关键词： Animal models   Rare paediatric diseases   Orphan medicines designations   Neurologic diseases   Aicardi-Goutieres syndrome   Centronuclear myopathy  

摘要： Rare diseases are characterized by a substantial unmet need mostly because the majority have limited, or no treatment options and a large number also affect children. Appropriate animal models, based on the knowledge of the molecular pathology of the human disease, are a significant element to support the medical plausibility of an orphan designation during the development of orphan medicines for rare neurological diseases. This observational, retrospective study aims to investigate the clinical or nonclinical nature of data submitted to support medical plausibility of orphan designations in the EU (2001-2019), for a group of rare and paediatric neurological diseases. From our sample of 30 diseases, 70% are rare with paediatric onset and 37% have approved orphan designations. The use of nonclinical data was significantly higher than clinical data (65% vs. 35%, p = 0.013) to support medical plausibility. Examples of diseases, with orphan designations based only in nonclinical data, are also discussed: Aicardi-Goutie`res syndrome and Centronuclear myopathy animal disease models, potentially used to support medical plausibility of medicines. Nonclinical appropriate models, assessing disease relevant endpoints, may contribute to increase the translational value of animal models, in paediatric and rare neurological area, to accelerate research and the effective development of treatment options.

关键词： C1q   Acute Ischemic Stroke   Inflammation   National Institute of Health Stroke Scale  

摘要： Background: Inflammation occurs after acute ischemic stroke (AIS), and complement C1q is involved in inflammation. However, studies about the association of complement C1q with AIS are still rare. The aim of our study is to investigate the relationship between serum C1q concentration and the clinical severity of AIS. Methods: A total of 1294 patients were enrolled in our study, including 647 patients with AIS and 647 non-stroke controls. The infarction volume of AIS was assessed by the diameter of maximum transverse section (DMTS) based on diffusion-weighted imaging (DWI) of brain magnetic resonance imaging. Neurological impairment was assessed by the National Institute of Health Stroke Scale (NIHSS). The association of serum C1q levels with DMTS or NIHSS was investigated by Pearson's or Spearman's correlation analysis. Results: Serum C1q levels of patients with AIS were significantly higher than those of individuals without AIS. Serum levels of C1q were associated with DMTS (r=0.511, p<0.001) and NIHSS (r=0.433, p<0.001) among patients with AIS. Conclusion: Serum C1q concentration was positively associated with DMTS and NIHSS of patients with AIS.

关键词： AChE activity   apple cider vinegar (ACV)   HFD   Neuro2A cells   oxidative stress markers   streptozotocin (STZ)  

摘要： Dementia linked with cognitive impairments is the most prominent indication of Alzheimer's disease (AD). In the current investigation, we have examined the streptozotocin- (STZ) induced cellular toxicity in mouse neuroblastoma (N2A) cells, and Zn with the high-fat diet- (HFD) induced neurotoxicity in mouse brain. These cells and animals were pretreated with apple cider vinegar (ACV), Chrysin, and Rivastigmine to examine their protection against cellular toxicity and neurotoxicity. Experiments have affirmed that pretreatment of ACV, Chrysin, and Rivastigmine has displayed protective outcomes in MTT reduction, tau phosphorylation, amyloid aggregation, attenuated memory impairment as well as oxidative stress, and protected cholinergic hippocampal neurons from degeneration. ACV showed better antioxidant and neuroprotection potential as compared with Chrysin and Rivastigmine. So the existence of excitatory/inhibitory enzymatic activity and higher antioxidant potential indicate that ACV, as a food beverage in a regular diet, could be promising and effective against neurological complications such as AD. Practical applications In the Urban lifestyle, HFD and stress are the critical factors of various chronic and prevalent diseases, including diabetes, obesity, cardiovascular, and neurodegenerative disorders like AD. We are already familiar with the multiple benefits of ACV, such as weight loss, antimicrobial activity, diabetes, skin disorders. So in the current research work, we have gauged the effectiveness of ACV against neurological complications in comparison with a synthetic flavonoid (Chrysin) and an anti-Alzheimer's drug (Rivastigmine). To enhance the pragmatic orientation of our results, we have used the ACV in our study, which is readily available in the market for domestic consumption. All the cellular, biochemical, behavioral, and histopathological data revealed that ACV had high antioxidant potential. Our findings suggest that the addition of ACV as a food addi

关键词： blood-brain barrier   COVID-19   neural invasion   neurological symptoms   SARS-CoV-2  

摘要： Manifestation of neurological symptoms in certain patients of coronavirus disease-2019 (COVID-19) has warranted for their virus-induced etiogenesis. SARS-CoV-2, the causative agent of COVID-19, belongs to the genus of betacoronaviruses which also includes SARS-CoV-1 and MERS-CoV;causative agents for severe acute respiratory syndrome (SARS) in 2002 and Middle East respiratory syndrome (MERS) in 2012, respectively. Studies demonstrating the neural invasion of SARS-CoV-2in vivoare still scarce, although such characteristics of certain other betacoronaviruses are well demonstrated in the literature. Based on the recent evidence for the presence of SARS-CoV-2 host cell entry receptors in specific components of the human nervous and vascular tissue, a neural (olfactory and/or vagal), and a hematogenous-crossing the blood-brain barrier, routes have been proposed. The neurological symptoms in COVID-19 may also arise as a consequence of the "cytokine storm" (characteristically present in severe disease) induced neuroinflammation, or co-morbidities. There is also a possibility that, there may be multiple routes of SARS-CoV-2 entry into the brain, or multiple mechanisms can be involved in the pathogenesis of the neurological symptoms. In this review article, we have discussed the possible routes of SARS-CoV-2 brain entry based on the emerging evidence for this virus, and that available for other betacoronaviruses in literature.

关键词： SARS-CoV-2   COVID-19   Angiotensin-converting enzyme 2   Comorbidities   Neurological manifestations  

摘要： First in 2002, severe acute respiratory syndrome coronavirus (SARS-CoV), second in 2012, Middle East respiratory syndrome coronavirus (MERS-CoV), and now the third in the December 2019, emergence of tremendously pathogenic and large-scale epidemic novel coronavirus (SARS-CoV-2) has brought the worst conditions into the human inhabitants of the twenty-first century. The SARS-CoV-2 uses the resembling receptor, angiotensin-converting enzyme 2 (ACE2) as that for SARS-CoV, and mainly feasts through the respiratory tract. The ACE2 receptor appearances have been also detected upon glial cells and neurons, which makes them a potential target of SARS-CoV-2 disease (COVID-19). Consequently, cells expressing ACE2, apart from lung and cardiovascular tissue, neurons and glial cells may act as targets and are thus vulnerable to SARS-CoV-2 systemic infection as well as its central nervous system (CNS) comorbidities. Investigation of the neurological manifestations of COVID-19 is a step towards better understanding the SARS-CoV-2 infections, inhibiting the additional spread and treating patients affected by this pandemic. In this concern, more clinical examinations for CNS involvement of SARS-CoV-2 are warranted. In this article, we have reviewed the neurological characteristic features of COVID-19 patients, latent neurotropic mechanisms of SARS-CoV-2 involvement in the comorbidity associated with CNS disorders, and neurological manifestations associated with COVID-19. Therefore, in the perspective of COVID-19 pandemic, clinicians and healthcare workers should be aware of a wide spectrum of neurological manifestations associated with COVID-19 along with their signs and symptoms for initial diagnosis and isolation of the patients.

摘要： [...]information on neurological prognostication is sparse, especially for persistently comatose V-A ECMO patients. [...]many comatose survivors after cardiac arrest may have delayed awakening [10]. [...]the study includes only six patients with extracorporeal cardiopulmonary resuscitation (ECPR) and the overall mortality was 52% at discharge. [...]the degree of sedation and its impact on EEG suppression and reactivity was not controlled, which is particularly important in V-A ECMO population where hepatic and renal dysfunctions are commonly observed.

关键词： AD   Alzheimer's disease   CNS   central nervous system   FMT   fecal microbiota transplantation   GF   germ-free   GI   gastrointestinal   GLUT   glucose transporter   HMP   human genome project   IFN   interferon   IL   interleukin   MGB   microbiota-gut-brain   PAMP   pathogen-associated molecular pattern   PRR   pattern-recognition receptor   SCFA   short-chain fatty acid   TJ   tight junction   TLR   toll-like receptor   TMAO   trimethylamine N-oxide   TNF-α   tumor necrosis factor-α   T reg   regulatory T cell  

摘要： The gut microbiota is a complex ecosystem of bacteria, fungi, and viruses that acts as a critical regulator in microbial, metabolic, and immune responses in the host organism. Imbalances in the gut microbiota, termed "dysbiosis," often induce aberrant immune responses, which in turn disrupt the local and systemic homeostasis of the host. Emerging evidence has highlighted the importance of gut microbiota in intestinal diseases, and more recently, in age-related central nervous systems diseases, for example, stroke and Alzheimer's disease. It is now generally recognized that gut microbiota significantly influences host behaviors and modulates the interaction between microbiota, gut, and brain, via the "microbiota-gut-brain axis." Several approaches have been utilized to reduce age-related dysbiosis in experimental models and in clinical studies. These include strategies to manipulate the microbiome via fecal microbiota transplantation, administration of prebiotics and probiotics, and dietary interventions. In this review, we explore both clinical and preclinical therapies for treating age-related dysbiosis.