Search results for: brain connectome

Authors: Jillian M. Hagel, Joseph E. Tucker, Peter J. Facchini

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With the aim of establishing a holistic approach for the treatment of central nervous system (CNS) disorders, we are pursuing a drug development program rapidly progressing through discovery and characterization phases. The drug candidates identified in this program are referred to as neuroplastogens owing to their ability to mediate neuroplasticity, which can be beneficial to patients suffering from anxiety, depression, or posttraumatic stress disorder. These and other related neuropsychiatric conditions are associated with the onset of neuronal atrophy, which is defined as a reduction in the number and/or productivity of neurons. The stimulation of neuroplasticity results in an increase in the connectivity between neurons and promotes the restoration of healthy brain function. We have synthesized a substantial catalogue of proprietary indolethylamine derivatives based on the general structures of serotonin (5-hydroxytryptamine) and psychedelic molecules such as N,N-dimethyltryptamine (DMT) and psilocin (4-hydroxy-DMT) that function as neuroplastogens. A primary objective in our screening protocol is the identification of derivatives associated with a significant reduction in hallucination, which will allow administration of the drug at a dose that induces neuroplasticity and triggers other efficacious outcomes in the treatment of targeted CNS disorders but which does not cause a psychedelic response in the patient. Both neuroplasticity and hallucination are associated with engagement of the 5HT2A receptor, requiring drug candidates differentially coupled to these two outcomes at a molecular level. We use novel and proprietary artificial intelligence algorithms to predict the mode of binding to the 5HT2A receptor, which has been shown to correlate with the hallucinogenic response. Hallucination is tested using the mouse head-twitch response model, whereas mouse marble-burying and sucrose preference assays are used to evaluate anxiolytic and anti-depressive potential. Neuroplasticity is assays using dendritic outgrowth assays and cell-based ELISA analysis. Pharmacokinetics and additional receptor-binding analyses also contribute the selection of lead candidates. A summary of the program is presented.

Keywords: neuroplastogen, non-hallucinogenic, drug development, anxiety, depression, PTSD, indolethylamine derivatives, psychedelic-inspired, 5-HT2A receptor, computational chemistry, head-twitch response behavioural model, neurite outgrowth assay

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Authors: Bao Li, Aike Qiao, Gaoyang Li, Youjun Liu

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Background: Lumped parameter model (LPM) is a common numerical model for hemodynamic calculation. LPM uses circuit elements to simulate the human blood circulatory system. Physiological indicators and characteristics can be acquired through the model. However, due to the different physiological indicators of each individual, parameters in LPM should be personalized in order for convincing calculated results, which can reflect the individual physiological information. This study aimed to develop an automatic and effective optimization method to personalize the parameters in LPM of the blood circulatory system, which is of great significance to the numerical simulation of individual hemodynamics. Methods: A closed-loop LPM of the human blood circulatory system that is applicable for most persons were established based on the anatomical structures and physiological parameters. The patient-specific physiological data of 5 volunteers were non-invasively collected as personalized objectives of individual LPM. In this study, the blood pressure and flow rate of heart, brain, and limbs were the main concerns. The collected systolic blood pressure, diastolic blood pressure, cardiac output, and heart rate were set as objective data, and the waveforms of carotid artery flow and ankle pressure were set as objective waveforms. Aiming at the collected data and waveforms, sensitivity analysis of each parameter in LPM was conducted to determine the sensitive parameters that have an obvious influence on the objectives. Simulated annealing was adopted to iteratively optimize the sensitive parameters, and the objective function during optimization was the root mean square error between the collected waveforms and data and simulated waveforms and data. Each parameter in LPM was optimized 500 times. Results: In this study, the sensitive parameters in LPM were optimized according to the collected data of 5 individuals. Results show a slight error between collected and simulated data. The average relative root mean square error of all optimization objectives of 5 samples were 2.21%, 3.59%, 4.75%, 4.24%, and 3.56%, respectively. Conclusions: Slight error demonstrated good effects of optimization. The individual modeling algorithm developed in this study can effectively achieve the individualization of LPM for the blood circulatory system. LPM with individual parameters can output the individual physiological indicators after optimization, which are applicable for the numerical simulation of patient-specific hemodynamics.

Keywords: blood circulatory system, individual physiological indicators, lumped parameter model, optimization algorithm

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Authors: Cathal Merz, Gareth O’Donnell

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Coil reinforced thin-walled (CRTW) tubes are used in medicine to treat problems affecting blood vessels within the body through minimally invasive procedures. The CRTW tube considered in this research makes up part of such a device and is inserted into the patient via their femoral or brachial arteries and manually navigated to the site in need of treatment. This procedure replaces the requirement to perform open surgery but is limited by reduction of blood vessel lumen diameter and increase in tortuosity of blood vessels deep in the brain. In order to maximize the capability of these procedures, CRTW tube devices are being manufactured with decreasing wall thicknesses in order to deliver treatment deeper into the body and to allow passage of other devices through its inner diameter. This introduces significant stresses to the device materials which have resulted in an observed increase in the breaking of the proximal segment of the device into two separate pieces after it has failed by buckling. As there is currently no international standard for measuring the mechanical properties of these CRTW tube devices, it is difficult to accurately analyze this problem. The aim of the current work is to address this discrepancy in the biomedical device industry by developing a measurement system that can be used to quantify the effect of process and design changes on CRTW tube performance, aiding in the development of better performing, next generation devices. Using materials testing frames, micro-computed tomography (micro-CT) imaging, experiment planning, analysis of variance (ANOVA), T-tests and regression analysis, test methods have been developed for assessing the impact of process and design changes on the device. The major findings of this study have been an insight into the suitability of buckle and three-point bend tests for the measurement of the effect of varying processing factors on the device’s performance, and guidelines for interpreting the output data from the test methods. The findings of this study are of significant interest with respect to verifying and validating key process and design changes associated with the device structure and material condition. Test method integrity evaluation is explored throughout.

Keywords: neurovascular catheter, coil reinforced tube, buckling, three-point bend, tensile

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Authors: Rema Vazhappilly, Tapas Das

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Oleic acid is a cis unsaturated fatty acid and is known to be a partially essential fatty acid due to its limited endogenous synthesis during pregnancy and lactation. Previous studies have demonstrated the role of oleic acid in neuronal differentiation and brain phospholipid synthesis. These evidences indicate a major role for oleic acid in learning and memory. Interestingly, oleic acid has been shown to enhance hippocampal long term potentiation (LTP), the physiological correlate of long term synaptic plasticity. However the effect of oleic acid on short term synaptic plasticity has not been investigated. Short term potentiation (STP) is the physiological correlate of short term synaptic plasticity which is the key underlying molecular mechanism of short term memory and neuronal information processing. STP in the hippocampal CA1 region has been known to require the activation of N-methyl-D-aspartate receptors (NMDARs). The NMDAR dependent hippocampal STP as a potential mechanism for short term memory has been a subject of intense interest for the past few years. Therefore in the present study the effect of oleic acid on NMDAR dependent hippocampal STP was determined in mouse hippocampal slices (in vitro) using Multi-electrode array system. STP was induced by weak tetanic Stimulation (one train of 100 Hz stimulations for 0.1s) of the Schaffer collaterals of CA1 region of the hippocampus in slices treated with different concentrations of oleic acid in presence or absence of NMDAR antagonist D-AP5 (30 µM) . Oleic acid at 20 (mean increase in fEPSP amplitude = ~135 % Vs. Control = 100%; P<0.001) and 30 µM (mean increase in fEPSP amplitude = ~ 280% Vs. Control = 100%); P<0.001) significantly enhanced the STP following weak tetanic stimulation. Lower oleic acid concentrations at 10 µM did not modify the hippocampal STP induced by weak tetanic stimulation. The hippocampal STP induced by weak tetanic stimulation was completely blocked by the NMDA receptor antagonist D-AP5 (30µM) in both oleic acid and control treated hippocampal slices. This lead to the conclusion that the hippocampal STP elicited by weak tetanic stimulation and enhanced by oleic acid was NMDAR dependent. Together these findings suggest that oleic acid may enhance the short term memory and neuronal information processing through the modulation of NMDAR dependent hippocampal short-term synaptic plasticity. In conclusion this study suggests the possible role of oleic acid to prevent the short term memory loss and impaired neuronal function throughout development.

Keywords: oleic acid, short-term potentiation, memory, field excitatory post synaptic potentials, NMDA receptor

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Authors: Krisztina Bohacs, Klaudia Markus

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To author’s best knowledge we are in absence of studies on cognitive program evaluation and we are certainly short of programs that prove to have high effect sizes with strong retention results. The purpose of our study was to investigate the effectiveness of a comprehensive cognitive training program, namely BrainRx. This cognitive rehabilitation program target and remediate seven core cognitive skills and related systems of sub-skills through repeated engagement in game-like mental procedures delivered one-on-one by a clinician, supplemented by digital training. A larger sample of children with learning disability were given pretest and post-test cognitive assessments. The experimental group completed a twenty-week cognitive training program in a BrainRx center. A matched control group received another twenty-week intervention with Feuerstein’s Instrumental Enrichment programs. A second matched control group did not receive training. As for pre- and post-test, we used a general intelligence test to assess IQ and a computer-based test battery for assessing cognition across the lifespan. Multiple regression analyses indicated that the experimental BrainRx treatment group had statistically significant higher outcomes in attention, working memory, processing speed, logic and reasoning, auditory processing, visual processing and long-term memory compared to the non-treatment control group with very large effect sizes. With the exception of logic and reasoning, the BrainRx treatment group realized significantly greater gains in six of the above given seven cognitive measures compared to the Feuerstein control group. Our one-year retention measures showed that all the cognitive training gains were above ninety percent with the greatest retention skills in visual processing, auditory processing, logic, and reasoning. The BrainRx program may be an effective tool to establish long-term cognitive changes in case of students with learning disabilities. Recommendations are made for treatment centers and special education institutions on the cognitive training of students with special needs. The importance of our study is that targeted, systematic, progressively loaded and intensive brain training approach may significantly change learning disabilities.

Keywords: cognitive rehabilitation training, cognitive skills, learning disability, permanent structural cognitive changes

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Authors: M. M. Essa, S. Subash, M. Akbar, S. Al-Adawi, A. Al-Asmi, G. J. Guillemein

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Objective: Transgenic (tg) mice which contain an amyloid precursor protein (APP) gene mutation, develop extracellular amyloid beta (Aβ) deposition in the brain, and severe memory and behavioural deficits with age. These mice serve as an important animal model for testing the efficacy of novel drug candidates for the treatment and management of symptoms of Alzheimer's disease (AD). Several reports have suggested that oxidative stress is the underlying cause of Aβ neurotoxicity in AD. Pomegranates contain very high levels of antioxidants and several medicinal properties that may be useful for improving the quality of life in AD patients. In this study, we investigated the effect of dietary supplementation of Omani pomegranate extract on the memory, anxiety and learning skills along with inflammation in an AD mouse model containing the double Swedish APP mutation (APPsw/Tg2576). Methods: The experimental groups of APP-transgenic mice from the age of 4 months were fed custom-mix diets (pellets) containing 4% pomegranate. We assessed spatial memory and learning ability, psychomotor coordination, and anxiety-related behavior in Tg and wild-type mice at the age of 4-5 months and 18-19 months using the Morris water maze test, rota rod test, elevated plus maze test, and open field test. Further, inflammatory parameters also analysed. Results: APPsw/Tg2576 mice that were fed a standard chow diet without pomegranates showed significant memory deficits, increased anxiety-related behavior, and severe impairment in spatial learning ability, position discrimination learning ability and motor coordination along with increased inflammation compared to the wild type mice on the same diet, at the age of 18-19 months In contrast, APPsw/Tg2576 mice that were fed a diet containing 4% pomegranates showed a significant improvements in memory, learning, locomotor function, and anxiety with reduced inflammatory markers compared to APPsw/Tg2576 mice fed the standard chow diet. Conclusion: Our results suggest that dietary supplementation with pomegranates may slow the progression of cognitive and behavioural impairments in AD. The exact mechanism is still unclear and further extensive research needed.

Keywords: Alzheimer's disease, pomegranates, oman, cognitive decline, memory loss, anxiety, inflammation

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Authors: Syed Asif Hassan, Tabrej Khan

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Multiple sclerosis (MS) is a chronic demyelinating autoimmune disorder, of the central nervous system (CNS). In the present scenario, the current therapies either do not halt the progression of the disease or have side effects which limit the usage of current Disease Modifying Therapies (DMTs) for a longer period of time. Therefore, keeping the current treatment failure schema, we are focusing on screening novel analogues of the available DMTs that specifically bind and inhibit the Sphingosine1-phosphate receptor1 (S1PR1) thereby hindering the lymphocyte propagation toward CNS. The novel drug-like analogs molecule will decrease the frequency of relapses (recurrence of the symptoms associated with MS) with higher efficacy and lower toxicity to human system. In this study, an integrated approach involving ligand-based virtual screening protocol (Ultrafast Shape Recognition with CREDO Atom Types (USRCAT)) to identify the non-toxic drug like analogs of the approved DMTs were employed. The potency of the drug-like analog molecules to cross the Blood Brain Barrier (BBB) was estimated. Besides, molecular docking and simulation using Auto Dock Vina 1.1.2 and GOLD 3.01 were performed using the X-ray crystal structure of Mtb LprG protein to calculate the affinity and specificity of the analogs with the given LprG protein. The docking results were further confirmed by DSX (DrugScore eXtented), a robust program to evaluate the binding energy of ligands bound to the ligand binding domain of the Mtb LprG lipoprotein. The ligand, which has a higher hypothetical affinity, also has greater negative value. Further, the non-specific ligands were screened out using the structural filter proposed by Baell and Holloway. Based on the USRCAT, Lipinski’s values, toxicity and BBB analysis, the drug-like analogs of fingolimod and BG-12 showed that RTL and CHEMBL1771640, respectively are non-toxic and permeable to BBB. The successful docking and DSX analysis showed that RTL and CHEMBL1771640 could bind to the binding pocket of S1PR1 receptor protein of human with greater affinity than as compared to their parent compound (Fingolimod). In this study, we also found that all the drug-like analogs of the standard MS drugs passed the Bell and Holloway filter.

Keywords: antagonist, binding affinity, chemotherapeutics, drug-like, multiple sclerosis, S1PR1 receptor protein

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Authors: Lalita Subedi, Jae Kyoung Chae, Yong Un Park, Cho Kyo Hee, Lee Jae Hyuk, Kang Min Cheol, Sun Yeou Kim

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Neuroinflammation may mediate the relationship between low levels of estrogens and neurodegenerative disease. Estrogens are neuroprotective and anti-inflammatory in neurodegenerative disease models. Due to the long term side effects of estrogens, researches have been focused on finding an effective phytoestrogens for biological activities. Daidzein present in soybeans and its active metabolite equol (7-hydroxy-3-(4'-hydroxyphenyl)-chroman) bears strong antioxidant and anticancer showed more potent anti-inflammatory and neuroprotective role in neuroinflammatory model confirmed its in vitro activity with molecular mechanism through NF-κB pathway. Three major CNS cells Microglia (BV-2), Astrocyte (C6), Neuron (N2a) were used to find the effect of equol in inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), MAPKs signaling proteins, apoptosis related proteins by western blot analysis. Nitric oxide (NO) and prostaglandin E2 (PGE2) was measured by the Gries method and ELISA, respectively. Cytokines like tumor necrosis factor-α (TNF-α) and IL-6 were also measured in the conditioned medium of LPS activated cells with or without equol. Equol inhibited the NO production, PGE-2 production and expression of COX-2 and iNOS in LPS-stimulated microglial cells at a dose dependent without any cellular toxicity. At the same time Equol also showed promising effect in modulation of MAPK’s and nuclear factor kappa B (NF-κB) expression with significant inhibition of the production of proinflammatory cytokine like interleukin -6 (IL-6), and tumor necrosis factor -α (TNF-α). Additionally, it inhibited the LPS activated microglia-induced neuronal cell death by downregulating the apoptotic phenomenon in neuronal cells. Furthermore, equol increases the production of neurotrophins like NGF and increase the neurite outgrowth as well. In conclusion the natural daidzein metabolite equol are more active than daidzein, which showed a promising effectiveness as an anti-neuroinflammatory and neuroprotective agent via downregulating the LPS stimulated microglial activation and neuronal apoptosis. This work was supported by Brain Korea 21 Plus project and High Value-added Food Technology Development Program 114006-4, Ministry of Agriculture, Food and Rural Affairs.

Keywords: apoptosis, equol, neuroinflammation, phytoestrogen

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Authors: Felicia N. Obialo, Aliza Wingo, Thomas Wingo

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Psychosocial factors such as personality traits and social networks influence cognitive aging and dementia outcomes both positively and negatively. The inherent complexity of these factors makes defining the underlying mechanisms of their influence difficult; however, exploring their interactions affords promise in the field of cognitive aging. The objective of this study was to elucidate some of these interactions by determining the relationship between social network size and dementia outcomes and by determining whether personality traits mediate this relationship. The longitudinal Alzheimer’s Disease (AD) database provided by Rush University’s Religious Orders Study/Memory and Aging Project was utilized to perform retrospective regression and mediation analyses on 3,591 participants. Participants who were cognitively impaired at baseline were excluded, and analyses were adjusted for age, sex, common chronic diseases, and vascular risk factors. Dementia outcome measures included cognitive trajectory, clinical dementia diagnosis, and postmortem beta-amyloid plaque (AB), and neurofibrillary tangle (NT) accumulation. Personality traits included agreeableness (A), conscientiousness (C), extraversion (E), neuroticism (N), and openness (O). The results show a positive correlation between social network size and cognitive trajectory (p-value = 0.004) and a negative relationship between social network size and odds of dementia diagnosis (p = 0.024/ Odds Ratio (OR) = 0.974). Only neuroticism mediates the positive relationship between social network size and cognitive trajectory (p < 2e-16). Agreeableness, extraversion, and neuroticism all mediate the negative relationship between social network size and dementia diagnosis (p=0.098, p=0.054, and p < 2e-16, respectively). All personality traits are independently associated with dementia diagnosis (A: p = 0.016/ OR = 0.959; C: p = 0.000007/ OR = 0.945; E: p = 0.028/ OR = 0.961; N: p = 0.000019/ OR = 1.036; O: p = 0.027/ OR = 0.972). Only conscientiousness and neuroticism are associated with postmortem AD pathologies; specifically, conscientiousness is negatively associated (AB: p = 0.001, NT: p = 0.025) and neuroticism is positively associated with pathologies (AB: p = 0.002, NT: p = 0.002). These results support the study’s objectives, demonstrating that social network size and personality traits are strongly associated with dementia outcomes, particularly the odds of receiving a clinical diagnosis of dementia. Personality traits interact significantly and beneficially with social network size to influence the cognitive trajectory and future dementia diagnosis. These results reinforce previous literature linking social network size to dementia risk and provide novel insight into the differential roles of individual personality traits in cognitive protection.

Keywords: Alzheimer’s disease, cognitive trajectory, personality traits, social network size

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Authors: Rosa S. Wong, Keith T.S. Tung, H.W. Tsang, Frederick K. Ho, Patrick Ip

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Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention and hyperactive-impulsive behavior. Evidence shows that ADHD and mood problems such as depression and anxiety often co-occur and yet not everyone with ADHD reported elevated emotional problems. Given that cholesterol is essential for healthy brain development including the regions governing emotion regulation, reports found lower cholesterol levels in patients with major depressive disorder and those with suicide attempt behavior compared to healthy subjects. This study explored whether ADHD adolescents experienced more emotional problems and whether emotional problems correlated with cholesterol levels in these adolescents. This study used a portion of data from the longitudinal cohort study which was designed to investigate the long-term impact of family socioeconomic status on child development. In 2018/19, parents of 300 adolescents (average age: 12.57+/-0.49 years) were asked to rate their children’s emotional problems and report whether their children had doctor-diagnosed psychiatric diseases. We further collected blood samples from 263 children to study their lipid profile (total cholesterol, high-density lipoprotein (HDL)-cholesterol, and low-density lipoprotein (LDL)-cholesterol). Regression analyses were performed to test the relationships between variables of interest. Among 300 children, 27 (9%) had ADHD diagnosis. Analysis based on overall sample found no association between ADHD and emotional problems, but when investigating the relationship by gender, there was a significant interaction effect of ADHD and gender on emotional problems (p=0.037), with ADHD males displaying more emotional problems than ADHD females. Further analyses based on 263 children (21 with ADHD diagnosis) found significant interaction effect of ADHD and gender on total cholesterol (p=0.038) and low LDL-cholesterol levels (p=0.013) after adjusting for the child’s physical disease history. Specifically, ADHD males had significantly lower total cholesterol and low lipoprotein-cholesterol levels than ADHD females. In ADHD males, more emotional problems were associated with lower LDL-cholesterol levels (B = -4.26, 95%CI (-7.46, -1.07), p=0.013). We found preliminary support for the association between more emotional problems and lower cholesterol levels in ADHD children, especially among males. Although larger prospective studies are needed to substantiate these claims, the evidence highlights the importance of healthy lifestyle to keep cholesterol levels in normal range which can have positive effects on physical and mental health.

Keywords: attention-deficit hyperactivity disorder, cholesterol, emotional problems, adolescents

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Authors: Angelis P. Barlampas

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Objective: The confusion of terms is a common practice in many situations of the everyday life. But, in some circumstances, such as in medicine, the precise meaning of a word curries a critical role for the health of the patient. Fahr disease and Fahr syndrome are often falsely used interchangeably, but they are two different conditions with different physical histories of different etiology and different medical management. A case of the seldom Fahr disease is presented, and a comparison with the more common Fahr syndrome follows. Materials and method: A 72 years old patient came to the emergency department, complaining of some kind of non specific medal disturbances, like anxiety, difficulty of concentrating, and tremor. The problems had a long course, but he had the impression of getting worse lately, so he decided to check them. Past history and laboratory tests were unremarkable. Then, a computed tomography examination was ordered. Results: The CT exam showed bilateral, hyperattenuating areas of heavy, dense calcium type deposits in basal ganglia, striatum, pallidum, thalami, the dentate nucleus, and the cerebral white matter of frontal, parietal and iniac lobes, as well as small areas of the pons. Taking into account the absence of any known preexisting illness and the fact that the emergency laboratory tests were without findings, a hypothesis of the rare Fahr disease was supposed. The suspicion was confirmed with further, more specific tests, which showed the lack of any other conditions which could probably share the same radiological image. Differentiating between Fahr disease and Fahr syndrome. Fahr disease: Primarily autosomal dominant Symmetrical and bilateral intracranial calcifications The patient is healthy until the middle age Absence of biochemical abnormalities. Family history consistent with autosomal dominant Fahr syndrome :Earlier between 30 to 40 years old. Symmetrical and bilateral intracranial calcifications Endocrinopathies: Idiopathic hypoparathyroidism, secondary hypoparathyroidism, hyperparathyroidism, pseudohypoparathyroidism ,pseudopseudohypoparathyroidism, e.t.c The disease appears at any age There are abnormal laboratory or imaging findings. Conclusion: Fahr disease and Fahr syndrome are not the same illness, although this is not well known to the inexperienced doctors. As clinical radiologists, we have to inform our colleagues that a radiological image, along with the patient's history, probably implies a rare condition and not something more usual and prompt the investigation to the right route. In our case, a genetic test could be done earlier and reveal the problem, and thus avoiding unnecessary and specific tests which cost in time and are uncomfortable to the patient.

Keywords: fahr disease, fahr syndrome, CT, brain calcifications

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Authors: Fikret Yalcinkaya, Hamza Unsal

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To understand how neurons work, it is required to combine experimental studies on neural science with numerical simulations of neuron models in a computer environment. In this regard, the simplicity and applicability of spiking neuron modeling functions have been of great interest in computational neuron science and numerical neuroscience in recent years. Spiking neuron models can be classified by exhibiting various neuronal behaviors, such as spiking and bursting. These classifications are important for researchers working on theoretical neuroscience. In this paper, three different spiking neuron models; Izhikevich, Adaptive Exponential Integrate Fire (AEIF) and Hindmarsh Rose (HR), which are based on first order differential equations, are discussed and compared. First, the physical meanings, derivatives, and differential equations of each model are provided and simulated in the Matlab environment. Then, by selecting appropriate parameters, the models were visually examined in the Matlab environment and it was aimed to demonstrate which model can simulate well-known biological neuron behaviours such as Tonic Spiking, Tonic Bursting, Mixed Mode Firing, Spike Frequency Adaptation, Resonator and Integrator. As a result, the Izhikevich model has been shown to perform Regular Spiking, Continuous Explosion, Intrinsically Bursting, Thalmo Cortical, Low-Threshold Spiking and Resonator. The Adaptive Exponential Integrate Fire model has been able to produce firing patterns such as Regular Ignition, Adaptive Ignition, Initially Explosive Ignition, Regular Explosive Ignition, Delayed Ignition, Delayed Regular Explosive Ignition, Temporary Ignition and Irregular Ignition. The Hindmarsh Rose model showed three different dynamic neuron behaviours; Spike, Burst and Chaotic. From these results, the Izhikevich cell model may be preferred due to its ability to reflect the true behavior of the nerve cell, the ability to produce different types of spikes, and the suitability for use in larger scale brain models. The most important reason for choosing the Adaptive Exponential Integrate Fire model is that it can create rich ignition patterns with fewer parameters. The chaotic behaviours of the Hindmarsh Rose neuron model, like some chaotic systems, is thought to be used in many scientific and engineering applications such as physics, secure communication and signal processing.

Keywords: Izhikevich, adaptive exponential integrate fire, Hindmarsh Rose, biological neuron behaviours, spiking neuron models

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Authors: Saifalarab A. Mohmmed, Morgana E. Vianna, Jonathan C. Knowles

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The issue of apical periodontitis has received considerable critical attention. Bacteria is integrated into communities, attached to surfaces and consequently form biofilm. The biofilm structure provides bacteria with a series protection skills against, antimicrobial agents and enhances pathogenicity (e.g. apical periodontitis). Sodium hypochlorite (NaOCl) has become the irrigant of choice for elimination of bacteria from the root canal system based on its antimicrobial findings. The aim of the study was to investigate the effect of different agitation techniques on the efficacy of 2.5% NaOCl to eliminate the biofilm from the surface of the lateral canal using the residual biofilm, and removal rate of biofilm as outcome measures. The effect of canal complexity (lateral canal) on the efficacy of the irrigation procedure was also assessed. Forty root canal models (n = 10 per group) were manufactured using 3D printing and resin materials. Each model consisted of two halves of an 18 mm length root canal with apical size 30 and taper 0.06, and a lateral canal of 3 mm length, 0.3 mm diameter located at 3 mm from the apical terminus. E. faecalis biofilms were grown on the apical 3 mm and lateral canal of the models for 10 days in Brain Heart Infusion broth. Biofilms were stained using crystal violet for visualisation. The model halves were reassembled, attached to an apparatus and tested under a fluorescence microscope. Syringe and needle irrigation protocol was performed using 9 mL of 2.5% NaOCl irrigant for 60 seconds. The irrigant was either left stagnant in the canal or activated for 30 seconds using manual (gutta-percha), sonic and ultrasonic methods. Images were then captured every second using an external camera. The percentages of residual biofilm were measured using image analysis software. The data were analysed using generalised linear mixed models. The greatest removal was associated with the ultrasonic group (66.76%) followed by sonic (45.49%), manual (43.97%), and passive irrigation group (control) (38.67%) respectively. No marked reduction in the efficiency of NaOCl to remove biofilm was found between the simple and complex anatomy models (p = 0.098). The removal efficacy of NaOCl on the biofilm was limited to the 1 mm level of the lateral canal. The agitation of NaOCl results in better penetration of the irrigant into the lateral canals. Ultrasonic agitation of NaOCl improved the removal of bacterial biofilm.

Keywords: 3D printing, biofilm, root canal irrigation, sodium hypochlorite

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Authors: Azieva A. M., Yastremsky E. V., Kirillova D. A., Patsaev T. D., Sharikov R. V., Kamyshinsky R. A., Lukanina K. I., Sharikova N. A., Grigoriev T. E., Vasiliev A. L.

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Adhesive properties of scaffolds, which predominantly depend on the chemical and structural features of their surface, play the most important role in tissue engineering. The basic requirements for such scaffolds are biocompatibility, biodegradation, high cell adhesion, which promotes cell proliferation and differentiation. In many cases, synthetic polymers scaffolds have proven advantageous because they are easy to shape, they are tough, and they have high tensile properties. The regeneration of nerve tissue still remains a big challenge for medicine, and neural stem cells provide promising therapeutic potential for cell replacement therapy. However, experiments with stem cells have their limitations, such as low level of cell viability and poor control of cell differentiation. Whereas the study of already differentiated neuronal cell culture obtained from newborn mouse brain is limited only to cell adhesion. The growth and implantation of neuronal culture requires proper scaffolds. Moreover, the polymer scaffolds implants with neuronal cells could demand specific morphology. To date, it has been proposed to use numerous synthetic polymers for these purposes, including polystyrene, polylactic acid (PLA), polyglycolic acid, and polylactide-glycolic acid. Tissue regeneration experiments demonstrated good biocompatibility of PLA scaffolds, despite the hydrophobic nature of the compound. Problem with poor wettability of the PLA scaffold surface could be overcome in several ways: the surface can be pre-treated by poly-D-lysine or polyethyleneimine peptides; roughness and hydrophilicity of PLA surface could be increased by plasma treatment, or PLA could be combined with natural fibers, such as collagen or chitosan. This work presents a study of adhesion of both induced pluripotent stem cells (iPSCs) and mouse primary neuronal cell culture on the polylactide scaffolds of various types: oriented and non-oriented fibrous nonwoven materials and sponges – with and without the effect of plasma treatment and composites with collagen and chitosan. To evaluate the effect of different types of PLA scaffolds on the neuronal differentiation of iPSCs, we assess the expression of NeuN in differentiated cells through immunostaining. iPSCs more effectively differentiate into neurons on PLA scaffolds with high adhesive properties for primary neuronal cells.

Keywords: PLA scaffold, neurons, neuronal differentiation, stem cells, polylactid

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Authors: Garry Gorman, Nigel McKelvey, James Connolly

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This study will evaluate a growth mindset intervention with Junior Cycle Coding and Senior Cycle Computer Science students in Ireland, where gamification will be used to incentivise growth mindset behaviour. An artificial intelligence (AI) driven personalised learning system will be developed to present computer programming learning tasks in a manner that is best suited to the individuals’ own learning preferences while incentivising and rewarding growth mindset behaviour of persistence, mastery response to challenge, and challenge seeking. This research endeavours to measure mindset with before and after surveys (conducted nationally) and by recording growth mindset behaviour whilst playing a digital game. This study will harness the capabilities of AI and aims to determine how a personalised learning (PL) experience can impact the mindset of a broad range of students. The focus of this study will be to determine how personalising the learning experience influences female and disadvantaged students' sense of belonging in the computer science classroom when tasks are presented in a manner that is best suited to the individual. Whole Brain Learning will underpin this research and will be used as a framework to guide the research in identifying key areas such as thinking and learning styles, cognitive potential, motivators and fears, and emotional intelligence. This research will be conducted in multiple school types over one academic year. Digital games will be played multiple times over this period, and the data gathered will be used to inform the AI algorithm. The three data sets are described as follows: (i) Before and after survey data to determine the grit scores and mindsets of the participants, (ii) The Growth Mind-Set data from the game, which will measure multiple growth mindset behaviours, such as persistence, response to challenge and use of strategy, (iii) The AI data to guide PL. This study will highlight the effectiveness of an AI-driven personalised learning experience. The data will position AI within the Irish educational landscape, with a specific focus on the teaching of CS. These findings will benefit coding and computer science teachers by providing a clear pedagogy for the effective delivery of personalised learning strategies for computer science education. This pedagogy will help prevent students from developing a fixed mindset while helping pupils to exhibit persistence of effort, use of strategy, and a mastery response to challenges.

Keywords: computer science education, artificial intelligence, growth mindset, pedagogy

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Authors: M. M. Essa, S. Subash, M. Akbar, S. Al-Adawi, A. Al-Asmi, G. J. Guillemein

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Transgenic (tg) mice which contain an amyloid precursor protein (APP) gene mutation, develop extracellular amyloid beta (Aβ) deposition in the brain, and severe memory and behavioral deficits with age. These mice serve as an important animal model for testing the efficacy of novel drug candidates for the treatment and management of symptoms of Alzheimer's disease (AD). Several reports have suggested that oxidative stress is the underlying cause of Aβ neurotoxicity in AD. Date palm fruits contain very high levels of antioxidants and several medicinal properties that may be useful for improving the quality of life in AD patients. In this study, we investigated the effect of dietary supplementation of Omani date palm fruits on the memory, anxiety and learning skills along with inflammation in an AD mouse model containing the double Swedish APP mutation (APPsw/Tg2576). The experimental groups of APP-transgenic mice from the age of 4 months were fed custom-mix diets (pellets) containing 2% and 4% Date palm fruits. We assessed spatial memory and learning ability, psychomotor coordination, and anxiety-related behavior in Tg and wild-type mice at the age of 4-5 months and 18-19 months using the Morris water maze test, rota rod test, elevated plus maze test, and open field test. Further, inflammatory parameters also analyzed. APPsw/Tg2576 mice that were fed a standard chow diet without dates showed significant memory deficits, increased anxiety-related behavior, and severe impairment in spatial learning ability, position discrimination learning ability and motor coordination along with increased inflammation compared to the wild type mice on the same diet, at the age of 18-19 months In contrast, PPsw/Tg2576 mice that were fed a diet containing 2% and 4% dates showed a significant improvements in memory, learning, locomotor function, and anxiety with reduced inflammatory markers compared to APPsw/Tg2576 mice fed the standard chow diet. Our results suggest that dietary supplementation with dates may slow the progression of cognitive and behavioral impairments in AD. The exact mechanism is still unclear and further extensive research needed.

Keywords: Alzheimer's disease, date palm fruits, Oman, cognitive decline, memory loss, anxiety, inflammation

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Authors: Margo O'Sullivan, Xuefeng Chen, Qi Zhao, J. Jiang, Ning Fu

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Early childhood development, or ECD, is about the 'whole child' – the physical, social and emotional, cognitive thinking and language progression of each young individual. Overwhelming evidence is now available to support investment in Early Childhood Development internationally, attendance at ECD leads to: improved learning outcomes; improved completion and reduced less dropout rates; and most notably, Professor Heckman, Nobel Laureate’s, findings that for every dollar invested, there is an economic return of up to 17%. Notably, ECD has been included in the 2015-2030 Sustainable Development Goals. The Government of China (GOC) has embraced this research and in 2010, State Council, announced focus on ECD setting a target to provide access to ECD for 85% of 3-6 year olds by 2020; to date, the target has surpassed expectations and reached 70.4%. GoC is also increasingly focusing on the even more critical 0-3 age group, when the plasticity of the brain is at its peak and neurons form connections as fast as 1,000 per second. Key to ECD are parents and caregivers of young children, with parental education critical to fully exploiting the significant potential of the early years of children. In China, with such vast numbers, one in seven pre-school age children in the world live in China, the Ministry of Education (MoE) and the National Centre for Education Technology, explored how to best provide parental education and provide key child developmental related knowledge to parents and caregivers. In response, MoE and UNICEF created a resource for parenting information that began with a computer website in 2012, followed by piloting a kiosk service in 2013 for parents in remote areas without access to the internet, and then a mobile phone application in 2014. The resource includes 269 ECD messages and 200 micro-videos covering critical issues of early childhood development from birth to age 6 years: daily care, nutrition and feeding, disease prevention, immunization, development and education, and safety and protection. To date, there have been 397,599 unique views on the website, and data for the mobile app currently being analysed (Links: http://yuer.cbern.gov.cn/; App: https://appsto.re/cn/OiKPZ.i). This paper will explore the development of this resource, its use by parents and the public, efforts to assess the effectiveness in improving parenting and child development, and future plans to roll an updated version in 2016 to all parents.

Keywords: early childhood development, mobile apps for education, parental education, China

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Authors: Abel Sichinava

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The need for organ transplantation is vigorously increasing worldwide. The numbers on the waiting lists grow, but the number of donors is not keeping up with the demand even though there is a legal possibility of decreasing the gap between the demand and supply. Most countries around the globe are facing an organ donation problem (living or deceased); however, the extent of the problem differs based on how well developed a country is. The determining issues seem to be centered on how aware the society is about the concept of organ donation, as well as cultural and religious factors. Even if people are aware of the benefits of organ donation, they may still have fears that keep them from being in complete agreement with the idea. Some believe that in the case of deceased organ donation: “the brain dead human body may recover from its injuries” or “the sick might get less appropriate treatment if doctors know they are potential donors.” In the case of living organ donations, people sometimes fear that after the donation, “it might reduce work efficiency, cause health deterioration or even death.” Another major obstacle in the organ shortage is a lack of a well developed ethical framework. In reality, there are truly an immense number of people on the waiting list, and they have only two options in order to receive a suitable organ. First is the legal way, which is to wait until their turn. Sadly, numerous patients die while on the waiting list before an appropriate organ becomes available for transplant. The second option is an illegal way: seeking an organ in a country where they can possibly get. To tell the truth, in people’s desire to live, they may choose the second option if their resources are sufficient. This process automatically involves “organ brokers.” These are people who get organs from vulnerable poor people by force or betrayal. As mentioned earlier, the high demand and low supply leads to human trafficking. The subject of the study was the large number of society from different backgrounds of their belief, culture, nationality, level of education, socio-economic status. The great majority of them interviewed online used “Google Drive Survey” and others in person. All statistics and information gathered from trusted sources annotated in the reference list and above mentioned considerable testimonies shared by the respondents are the fundamental evidence of a lack of the well developed ethical framework. In conclusion, the continuously increasing number of people on the waiting list and an irrelevant ethical framework, lead people to commit to atrocious, dehumanizing crimes. Therefore, world society should be equally obligated to think carefully and make vital decisions together for the advancement of an organ donations and its ethical framework.

Keywords: donation, ethical framwork, organ, transplant

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Authors: Priyanka Bharti

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Decades ago designs were based on common sense and tradition, but after an enhancement in visualization technology and research, we are now able to comprehend the cognitive ability involved in the decoding of the visual information. However, many fields in visuals need intense research to deliver an efficient explanation for the events. Visuals are an information representation mode through images, symbols and graphics. It plays an impactful role in decision making by facilitating quick recognition, comprehension, and analysis of a situation. They enhance problem-solving capabilities by enabling the processing of more data without overloading the decision maker. As research proves that, visuals offer an improved learning environment by a factor of 400 compared to textual information. Visual information engages learners at a cognitive level and triggers the imagination, which enables the user to process the information faster (visuals are processed 60,000 times faster in the brain than text). Appropriate information, visualization, and its presentation are known to aid and intensify the decision-making process for the users. However, most literature discusses the role of visual aids in comprehension and decision making during normal conditions alone. Unlike emergencies, in a normal situation (e.g. our day to day life) users are neither exposed to stringent time constraints nor face the anxiety of survival and have sufficient time to evaluate various alternatives before making any decision. An emergency is an unexpected probably fatal real-life situation which may inflict serious ramifications on both human life and material possessions unless corrective measures are taken instantly. The situation demands the exposed user to negotiate in a dynamic and unstable scenario in the absence or lack of any preparation, but still, take swift and appropriate decisions to save life/lives or possessions. But the resulting stress and anxiety restricts cue sampling, decreases vigilance, reduces the capacity of working memory, causes premature closure in evaluating alternative options, and results in task shedding. Limited time, uncertainty, high stakes and vague goals negatively affect cognitive abilities to take appropriate decisions. More so, theory of natural decision making by experts has been understood with far more depth than that of an ordinary user. Therefore, in this study, the author aims to understand the role of visual aids in supporting rapid comprehension to take appropriate decisions during an emergency situation.

Keywords: cognition, visual, decision making, graphics, recognition

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Authors: Yuji Fujino, Kazu Amimoto, Kazuhiro Fukata, Masahide Inoue, Hidetoshi Takahashi, Shigeru Makita

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Aim: Pusher behavior (PB) is a disorder in which stroke patients shift their body weight toward the affected side of the body (the hemiparetic side) and push away from the non-hemiparetic side. These patients often use further pushing to resist any attempts to correct their position to upright. It is known that the subcortical white matter lesion (SWML) usually correlates of gait or balance function in stroke patients. However, it is unclear whether the SWML influences PB. The purpose of this study was to investigate if the damage of SWML affects the severity of PB on acute stroke patients. Methods: Fourteen PB patients without thalamic or cortical lesions (mean age 73.4 years, 17.5 days from onset) participated in this study. Evaluation of PB was performed according to the Scale for Contraversive Pushing (SCP) for sitting and/or standing. We used modified criteria wherein the SCP subscale scores in each section of the scale were >0. As a clinical measurement, patients were evaluated by the Stroke Impairment Assessment Set (SIAS). For the depiction of SWML, we used T2-weighted fluid-attenuated inversion-recovery imaging. The degree of damage on SWML was assessed using the Fazekas scale. Patients were divided into two groups in the presence of SWML (SWML+ group; Fazekas scale grade 1-3, SWML- group; Fazekas scale grade 0). The independent t-test was used to compare the SCP and SIAS. This retrospective study was approved by the Ethics Committee. Results: In SWML+ group, the SCP was 3.7±1.0 points (mean±SD), the SIAS was 28.0 points (median). In SWML- group, the SCP was 2.0±0.2 points, and the SIAS was 31.5 points. The SCP was significantly higher in SWML+ group than in SWML- group (p<0.05). The SIAS was not significant in both groups (p>0.05). Discussion: It has been considered that the posterior thalamus is the neural structures that process the afferent sensory signals mediating graviceptive information about upright body orientation in humans. Therefore, many studies reported that PB was typically associated with unilateral lesions of the posterior thalamus. However, the result indicates that these extra-thalamic brain areas also contribute to the network controlling upright body posture. Therefore, SMWL might induce dysfunction through malperfusion in distant thalamic or other structurally intact neural structures. This study had a small sample size. Therefore, future studies should be performed with a large number of PB patients. Conclusion: The present study suggests that SWML can be definitely associated with PB. The patients with SWML may be severely incapacitating.

Keywords: pushing behavior, subcortical white matter lesion, acute phase, stroke

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Authors: Raphael C. Zero, Marita V. Cardozo, Thiago A. S. S. Rocha, Mariana T. Kihara, Fernando A. Ávila, Fabrício S. Oliveira

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There are several fixative and preservative solutions for use on cadavers, many of them using formaldehyde as the fixative or anatomical part preservative. In some countries, such as Brazil, this toxic agent has been increasingly restricted. The objective of this study was to microbiologically identify and quantify the key agents in tanks containing 96GL ethanol or sodium chloride solutions, used respectively as fixatives and preservatives of cat cadavers. Eight adult cat corpses, three females and five males, with an average weight of 4.3 kg, were used. After injection via the external common carotid artery (120 ml/kg, 95% 96GL ethyl alcohol and 5% pure glycerin), the cadavers were fixed in a plastic tank with 96GL ethanol for 60 days. After fixing, they were stored in a 30% sodium chloride aqueous solution for 120 days in a similar tank. Samples were collected at the start of the experiment - before the animals were placed in the ethanol tanks, and monthly thereafter. The bacterial count was performed by Pour Plate Method in BHI agar (Brain Heart Infusion) and the plates were incubated aerobically and anaerobically for 24h at 37ºC. MacConkey agar, SPS agar (Sulfite Polymyxin Sulfadizine) and MYP Agar Base were used to isolate the microorganisms. There was no microbial growth in the samples prior to alcohol fixation. After 30 days of fixation in the alcohol solution, total aerobic and anaerobic (<1.0 x 10 CFU/ml) were found and Pseudomonas sp., Staphylococcus sp., Clostridium sp. were the identified agents. After 60 days in the alcohol fixation solution, total aerobes (<1.0 x 10 CFU/ml) and total anaerobes (<2.2 x 10 CFU/mL) were found, and the identified agents were the same. After 30 days of storage in the aqueous solution of 30% sodium chloride, total aerobic (<5.2 x 10 CFU/ml) and total anaerobes (<3.7 x 10 CFU/mL) were found and the agents identified were Staphylococcus sp., Clostridium sp., and fungi. After 60 days of sodium chloride storage, total aerobic (<3.0 x 10 CFU / ml) and total anaerobes (<7.0 x 10 CFU/mL) were found and the identified agents remained the same: Staphylococcus sp., Clostridium sp., and fungi. The microbiological count was low and visual inspection did not reveal signs of contamination in the tanks. There was no strong odor or purification, which proved the technique to be microbiologically effective in fixing and preserving the cat cadavers for the four-month period in which they are provided to undergraduate students of University of Veterinary Medicine for surgery practice. All experimental procedures were approved by the Municipal Legal Department (protocol 02.2014.000027-1). The project was funded by FAPESP (protocol 2015-08259-9).

Keywords: anatomy, fixation, microbiology, small animal, surgery

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Authors: Ludmila Vucolova

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The thought is a process that underlies consciousness and cognition and understanding its origin and processes is a longstanding goal of many academic disciplines. By integrating over twenty novel ideas and hypotheses of this theoretical proposal, we can speculate that thought is an emergent property of coded neural events, translating the electro-chemical interactions of the body with its environment—the objects of sensory stimulation, X, and Y. The latter is a self- generated feedback entity, resulting from the arbitrary pattern of the motion of a body’s motor repertory (M). A culmination of these neural events gives rise to a thought: a state of identity between an observed object X and a symbol Y. It manifests as a “state of awareness” or “state of knowing” and forms our perception of the physical world. The values of the variables of a construct—X (object), S1 (sense for the perception of X), Y (object), S2 (sense for perception of Y), and M (motor repertory that produces Y)—will specify the particular conscious percept at any given time. The proposed principle of interaction between the elements of a construct (X, Y, S1, S2, M) is universal and applies for all modes of communication (normal, deaf, blind, deaf and blind people) and for various language systems (Chinese, Italian, English, etc.). The particular arrangement of modalities of each of the three modules S1 (5 of 5), S2 (1 of 3), and M (3 of 3) defines a specific mode of communication. This multifaceted paradigm demonstrates a predetermined pattern of relationships between X, Y, and M that passes from generation to generation. The presented analysis of a cognitive experience encompasses the key elements of embodied cognition theories and unequivocally accords with the scientific interpretation of cognition as the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses, and cognition means thinking and awareness. By assembling the novel ideas presented in twelve sections, we can reveal that in the invisible “chaos”, there is an order, a structure with landmarks and principles of operations and mental processes (thoughts) are physical and have a biological basis. This innovative proposal explains the phenomenon of mental imagery; give the first insight into the relationship between mental states and brain states, and support the notion that mind and body are inseparably connected. The findings of this theoretical proposal are supported by the current scientific data and are substantiated by the records of the evolution of language and human intelligence.

Keywords: agent, awareness, cognitive, element, experience, feedback, first person, imagery, language, mental, motor, object, sensory, symbol, thought

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Authors: Pamela R. Jackson, Andrea Hawkins-Daarud, Cassandra R. Rickertsen, Kamala Clark-Swanson, Scott A. Whitmire, Kristin R. Swanson

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Glioblastoma Multiforme (GBM), the most common primary brain tumor, often presents with hyperintensity on T2-weighted or T2-weighted fluid attenuated inversion recovery (T2/FLAIR) magnetic resonance imaging (MRI). This hyperintensity corresponds with vasogenic edema, however there are likely many infiltrating tumor cells within the hyperintensity as well. While MRIs do not directly indicate tumor cells, MRIs do reflect the microenvironmental water abnormalities caused by the presence of tumor cells and edema. The inherent heterogeneity and resulting MRI features of GBMs complicate assessing disease response. To understand how hyperintensity on T2/FLAIR MRI may correlate with edema in the extracellular space (ECS), a multi-compartmental MRI signal equation which takes into account tissue compartments and their associated volumes with input coming from a mathematical model of glioma growth that incorporates edema formation was explored. The reasonableness of two possible extracellular space schema was evaluated by varying the T2 of the edema compartment and calculating the possible resulting T2s in tumor and peripheral edema. In the mathematical model, gliomas were comprised of vasculature and three tumor cellular phenotypes: normoxic, hypoxic, and necrotic. Edema was characterized as fluid leaking from abnormal tumor vessels. Spatial maps of tumor cell density and edema for virtual tumors were simulated with different rates of proliferation and invasion and various ECS expansion schemes. These spatial maps were then passed into a multi-compartmental MRI signal model for generating simulated T2/FLAIR MR images. Individual compartments’ T2 values in the signal equation were either from literature or estimated and the T2 for edema specifically was varied over a wide range (200 ms – 9200 ms). T2 maps were calculated from simulated images. T2 values based on simulated images were evaluated for regions of interest (ROIs) in normal appearing white matter, tumor, and peripheral edema. The ROI T2 values were compared to T2 values reported in literature. The expanding scheme of extracellular space is had T2 values similar to the literature calculated values. The static scheme of extracellular space had a much lower T2 values and no matter what T2 was associated with edema, the intensities did not come close to literature values. Expanding the extracellular space is necessary to achieve simulated edema intensities commiserate with acquired MRIs.

Keywords: extracellular space, glioblastoma multiforme, magnetic resonance imaging, mathematical modeling

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Authors: Hsiang-Ru Lin

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Cholesterol plays an essential role in the regulation of the progression of numerous important diseases including atherosclerosis and Alzheimer disease so the generation of suitable cholesterol-lowering reagents is urgent to develop. Liver X receptor (LXR) is a ligand-activated transcription factor whose natural ligands are cholesterols, oxysterols and glucose. Once being activated, LXR can transactivate the transcription action of various genes including CYP7A1, ABCA1, and SREBP1c, involved in the lipid metabolism, glucose metabolism and inflammatory pathway. Essentially, the upregulation of ABCA1 facilitates cholesterol efflux from the cells and attenuates the production of beta-amyloid (ABeta) 42 in brain so LXR is a promising target to develop the cholesterol-lowering reagents and preventative treatment of Alzheimer disease. Engelhardia roxburghiana is a deciduous tree growing in India, China, and Taiwan. However, its chemical composition is only reported to exhibit antitubercular and anti-inflammatory effects. In this study, four compounds, engelheptanoxides A, C, engelhardiol A, and B isolated from the root of Engelhardia roxburghiana were evaluated for their agonistic activity against LXR by the transient transfection reporter assays in the HepG2 cells. Furthermore, their interactive modes with LXR ligand binding pocket were generated by molecular modeling programs. By using the cell-based biological assays, engelheptanoxides A, C, engelhardiol A, and B showing no cytotoxic effect against the proliferation of HepG2 cells, exerted obvious LXR agonistic effects with similar activity as T0901317, a novel synthetic LXR agonist. Further modeling studies including docking and SAR (structure-activity relationship) showed that these compounds can locate in LXR ligand binding pocket in the similar manner as T0901317. Thus, LXR is one of nuclear receptors targeted by pharmaceutical industry for developing treatments of Alzheimer and atherosclerosis diseases. Importantly, the cell-based assays, together with molecular modeling studies suggesting a plausible binding mode, demonstrate that engelheptanoxides A, C, engelhardiol A, and B function as LXR agonists. This is the first report to demonstrate that the extract of Engelhardia roxburghiana contains LXR agonists. As such, these active components of Engelhardia roxburghiana or subsequent analogs may show important therapeutic effects through selective modulation of the LXR pathway.

Keywords: Liver X receptor (LXR), Engelhardia roxburghiana, CYP7A1, ABCA1, SREBP1c, HepG2 cells

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Authors: Jessica A. Hellings, Piyushkumar Jani

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Background: Systemic autoimmune disorders are increasingly implicated in neuropsychiatric illness, especially in the setting of treatment resistance in individuals of all ages. Gluten allergy in fullest extent results in celiac disease, affecting multiple organs including central nervous system (CNS). Clinicians often lack awareness of the association between neuropsychiatric illness and gluten allergy, partly since many such research studies are published in immunology and gastroenterology journals. Methods: Following a Pubmed literature search and online searches on celiac disease websites, 40 articles are critically reviewed in detail. This work reviews celiac disease, gluten intolerance and current evidence of their relationship to neuropsychiatric and systemic illnesses. The review also covers current work-up and diagnosis, as well as dietary interventions, gluten restriction outcomes, and future research directions. Results: Gluten allergy in susceptible individuals damages the small intestine, producing a leaky gut and malabsorption state, as well as allowing antibodies into the bloodstream, which attack major organs. Lack of amino acid precursors for neurotransmitter synthesis together with antibody-associated brain changes and hypoperfusion may result in neuropsychiatric illness. This is well documented; however, studies in neuropsychiatry are often small. In the large CATIE trial, subjects with schizophrenia had significantly increased antibodies to tissue transglutaminase (TTG), and antigliadin antibodies, both significantly greater gluten antibodies than in control subjects. On later follow up, TTG-6 antibodies were identified in these subjects’ brains but not in their intestines. Significant evidence mostly from small studies also exists for gluten allergy and celiac-related depression, anxiety disorders, attention-deficit/hyperactivity disorder, autism spectrum disorders, ataxia, and epilepsy. Dietary restriction of gluten resulted in remission in several published cases, including for treatment-resistant schizophrenia. Conclusions: Ongoing and larger studies are needed of the diagnosis and treatment efficacy of the gluten-free diet in neuropsychiatric illness. Clinicians should ask about the patient history of anemia, hypothyroidism, irritable bowel syndrome and family history of benefit from the gluten-free diet, not limited to but especially in cases of treatment resistance. Obtaining gluten antibodies by a simple blood test, and referral for gastrointestinal work-up in positive cases should be considered.

Keywords: celiac, gluten, neuropsychiatric, translational

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Authors: I. S. Gandhi, D. N. Patel, M. Johnson, A. R. Hirsch

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Although distortion of taste perception following a cerebrovascular event may seem to be a frivolous consequence of a classic stroke presentation, altered taste perception places patients at an increased risk for malnutrition, weight loss, and depression, all of which negatively impact the quality of life. Impaired taste perception can result from a wide variety of cerebrovascular lesions to various locations, including pons, insular cortices, and ventral posteromedial nucleus of the thalamus. Wallenberg syndrome, also known as a lateral medullary syndrome, has been described to impact taste; however, specific sweet to bitter taste dysgeusia from a territory infarction is an infrequent event; as such, a case is presented. One year prior to presentation, this 64-year-old right-handed woman, suffered a right posterior inferior cerebellar artery aneurysm rupture with resultant infarction, culminating in a ventriculoperitoneal shunt placement. One and half months after this event, she noticed the gradual onset of lack of ability to taste sweet, to eventually all sweet food tasting bitter. Since the onset of her chemosensory problems, the patient has lost 60-pounds. Upon gustatory testing, the patient's taste threshold showed ageusia to sucrose and hydrochloric acid, while normogeusia to sodium chloride, urea, and phenylthiocarbamide. The gustatory cortex is made in part by the right insular cortex as well as the right anterior operculum, which are primarily involved in the sensory taste modalities. In this model, sweet is localized in the posterior-most along with the rostral aspect of the right insular cortex, notably adjacent to the region responsible for bitter taste. The sweet to bitter dysgeusia in our patient suggests the presence of a lesion in this localization. Although the primary lesion in this patient was located in the right medulla of the brainstem, neurodegeneration in the rostal and posterior-most aspect, of the right insular cortex may have occurred due to diaschisis. Diaschisis has been described as neurophysiological changes that occur in remote regions to a focal brain lesion. Although hydrocephalus and vasospasm due to aneurysmal rupture may explain the distal foci of impairment, the gradual onset of dysgeusia is more indicative of diaschisis. The perception of sweet, now tasting bitter, suggests that in the absence of sweet taste reception, the intrinsic bitter taste of food is now being stimulated rather than sweet. In the evaluation and treatment of taste parageusia secondary to cerebrovascular injury, prophylactic neuroprotective measures may be worthwhile. Further investigation is warranted.

Keywords: diaschisis, dysgeusia, stroke, taste

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Authors: J. Jessa

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Background: Autism is a pervasive developmental disorder, the incidence of which has significantly increased in recent years. Children with autism have impairments in social skills, communication, and imagination. Children with autism has more common than healthy children feeding problems: food selectivity, problems with gastrointestinal tract: diarrhea, constipations, abdominal pain, reflux and others. Many parents of autistic children report that after implementation of gluten-, casein- and sugar free diet those symptoms disappear and even cognitive functions become better. Some children begin to understand speech and to communicate with parents, regain eye contact, become more calm, sleep better and has better concentration. Probably at the root of this phenomenon lies elimination from the diet peptides construction of which is similar to opiates. Enhanced permeability of gut causes absorption of not fully digested opioid-like peptides from food, like gluten and casein and probably others (proteins from soy and corn) which impact on brain of autistic children. Aim of the study: The aim of the study is to assess the safety of gluten-free diet in children with autism, aged 2,5-7. Methods: Participants of the study (n=70) – children aged 2,5-7 with autism are divided into 3 groups. The first group (research group) are patients whose parents want to implement a gluten-free diet. The second group are patients who have been recommended to eliminate from the diet artificial substances, such as preservatives, artificial colors and flavors, and others (control group 1). The third group (control group 2) are children whose parents did not agree for implementation of the diet. Caregivers of children on the diet are educated about the specifics of the diet and how to avoid malnutrition. At the start of the study we exclude celiac disease. Before the implementation of the diet we performe a blood test for patients (morphology, ferritin, total cholesterol, dry peripheral blood drops to detect some genetic metabolic diseases), plasma aminogram) and urine tests (excretion of ions: Mg, Na, Ca, the profile of organic acids in urine), which assess nutritional status as well as the psychological test assessing the degree of the child's psychological functioning (PEP-R). All of these tests will be repeated after one year from the implementation of the diet. Results: To the present moment we examined 42 children with autism. 12 of children are on gluten- free diet. Our preliminary results are promising. Parents of 9 of them report that, there is a big improvement in child behavior, concentration, less aggression incidents, better eye contact and better verbal skills. Conclusion: Our preliminary results suggest that dietary intervention may positively affect developmental outcome for some children diagnosed with ASD.

Keywords: gluten free diet, autism spectrum disorder, autism, blood test

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Authors: Ivette Gonzalez-Rivera, Diana B. Paz-Trejo, Oscar Galicia-Castillo, David N. Velazquez-Martinez, Hugo Sanchez-Castillo

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Prolonged exposure to stress can cause disorders related with dysfunction in the prefrontal cortex such as generalized anxiety and depression. These disorders involve alterations in neurotransmitter systems; the serotonergic system—a target of the drugs that are commonly used as a treatment to these disorders—is one of them. Recent studies suggest that 5-HT1A receptors play a pivotal role in the serotonergic system regulation and in stress responses. In the same way, there is increasing evidence that astrocytes are involved in the pathophysiology of stress. The aim of this study was to examine the effects of 8-OH-DPAT, a selective agonist of 5-HT1A receptors, in the behavioral signs of anxiety and anhedonia as well as in the number of astrocytes in the medial prefrontal cortex (mPFC) after exposure to chronic stress. They used 50 male Wistar rats of 250-350 grams housed in standard laboratory conditions and treated in accordance with the ethical standards of use and care of laboratory animals. A protocol of chronic unpredictable stress was used for 10 consecutive days during which the presentation of stressors such as motion restriction, water deprivation, wet bed, among others, were used. 40 rats were subjected to the stress protocol and then were divided into 4 groups of 10 rats each, which were administered 8-OH-DPAT (Tocris, USA) intraperitoneally with saline as vehicle in doses 0.0, 0.3, 1.0 and 2.0 mg/kg respectively. Another 10 rats were not subjected to the stress protocol or the drug. Subsequently, all the rats were measured in an open field test, a forced swimming test, sucrose consume, and a cero maze test. At the end of this procedure, the animals were sacrificed, the brain was removed and the tissue of the mPFC (Bregma: 4.20, 3.70, 2.70, 2.20) was processed in immunofluorescence staining for astrocytes (Anti-GFAP antibody - astrocyte maker, ABCAM). Statistically significant differences were found in the behavioral tests of all groups, showing that the stress group with saline administration had more indicators of anxiety and anhedonia than the control group and the groups with administration of 8-OH-DPAT. Also, a dose dependent effect of 8-OH-DPAT was found on the number of astrocytes in the mPFC. The results show that 8-OH-DPAT can modulate the effect of stress in both behavioral and anatomical level. Also they indicate that 5-HT1A receptors and astrocytes play an important role in the stress response and may modulate the therapeutic effect of serotonergic drugs, so they should be explored as a fundamental part in the treatment of symptoms of stress and in the understanding of the mechanisms of stress responses.

Keywords: anxiety, prefrontal cortex, serotonergic system, stress

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Authors: Nina Ivanova

Abstract:

More than one third of the population and animals are infected with parasitic helminths. It is especially difficult to cure the larval forms of parasites. The larvae of Hymenolepis nana invade the villi of the intestinal mucosa. Toxocara larvae can live in the liver, heart, lungs, brain, eyes, and pancreas. Commercial antiparasitic drugs cannot guarantee a 100% cure after a single course of treatment, because parasite larvae invade the villi of the intestinal mucosa and the anthelmintics do not reach and kill cestode larvae. The aim of this work was to conduct a study of liposomal antihelminthics on the laboratory animals under the certification received from the Committee on Bioethics and Deontology. It has been checked: 1) anthelmintic activity of the liposomal form of fenasal in experimental hymenolepidosis of white mice (larval stage - Hymenolepis nana). 2) anthelmintic activity of the liposomal form of albendazole in experimental toxocariasis of white mice (in the lungs at the stage of larval migration). Since some helminths cause hemolysis of erythrocytes as we used a mixture of polar lipids developed by us with antihemolytic activity to obtain liposomes Fenasal and albendazole were included in the liposome membrane in the ratio of anthelmintic: lipids 1:10. . The average size of liposomes was 180 nm, and the concentration of lipids in liposomes was 1%. The researches were carried out on white male mice who were infected with Hymenolepis Nana invasional eggs in a peroral way with a doze of 100 eggs per animal. On the 5th day after infection, a liposomal fenasal and commercial fenasal were administered orally for comparison. The animals were observed for 15 days. Before the introduction of liposomes and on the 3rd, 5th, 15th day after the administration of the drug, studies were carried out on the presence of helminths in the organs of animals. The liposomal fenasal, when administered orally, had an anthelmintic effect on Hymenolepis Nana cysticercoids at a dose of 25 mg/kg. The percentage of efficiency was 90.06, 91.36 96.85% on days 3, 5, 15, respectively. For comparison, the commercial activity was at a dose of 200 mg/ml, which is 8 times higher than the dose of liposomal fenasal. To evaluate the anthelmintic effect of the liposomal form of albendazole in experimental toxocariasis of white mice (toxascaris in the lungs at the stage of larval migration), studies were also carried out on white mice. The animals were infected with invasive eggs of Toxocara canis, orally, at a dose of 100 eggs per animal. On the 5th day after infection, the liposomal albendazole was administered orally. The efficacy of the study dosage form was determined by counting Larva mirgans larvae in the lungs. The results obtained showed that the liposomal albendazole had the greatest anthelmintic effect on Toxocara larvae at a dose of 2.0 mg/kg, which was 3.75 times less than the therapeutic one. At the same time, the percentage of efficiency was 93.75% on the 3rd day, and 98.66% on the 5th day.

Keywords: hymenolepis, Toxocara, larvae, liposomes

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Authors: Mrinalini Ranjan, Sudheesh Chethil

Abstract:

Epilepsy is a common neurological disorder characterised by the recurrence of seizures. Electroencephalogram (EEG) signals are complex biomedical signals which exhibit nonlinear and nonstationary behavior. We use two methods 1) Detrended Fluctuation Analysis (DFA) and 2) Recurrence Plots (RP) to capture this complex behavior of EEG signals. DFA considers fluctuation from local linear trends. Scale invariance of these signals is well captured in the multifractal characterisation using detrended fluctuation analysis (DFA). Analysis of long-range correlations is vital for understanding the dynamics of EEG signals. Correlation properties in the EEG signal are quantified by the calculation of a scaling exponent. We report the existence of two scaling behaviours in the epileptic EEG signals which quantify short and long-range correlations. To illustrate this, we perform DFA on extant ictal (seizure) and interictal (seizure free) datasets of different patients in different channels. We compute the short term and long scaling exponents and report a decrease in short range scaling exponent during seizure as compared to pre-seizure and a subsequent increase during post-seizure period, while the long-term scaling exponent shows an increase during seizure activity. Our calculation of long-term scaling exponent yields a value between 0.5 and 1, thus pointing to power law behaviour of long-range temporal correlations (LRTC). We perform this analysis for multiple channels and report similar behaviour. We find an increase in the long-term scaling exponent during seizure in all channels, which we attribute to an increase in persistent LRTC during seizure. The magnitude of the scaling exponent and its distribution in different channels can help in better identification of areas in brain most affected during seizure activity. The nature of epileptic seizures varies from patient-to-patient. To illustrate this, we report an increase in long-term scaling exponent for some patients which is also complemented by the recurrence plots (RP). RP is a graph that shows the time index of recurrence of a dynamical state. We perform Recurrence Quantitative analysis (RQA) and calculate RQA parameters like diagonal length, entropy, recurrence, determinism, etc. for ictal and interictal datasets. We find that the RQA parameters increase during seizure activity, indicating a transition. We observe that RQA parameters are higher during seizure period as compared to post seizure values, whereas for some patients post seizure values exceeded those during seizure. We attribute this to varying nature of seizure in different patients indicating a different route or mechanism during the transition. Our results can help in better understanding of the characterisation of epileptic EEG signals from a nonlinear analysis.

Keywords: detrended fluctuation, epilepsy, long range correlations, recurrence plots

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