOR]
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- 2023
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89. Combining RNAscope and immunohistochemistry to visualize inflammatory gene products in neurons and microglia.
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Ball, Jayson B., McNulty, Connor J., Green-Fulgham, Suzanne M., Dragavon, Joseph M., Correia Rocha, Igor R., Finch, Maggie R., Prévost, Emily D., Siddique, Imaad I., Woodall, Brodie J., Watkins, Linda R., Baratta, Michael V., and Root, David H.
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FLUORESCENCE in situ hybridization ,IMMUNOGLOBULINS ,NEURONS ,CENTRAL nervous system ,SCIATIC nerve injuries ,GENE expression - Abstract
A challenge for central nervous system (CNS) tissue analysis in neuroscience research has been the difficulty to codetect and colocalize gene and protein expression in the same tissue. Given the importance of identifying gene expression relative to proteins of interest, for example, cell-type specific markers, we aimed to develop a protocol to optimize their codetection. RNAscope fluorescent in situ hybridization (FISH) combined with immunohistochemistry (IHC) in fixed (CNS) tissue sections allows for reliable quantification of gene transcripts of interest within IHC-labeled cells. This paper describes a new method for simultaneous visualization of FISH and IHC in thicker (14-µm), fixed tissue samples, using spinal cord sections. This method's effectiveness is shown by the cell-type-specific quantification of two genes, namely the proinflammatory cytokine interleukin-1beta (IL-1b) and the inflammasome NLR family pyrin domain containing 3 (NLRP3). These genes are challenging to measure accurately using immunohistochemistry (IHC) due to the nonspecificity of available antibodies and the hard-todistinguish, dot-like visualizations of the labeled proteins within the tissue. These measurements were carried out in spinal cord sections after unilateral chronic constriction injury of the sciatic nerve to induce neuroinflammation in the spinal cord. RNAscope is used to label transcripts of genes of interest and IHC is used to label cell-type specific antigens (IBA1 for microglia, NeuN for neurons). This combination allowed for labeled RNA transcripts to be quantified within celltype specific boundaries using confocal microscopy and standard image analysis methods. This method makes it easy to answer empirical questions that are intractable with standard IHC or in situ hybridization alone. The method, which has been optimized for spinal cord tissue and to minimize tissue preparation time and costs, is described in detail from tissue collection to image analysis. Further, the relative expression changes in inflammatory genes NLRP3 and IL-1b in spinal cord microglia vs. neurons of somatotopically relevant laminae are described for the first time. [ABSTRACT FROM AUTHOR]
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- 2023
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90. Neurotoxicology of alcohol: a bibliometric and science mapping analysis.
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Santos Mendes, Paulo Fernando, Claydes Baia-da-Silva, Daiane, Pereira Melo, Wallacy Watson, Oliveira Bittencourt, Leonardo, Duarte Souza-Rodrigues, Renata, Pereira Fernandes, Luanna Melo, Ferraz Maia, Cristiane do Socorro, and Rodrigues Lima, Rafael
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NEUROTOXICOLOGY ,ALCOHOL drinking ,FETAL alcohol syndrome ,ALCOHOL ,CENTRAL nervous system ,BEVERAGES - Abstract
Alcohol consumption is common in many societies and has increased considerably, resulting in many socioeconomic and public health problems. In this sense, studies have been carried out in order to understand the mechanisms involved in alcohol consumption and related harmful effects. This study aimed to identify and map the knowledge and to perform bibliometric analysis of the neurotoxicology of alcohol based on the 100 most cited articles. A search was carried out in the Web of Science Core Collection database and information was extracted regarding the journal, authors, keywords, year of publication, number of citations, country and continent of the corresponding author. For each selected manuscript, the study design, alcohol exposure model, dose, period of exposure, and effect on the central nervous system and research hotspots were mapped. The journal with the highest number of publications was Alcoholism: Clinical and Experimental Research (n = 11 papers), the author who contributed the most was Crews FT (n = 8 papers), the studies had a total of 288 keywords and 75% of the publications were from the United States of America. The experimental studies evaluated the effects of prenatal and postnatal exposure and were conducted in rats and mice using doses ranging from 2.5 to 14 g/kg/day, with administration by subcutaneous, intraperitoneal, intragastric, or inhalation route or with free access through drinking bottles. Among the studies mapped, the oldest one (1989) aimed to understand the systemic damage and mechanisms of action involved, while the most recent focused on understanding the receptors and mechanisms involved in addiction, as well as genetic factors. Our results show the panorama of the most widespread scientific production in the scientific community on the neurotoxicology of ethanol, a high prevalence was observed in studies that addressed fetal alcohol syndrome and/or the effects of ethanol on neurodevelopment. [ABSTRACT FROM AUTHOR]
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- 2023
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91. Autoimmune Encephalitis with Antibodies: Anti-NMDAR, Anti-AMPAR, Anti-GQ1b, Anti-DPPX, Anti-CASPR2, Anti-LGI1, Anti-RI, Anti-Yo, Anti-Hu, Anti-CV2 and Anti-GABAAR, in the Course of Psychoses, Neoplastic Diseases, and Paraneoplastic Syndromes.
- Author
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Braczkowski, Michał, Soszyński, Dariusz, Sierakowska, Alicja, Braczkowski, Ryszard, Kufel, Klaudia, and Łabuz-Roszak, Beata
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ANTI-NMDA receptor encephalitis ,PARANEOPLASTIC syndromes ,PSYCHOSES ,CELL surface antigens ,CENTRAL nervous system ,GLUTAMATE receptors - Abstract
Encephalitis is a condition with a variety of etiologies, clinical presentations, and degrees of severity. The causes of these disorders include both neuroinfections and autoimmune diseases in which host antibodies are pathologically directed against self-antigens. In autoimmune encephalitis, autoantibodies are expressed in the central nervous system. The incidence of this disease is approximately 4% of all reported cases of encephalitis. Autoimmune encephalitis can be induced by antibodies against neuronal surface antigens such as N-methyl-D-aspartate-activated glutamate receptors (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPAR) or gangliosides GQ1b, DPPX, CASPR2, LGI1, as well as by antibodies against neuronal intracellular antigens. The paper presents a number of both mental and neurological symptoms of autoimmune encephalitis. Moreover, the coexistence of psychoses, neoplastic diseases, and the methods of diagnosing autoimmune encephalitis are discussed. Attention was also drawn to the fact that early diagnosis, as well as early initiation of targeted treatment, increases the chance of a successful course of the therapeutic process. Strategy and Methodology: The articles on which the following paper was based were searched using search engines such as PubMed and Medline. Considering that anti-NMDAR antibodies were first described in 2007, the articles were from 2007 to 2023. The selection of papers was made by entering the phrases "autoimmune encephalitis and psychosis/paraneplastic syndromes or cancer". The total number of articles that could be searched was 747, of which 100 items were selected, the most recent reports illustrating the presented topic. Thirty-four of them were rejected in connection with case reports or papers that could not be accessed. [ABSTRACT FROM AUTHOR]
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- 2023
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92. Innovative high-resolution microCT imaging of animal brain vasculature
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Petr Soukup, Johannes C. Schittny, Audrey Bouchet, Neda Haghayegh Jahromi, Ruslan Hlushchuk, Oleksiy-Zakhar Khoma, Valentin Djonov, Britta Engelhardt, David Haberthür, and Sébastien F. Barré
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Histology ,Materials science ,Computed Tomography Angiography ,Swine ,Dura mater ,Methods Paper ,Central nervous system ,610 Medicine & health ,Gliosarcoma ,Bone tissue ,03 medical and health sciences ,0302 clinical medicine ,Blood vessels ,Image Processing, Computer-Assisted ,medicine ,Animals ,Rats, Wistar ,030304 developmental biology ,0303 health sciences ,microCT ,microangioCT ,General Neuroscience ,Leptomeninges ,Brain ,X-Ray Microtomography ,Visualization of the vasculature ,Rats ,Mice, Inbred C57BL ,Skull ,medicine.anatomical_structure ,Swine, Miniature ,Angiogenesis ,Tomography ,Anatomy ,030217 neurology & neurosurgery ,Preclinical imaging ,Vertebral column ,Biomedical engineering - Abstract
Analysis of the angioarchitecture and quantification of the conduit vessels and microvasculature is of paramount importance for understanding the physiological and pathological processes within the central nervous system (CNS). Most of the available in vivo imaging methods lack penetration depth and/or resolution. Some ex vivo methods may provide better resolution, but are mainly destructive, as they are designed for imaging the CNS tissues after their removal from the skull or vertebral column. The removal procedure inevitably alters the in situ relations of the investigated structures and damages the dura mater and leptomeninges. µAngiofil, a polymer-based contrast agent, permits a qualitatively novel postmortem microangio-computed tomography (microangioCT) approach with excellent resolution and, therefore, visualization of the smallest brain capillaries. The datasets obtained empower a rather straightforward quantitative analysis of the vascular tree, including the microvasculature. The µAngiofil has an excellent filling capacity as well as a radio-opacity higher than the one of bone tissue, which allows imaging the cerebral microvasculature even within the intact skull or vertebral column. This permits in situ visualization and thus investigation of the dura mater and leptomeningeal layers as well as their blood supply in their original geometry. Moreover, the methodology introduced here permits correlative approaches, i.e., microangioCT followed by classical histology, immunohistochemistry and even electron microscopy. The experimental approach presented here makes use of common desktop microCT scanners, rendering it a promising everyday tool for the evaluation of the (micro)vasculature of the central nervous system in preclinical and basic research. Electronic supplementary material The online version of this article (10.1007/s00429-020-02158-8) contains supplementary material, which is available to authorized users.
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- 2020
93. Peripheral Blood S100B Levels in Autism Spectrum Disorder: A Systematic Review and Meta-Analysis
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Zhen Zheng, Peng Zheng, and Xiaobing Zou
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Male ,medicine.medical_specialty ,Adolescent ,Autism Spectrum Disorder ,Central nervous system ,S100 Calcium Binding Protein beta Subunit ,S100B ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Developmental and Educational Psychology ,medicine ,Humans ,Child ,030304 developmental biology ,Original Paper ,0303 health sciences ,medicine.disease ,Confidence interval ,Peripheral blood ,Meta-analysis ,Blood ,medicine.anatomical_structure ,Autism spectrum disorder ,Strictly standardized mean difference ,Child, Preschool ,Autism ,Biomarker (medicine) ,Female ,Psychology ,Biomarkers ,030217 neurology & neurosurgery - Abstract
The S100 calcium-binding protein beta subunit (S100B) protein, which mostly exists in the central nervous system, is commonly noted as a marker of neuronal damage. We conducted the first systematic review with meta-analysis to compare peripheral blood S100B levels in individuals with ASD with those in healthy controls. A systematic search was carried out for studies published before May 5, 2020. In total, this meta-analysis involved ten studies with 822 participants and 451 cases. The meta-analysis revealed that individuals with ASD had higher peripheral blood S100B levels than healthy controls [standardized mean difference (SMD) = 0.97, 95% confidence interval (95% CI) = 0.41–1.53; p
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- 2020
94. MSC-derived exosomes promote recovery from traumatic brain injury via microglia/macrophages in rat
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Yunfei Chen, Junji Wei, Robert Chunhua Zhao, Shihua Wang, Li Na, Chunling Xue, Baitao Ma, Qin Han, Jing Li, and Zhao Sun
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Aging ,Microglia ,Traumatic brain injury ,business.industry ,human adipose-derived mesenchymal stem cells ,traumatic brain injury ,Neurogenesis ,Mesenchymal stem cell ,Central nervous system ,microglia ,Inflammation ,Cell Biology ,exosomes ,medicine.disease ,neurogenesis ,medicine.anatomical_structure ,medicine ,Cancer research ,Macrophage ,medicine.symptom ,business ,Neuroinflammation ,Research Paper - Abstract
Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in young individuals worldwide. There is currently no effective clinical treatment for TBI, but mesenchymal stem cell-derived exosomes have exhibited promising therapeutic effects. In this study, we performed intracerebroventricular microinjection of human adipose mesenchymal stem cell (hADSC)-derived exosomes (hADSC-ex) in a weight-drop-induced TBI rat model. We found that hADSC-ex promoted functional recovery, suppressed neuroinflammation, reduced neuronal apoptosis, and increased neurogenesis in TBI rats. The therapeutic effects of hADSC-ex were comparable to those of hADSC. Sequential in vivo imaging revealed increasing aggregation of DiR-labeled hADSC-ex in the lesion area. Immunofluorescent staining of coronal brain sections and primary mixed neural cell cultures revealed distinct overlap between CM-DiI-labeled hADSC-ex and microglia/macrophages, indicating that hADSC-ex were mainly taken up by microglia/macrophages. In a lipopolysaccharide-induced inflammatory model, hADSC-ex suppressed microglia/macrophage activation by inhibiting nuclear factor κB and P38 mitogen-activated protein kinase signaling. These data suggest that hADSC-ex specifically enter microglia/macrophages and suppress their activation during brain injury, thereby inhibiting inflammation and facilitating functional recovery. They also offer new insight into the cellular targeting, uptake and migration of hADSC-ex, and provide a theoretical basis for new therapeutic strategies for central nervous system diseases.
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- 2020
95. Transient coating of γ-Fe2O3 nanoparticles with glutamate for its delivery to and removal from brain nerve terminals
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Daniel Horák, Michal Babic, Olga Vasylchenko, Konstantin Paliienko, Artem Pastukhov, and Tatiana Borisova
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Nervous system ,Central nervous system ,General Physics and Astronomy ,Nanoparticle ,02 engineering and technology ,lcsh:Chemical technology ,lcsh:Technology ,Full Research Paper ,03 medical and health sciences ,chemistry.chemical_compound ,Blood plasma ,medicine ,Nanotechnology ,lcsh:TP1-1185 ,General Materials Science ,Electrical and Electronic Engineering ,lcsh:Science ,030304 developmental biology ,HEPES ,0303 health sciences ,protein biocorona ,lcsh:T ,Chemistry ,Glutamate receptor ,Albumin ,brain nerve terminals ,maghemite (γ-Fe2O3) nanoparticles ,021001 nanoscience & nanotechnology ,lcsh:QC1-999 ,Cortex (botany) ,Nanoscience ,medicine.anatomical_structure ,glutamate biocoating ,Biophysics ,lcsh:Q ,0210 nano-technology ,lcsh:Physics ,blood plasma - Abstract
Glutamate is the main excitatory neurotransmitter in the central nervous system and excessive extracellular glutamate concentration is a characteristic feature of stroke, brain trauma, and epilepsy. Also, glutamate is a potential tumor growth factor. Using radiolabeled ʟ-[14C]glutamate and magnetic fields, we developed an approach for monitoring the biomolecular coating (biocoating) with glutamate of the surface of maghemite (γ-Fe2O3) nanoparticles. The nanoparticles decreased the initial rate of ʟ-[14C]glutamate uptake, and increased the ambient level of ʟ-[14C]glutamate in isolated cortex nerve terminals (synaptosomes). The nanoparticles exhibit a high capability to adsorb glutamate/ʟ-[14C]glutamate in water. Some components of the incubation medium of nerve terminals, that is, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) and NaH2PO4, decreased the ability of γ-Fe2O3 nanoparticles to form a glutamate biocoating by about 50% and 90%, respectively. Only 15% of the amount of glutamate biocoating obtained in water was obtained in blood plasma. Albumin did not prevent the formation of a glutamate biocoating. It was shown that the glutamate biocoating is a temporal dynamic structure at the surface of γ-Fe2O3 nanoparticles. Also, components of the nerve terminal incubation medium and physiological fluids responsible for the desorption of glutamate were identified. Glutamate-coated γ-Fe2O3 nanoparticles can be used for glutamate delivery to the nervous system or for glutamate adsorption (but with lower effectiveness) in stroke, brain trauma, epilepsy, and cancer treatment following by its subsequent removal using a magnetic field. γ-Fe2O3 nanoparticles with transient glutamate biocoating can be useful for multifunctional theranostics.
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- 2020
96. TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis
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Danilo Licastro, Melissa Manis, Bryan Bollman, Fabia Filipello, Michael E. Buckland, Laura Piccio, Carlos Cruchaga, David M. Holtzman, Kathie A. Mihindukulasuriya, Adiljan Ibrahim, Bruno A. Benitez, Francesca Cignarella, Robert Mikesell, Alberto Locca, Claudia Cantoni, Ilaria Tassi, Arnon Rosenthal, Oscar Harari, Li Deng, and Tina Schwabe
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Adult ,Male ,Multiple Sclerosis ,CNS demyelination ,Central nervous system ,Biology ,Pathology and Forensic Medicine ,Cellular and Molecular Neuroscience ,Myelin ,Mice ,Phagocytosis ,medicine ,Animals ,Humans ,Remyelination ,Receptors, Immunologic ,Myelin Sheath ,Aged ,Mice, Knockout ,Original Paper ,Membrane Glycoproteins ,Microglia ,TREM2 ,Multiple sclerosis ,Middle Aged ,medicine.disease ,Oligodendrocyte ,Cell biology ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,nervous system ,Female ,Neurology (clinical) - Abstract
Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS) triggered by autoimmune mechanisms. Microglia are critical for the clearance of myelin debris in areas of demyelination, a key step to allow remyelination. TREM2 is expressed by microglia and promotes microglial survival, proliferation, and phagocytic activity. Herein we demonstrate that TREM2 was highly expressed on myelin-laden phagocytes in active demyelinating lesions in the CNS of subjects with MS. In gene expression studies, macrophages from subjects with TREM2 genetic deficiency displayed a defect in phagocytic pathways. Treatment with a new TREM2 agonistic antibody promoted the clearance of myelin debris in the cuprizone model of CNS demyelination. Effects included enhancement of myelin uptake and degradation, resulting in accelerated myelin debris removal by microglia. Most importantly, antibody-dependent TREM2 activation on microglia increased density of oligodendrocyte precursors in areas of demyelination, as well as the formation of mature oligodendrocytes thus enhancing remyelination and axonal integrity. These results are relevant as they propose TREM2 on microglia as a potential new target to promote remyelination. Electronic supplementary material The online version of this article (10.1007/s00401-020-02193-z) contains supplementary material, which is available to authorized users.
- Published
- 2020
97. Contractile apparatus in CNS capillary pericytes
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Şefik E. Erdener, Gülce Küreli, and Turgay Dalkara
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Paper ,Radiological and Ultrasound Technology ,pericyte ,Special Section on Imaging Neuroimmune, Neuroglial, and Neurovascular Interfaces (Part I) ,Neuroscience (miscellaneous) ,blood flow ,Radiology, Nuclear Medicine and imaging ,macromolecular substances ,central nervous system ,actin ,contractility ,capillary - Abstract
Significance: Whether or not capillary pericytes contribute to blood flow regulation in the brain and retina has long been debated. This was partly caused by failure of detecting the contractile protein α-smooth muscle actin (α-SMA) in capillary pericytes. Aim: The aim of this review is to summarize recent developments in detecting α-SMA and contractility in capillary pericytes and the relevant literature on the biology of actin filaments. Results: Evidence suggests that for visualization of the small amounts of α-SMA in downstream mid-capillary pericytes, actin depolymerization must be prevented during tissue processing. Actin filaments turnover is mainly based on de/re-polymerization rather than transcription of the monomeric form, hence, small amounts of α-SMA mRNA may evade detection by transcriptomic studies. Similarly, transgenic mice expressing fluorescent reporters under the α-SMA promoter may yield low fluorescence due to limited transcriptional activity in mid-capillary pericytes. Recent studies show that pericytes including mid-capillary ones express several actin isoforms and myosin heavy chain type 11, the partner of α-SMA in mediating contraction. Emerging evidence also suggests that actin polymerization in pericytes may have a role in regulating the tone of downstream capillaries. Conclusions: With guidance of actin biology, innovative labeling and imaging techniques can reveal the molecular machinery of contraction in pericytes.
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- 2022
98. Central nervous system monoaminergic activity in hip osteoarthritis patients with disabling pain: associations with pain severity and central sensitization
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Martin F. Bjurström, Kaj Blennow, Henrik Zetterberg, Mikael Bodelsson, Markus Waldén, Nicholas Dietz, Sara Hall, Oskar Hansson, Michael R. Irwin, and Niklas Mattsson-Carlgren
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Monoamines ,Aging ,Arthritis ,Pain Research ,Neurosciences ,Pain ,Central sensitization ,Cerebrospinal fluid ,Anesthesiology ,Central nervous system ,Clinical Research ,Musculoskeletal ,Osteoarthritis ,Neurological ,RD78.3-87.3 ,Chronic Pain ,Research Paper - Abstract
In patients with osteoarthritis undergoing total hip arthroplasty, higher cerebrospinal fluid concentrations of serotonin and dopamine metabolites are associated with increased pain severity and central sensitization., Introduction: Monoaminergic activity modulates nociceptive transmission in the central nervous system (CNS). Although pain is the most disabling symptom of osteoarthritis (OA), limited knowledge exists regarding the CNS mechanisms that amplify pain and drive sensitization processes in humans. Objectives: The main objective of this study was to evaluate associations between cerebrospinal fluid (CSF) monoamine metabolites, pain severity, and central sensitization in patients with OA undergoing total hip arthroplasty (THA). Methods: Patients with OA (n = 52) and pain-free controls (n = 30) provided CSF samples for measurement of serotonin (5-hydroxyindoleacetic acid [5-HIAA]), noradrenaline (3-methoxy-4-hydroxyphenylglycol [HMPG]), and dopamine (homovanillic acid [HVA]) monoamine metabolites. Patients with OA completed longitudinal evaluation of pain using clinical measures and quantitative sensory testing. Results: Patients with OA had higher HMPG levels when compared with controls (P = 0.036). Within patients with OA undergoing THA, higher 5-HIAA and HVA levels were consistently associated with higher preoperative pain severity. Higher concentrations of 5-HIAA and HVA were also associated with lower conditioned pain modulation levels, whereas higher HMPG levels were linked to more efficient conditioned pain modulation. Patients with higher levels of CSF HVA exhibited increased pressure pain sensitivity (arm pressure pain detection threshold < 250 kPa vs ≥ 250 kPa, P = 0.042). Higher preoperative levels of CSF 5-HIAA predicted poorer pain control 6 months postoperatively (brief pain inventory pain severity; adjusted β = 0.010, 95% CI 0.001–0.019). Conclusions: In OA patients with disabling pain, higher CSF levels of serotonin and dopamine metabolites are associated with increased pain severity and central sensitization. Increased noradrenergic activity may be associated with more efficient pain inhibitory capacity.
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- 2022
99. Chitotriosidase as a biomarker for gangliosidoses
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Sarah Kim, Chester B. Whitley, and Jeanine Jarnes
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medicine.medical_specialty ,Medicine (General) ,QH301-705.5 ,Mucopolysaccharidosis ,Central nervous system ,Inflammation ,Disease ,Gastroenterology ,Gangliosidoses ,Lysosomal diseases ,Endocrinology ,R5-920 ,Multiple sulfatase deficiency ,Internal medicine ,GM1-gangliosidosis ,Genetics ,medicine ,GM2-gangliosidosis ,Biology (General) ,Molecular Biology ,Chitotriosidase ,Surrogate endpoint ,business.industry ,medicine.disease ,medicine.anatomical_structure ,Gaucher ,Biomarker (medicine) ,medicine.symptom ,business ,Research Paper - Abstract
Elevated serum chitotriosidase (CHITO) is an indication of macrophage activation, and its capacity have been explored as a marker of inflammation in a number of disease states. For over a decade, CHITO plasma levels have been used by clinicians as a biomarker of inflammation in the lysosomal disease, Gaucher disease, including monitoring response to therapies in patients with Gaucher disease type I. Although it is becoming increasingly recognized that inflammation is a prominent component of many lysosomal diseases, the relation of CHITO levels to disease burden has not been well-characterized in the large majority of lysosomal diseases. Moreover, the role of CHITO in lysosomal diseases that affect the central nervous system (CNS) has not been systematically studied. In this study, one hundred and thirty-four specimens of CSF and serum were collected from 34 patients with lysosomal diseases affecting the CNS. This study included patients with GM1-gangliosidosis, GM2-gangliosidosis, mucopolysaccharidoses (MPS), multiple sulfatase deficiency and Gaucher disease. CHITO levels in the CSF were significantly higher in patients with more rapidly progressing severe neurological impairment: GM1-gangliosidosis vs MPS (p
- Published
- 2021
100. Paper strip electrophoresis of cerebrospinal fluid proteins in cysticercosis of the central nervous system
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Antonio Spina-França
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Pathology ,medicine.medical_specialty ,Globulin ,biology ,Central nervous system ,Albumin ,Cysticercosis ,Complement fixation test ,medicine.disease ,lcsh:RC321-571 ,medicine.anatomical_structure ,Cerebrospinal fluid ,Neurology ,Cytology ,Immunology ,medicine ,biology.protein ,Neurology (clinical) ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,CSF albumin - Abstract
In order to analyse the paper strip electrophoresis contribution to the knowledge of cerebrospinal fluid (CSF) proteins in cysticercosis of the central nervous system (CNS) 40 patients were studied (identification data in table 1); the clinical forms and diagnostic data of 30 of them, who had CNS cysticercosis (cases 1 to 30) are summarized in the table 2; cysticercosis of the CNS might play a role in the pathologic condition presented by the remaining 10 patients. CSF protein fractions were examined in all the cases (results in tables 4 and 7) and those of blood sera in cases from 1 to 15 (results in table 5) by paper strip electrophoresis under the specifications previously reported54. A second examination of CSF protein fractions was made some time later in 4 cases (results in table 6). CSF samples were analysed also in respect to cytology, total protein content, Pandy and colloidal benzoin reactions and complement fixation tests for syphillis and cysticercosis (results in table 3). The values obtained for CSF protein fractions were compared to norma) values found in 30 control subjects; these normal values were detailed in a prior publication55 and are summarized in table 8. This comparison shows that CNS cysticercosis produces changes in the electrophoretic prophiJe of CSF proteins (table 9); an increased y-globulin fraction was the main change observed, commonly associated to a low j8-globulin relative concentration. An inversion of a1/a2 quocient was found in 4 cases. The contributions to the study of CNS cysticercosis resulting from the electrophoretic analysis of CSF proteins are discussed in three groups: 1 - Informations obtained by paper electrophoresis of CSF proteins are independent from those resulting from the other laboratory aspects studied. Thus, if the protein fractions of blood sera are considered, although the changes found have mean values similar to those found to the CSF protein fractions (table 10), it was observed that there are individual differences in the protein fraction relative concentrations in blood and CSF (table 11), no correlation being found between them. Considering CSF itself, changes in its protein fractions induced by CNS cysticercosis are similar in ventricular and subarachnoid samples (lumbal and cisternal) (table 13); their intensity is related to the intensity of the whole of CSF changes (table 12). Informations obtained by electrophoretic analysis of CSF proteins, however, differ from those resulting from the other examinations conducted in the CSF sample as was shown in the analysis of cytology (tables 14 and 15), total protein content (table 16), colloidal benzoin reaction and positivity of complement fixation test for cysticercosis. 2 - The clinical value of data achieved by CSF proteins electrophoresis is discussed. Results may have an important role in diagnosis, in the knowledge of its clinical forms (table 17) and in the control of evolution if pathogenetic mechanisms involved in disease are considered. Cases 31 to 40 illustrate the clinical aspects of contributions given by CSF electrophoresis. 3 - The CSF protein fractions changes found in CNS cysticercosis justify their classification among those changes commonly observed in subchronic and chronic inflammatory diseases of the CNS and/or its leptomeningeal coverings. It is assumed in the literature that there occurs a local production of globulins, specially the y-globulin fraction, in such pathologic conditions. Concerning CNS cysticercosis, if CSF total protein content and electrophoretic data on its fractions are considered together (table IS and 19; graph. 1), it is possible to evidence that at least two mechanisms participate in the origin of protein changes (tables 20 and 21; graph. 2) : blood-CSF barrier disturbances are able to explain data concerning albumin, a and globulin changes, which are similar; the local production of y-globulin is the hypothesis most reliable to explain the peculiar changes of this fraction. This hypothesis agrees with literature data concerning other chronie inflammatory diseases of the CNS. The probable role of y-globulin in carrying specific antibodies is pointed out through correlative exploration of its concentration in the CSF sample and the corresponding positivity of complement fixation test for cysticercosis.
- Published
- 1960
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