Search results for: non-invasive brain stimulation

Authors: Deborah Zelinsky

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The retina filters millions of incoming signals into a smaller amount of exiting optic nerve fibers that travel to different portions of the brain. Most of the signals are for eyesight (called "image-forming" signals). However, there are other faster signals that travel "elsewhere" and are not directly involved with eyesight (called "non-image-forming" signals). This article centers on the neurons of the optic nerve connecting to parts of the limbic system. Eye care providers are currently looking at parvocellular and magnocellular processing pathways without realizing that those are part of an enormous "galaxy" of all the body systems. Lenses are modifying both non-image and image-forming pathways, taking A.M. Skeffington's seminal work one step further. Almost 100 years ago, he described the Where am I (orientation), Where is It (localization), and What is It (identification) pathways. Now, among others, there is a How am I (animation) and a Who am I (inclination, motivation, imagination) pathway. Classic eye testing considers pupils and often assesses posture and motion awareness, but classical prescriptions often overlook limbic involvement in visual processing. The limbic system is composed of the hippocampus, amygdala, hypothalamus, and anterior nuclei of the thalamus. The optic nerve's limbic connections arise from the intrinsically photosensitive retinal ganglion cells (ipRGC) through the "retinohypothalamic tract" (RHT). There are two main hypothalamic nuclei with direct photic inputs. These are the suprachiasmatic nucleus and the paraventricular nucleus. Other hypothalamic nuclei connected with retinal function, including mood regulation, appetite, and glucose regulation, are the supraoptic nucleus and the arcuate nucleus. The retino-hypothalamic tract is often overlooked when we prescribe eyeglasses. Each person is different, but the lenses we choose are influencing this fast processing, which affects each patient's aiming and focusing abilities. These signals arise from the ipRGC cells that were only discovered 20+ years ago and do not address the campana retinal interneurons that were only discovered 2 years ago. As eyecare providers, we are unknowingly altering such factors as lymph flow, glucose metabolism, appetite, and sleep cycles in our patients. It is important to know what we are prescribing as the visual processing evaluations expand past the 20/20 central eyesight.

Keywords: neuromodulation, retinal processing, retinohypothalamic tract, limbic system, visual processing

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Authors: Geetha Jayapathy, Lakshmi Muthukrishnan, Manoj Kumar Reddy Pulim , Radhika Raman

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Introduction: Ketones are the end products of fatty acid metabolism and a source of energy for vital organs such as the brain, heart and skeletal muscles. Ketones are produced in excess when glucose is not available as a source of energy or it cannot be utilized as in diabetic ketoacidosis. Children admitted in the emergency department often have starvation ketosis which is not clinically manifested. Decision on admission of children to the emergency room with subtle signs can be difficult at times. Point of care blood ketone testing can be done at the bedside even in a primary level care setting to supplement and guide us in our management decisions. Hence this study was done to explore the utility of this simple bedside parameter as a supplement in assessing pediatric patients presenting to the emergency department. Objectives: To estimate blood ketones of children admitted in the emergency department. To analyze the significance of blood ketones in various disease conditions. Methods: Blood ketones using point of care testing instrument (ABOTTprecision Xceed Pro meters) was done in patients getting admitted in emergency room and in out-patients (through sample collection centre). Study population: Children aged 1 month to 18 years were included in the study. 250 cases (In-patients) and 250 controls (out-patients) were collected. Study design: Prospective observational study. Data on details of illness and physiological status were documented. Blood ketones were compared between the two groups and all in patients were categorized into various system groups and analysed. Results: Mean blood ketones were high in in-patients ranging from 0 to 7.2, with a mean of 1.28 compared to out-patients ranging from 0 to 1.9 with a mean of 0.35. This difference was statistically significant with a p value < 0.001. In-patients with shock (mean of 4.15) and diarrheal dehydration (mean of 1.85) had a significantly higher blood ketone values compared to patients with other system involvement. Conclusion: Blood ketones were significantly high (above the normal range) in pediatric patients who are sick requiring admission. Patients with various forms of shock had very high blood ketone values as found in diabetic ketoacidosis. Ketone values in diarrheal dehydration were moderately high correlating to the degree of dehydration.

Keywords: admission, blood ketones, paediatric emergencies, point of care testing

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Authors: Morenikeji Aliu Balaji

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Gender inequality is seen as persistent discrimination of one group of people based gender, and it manifests itself differently according to race, culture, politics, country and economic situation. Multiple explanations have been offered for gender differences in literacy skill development. Three prominent explanations that precipitated the gender differences are; biological, where the assumption is that differential brain structures and hemispheric activation patterns cause the sexes to be hardwired differently for reading, with girls developing the cognitive skills associated with reading before boys. Secondly, schooling favour girls and ‘girly’ behaviour, and that boys are, as a result, lagging behind on several behavioural, social and academic measures and thirdly, cultural influences, where literacy is defined as a feminine characteristic – propagated by an overrepresentation of female teachers – and that modern culture steers boys towards activities such as sport and computers. Therefore the study investigated the influence of gender inequality on pre – primary school children literacy skills development in Ojo Local Government Area, Lagos State. Descriptive survey research design was adopted for the study. 100 pre-primary school teachers were involved in the study. A self-designed instrument was used for data collection titled ‘Influence of Gender Inequality on Literacy Skill Development in Children Questionnaire (IGILSDCQ)’. The instrument was validated and tested for reliability. The reliability index for IGILSDCQ (α = 0.79). Five research questions were answered using descriptive (frequency count, simple percentage, mean and standard deviation). The findings showed that that gender inequality to some extent influence children phonemic awareness (WA=1.76), the extent to which gender inequality influence children awareness of print is high (WA=2.8), gender inequality to some extent influence children vocabulary development (WA = 2.4), the extent to which gender inequality influence children speaking skill development is high (WA = 2.5) and lastly, the extent to which gender inequality influence children comprehension ability is high (WA = 2.5). It was recommended among others that effort by the school administrators is necessary in the provision of reading materials and literacy skill development packages that are both male-oriented and female-oriented.

Keywords: pre-primart, literacy, awareness, phonemic, gender

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Authors: Adnan A. Kadi, Nasser S. Al-Shakliah, Haitham Al-Rabiah

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Zorifertinib is a novel, potent, oral, a small molecule used to treat non-small cell lung cancer (NSCLC). zorifertinib is an Epidermal Growth Factor Receptor (EGFR) inhibitor and has good blood–brain barrier permeability for (NSCLC) patients with EGFR mutations. zorifertinibis currently at phase II/III clinical trials. The current research reports the characterization and identification of in vitro, in vivo and reactive intermediates of zorifertinib. Prediction of susceptible sites of metabolism and reactivity pathways (cyanide and GSH) of zorifertinib were performed by the Xenosite web predictor tool. In-vitro metabolites of zorifertinib were performed by incubation with rat liver microsomes (RLMs) and isolated perfused rat liver hepatocytes. Extraction of zorifertinib and it's in vitro metabolites from the incubation mixtures were done by protein precipitation. In vivo metabolism was done by giving a single oral dose of zorifertinib(10 mg/Kg) to Sprague Dawely rats in metabolic cages by using oral gavage. Urine was gathered and filtered at specific time intervals (0, 6, 12, 18, 24, 48, 72,96and 120 hr) from zorifertinib dosing. A similar volume of ACN was added to each collected urine sample. Both layers (organic and aqueous) were injected into liquid chromatography ion trap mass spectrometry(LC-IT-MS) to detect vivozorifertinib metabolites. N-methyl piperizine ring and quinazoline group of zorifertinib undergoe metabolism forming iminium and electro deficient conjugated system respectively, which are very reactive toward nucleophilic macromolecules. Incubation of zorifertinib with RLMs in the presence of 1.0 mM KCN and 1.0 Mm glutathione were made to check reactive metabolites as it is often responsible for toxicities associated with this drug. For in vitro metabolites there were nine in vitro phase I metabolites, four in vitro phase II metabolites, eleven reactive metabolites(three cyano adducts, five GSH conjugates metabolites, and three methoxy metabolites of zorifertinib were detected by LC-IT-MS. For in vivo metabolites, there were eight in vivo phase I, tenin vivo phase II metabolitesofzorifertinib were detected by LC-IT-MS. In vitro and in vivo phase I metabolic pathways wereN- demthylation, O-demethylation, hydroxylation, reduction, defluorination, and dechlorination. In vivo phase II metabolic reaction was direct conjugation of zorifertinib with glucuronic acid and sulphate.

Keywords: in vivo metabolites, in vitro metabolites, cyano adducts, GSH conjugate

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Authors: Sruthi Raveendran

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Developmental dyslexia, characterized by reading difficulties despite normal intelligence, presents a significant challenge for bilingual children navigating languages with varying degrees of orthographic transparency. This study bridges a critical gap in dyslexia interventions for bilingual populations in India by examining how consistency and predictability of letter-sound relationships in a writing system (orthographic transparency) influence the ability to understand and manipulate the building blocks of sound in language (phonological processing). The study employed a computerized visual rhyme-judgment task with concurrent EEG (electroencephalogram) recording. The task compared reaction times, accuracy of performance, and event-related potential (ERP) components (N170, N400, and LPC) for rhyming and non-rhyming stimuli in two orthographies: English (opaque orthography) and Kannada (transparent orthography). As hypothesized, the results revealed advantages in phonological processing tasks for transparent orthography (Kannada). Children with dyslexia were faster and more accurate when judging rhymes in Kannada compared to English. This suggests that a language with consistent letter-sound relationships (transparent orthography) facilitates processing, especially for tasks that involve manipulating sounds within words (rhyming). Furthermore, brain activity measured by event-related potentials (ERP) showed less effort required for processing words in Kannada, as reflected by smaller N170, N400, and LPC amplitudes. These findings highlight the crucial role of orthographic transparency in optimizing reading performance for bilingual children with dyslexia. These findings emphasize the need for language-specific intervention strategies that consider the unique linguistic characteristics of each language. While acknowledging the complexity of factors influencing dyslexia, this research contributes valuable insights into the impact of orthographic transparency on phonological awareness in bilingual children. This knowledge paves the way for developing tailored interventions that promote linguistic inclusivity and optimize literacy outcomes for children with dyslexia.

Keywords: developmental dyslexia, phonological awareness, rhyme judgment, orthographic transparency, Kannada, English, N170, N400, LPC

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Authors: Yang Xinyu, Gong Cong, Hu Changjuan

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Stairway spaces are a crucial component of the pathway systems and vertical transportation networks in mountain city parks. These spaces are closely integrated with the undulating terrain of mountain environments, resulting in continuously changing spatial conditions that can significantly influence participants' behavioral characteristics, thereby affecting their perception. EEG signals, which have been proven to reflect various non-attentive physiological activities in the brain, are widely used in studies related to stress recovery effects and emotional perception. Existing research predominantly examines the impact of spatial characteristics and landscape elements of trails and greenways in plain cities on participants' perception, utilizing EEG signals in laboratory-simulated environments. These studies have preliminarily revealed the relationship between spatial environments and perception preferences. However, on-site ergonomics research in mountain environments remains relatively underdeveloped. To address this gap, the Stairway spaces in Pipashan Park, Chongqing, were selected as the research object. Wearable hydrogel EEG devices were employed to monitor participants' EEG data in real environments, and a Generalized Linear Mixed Model (GLMM) was constructed to explore differences in participants' perception under different paths and modes of movement, as well as the impact of visual and auditory environmental elements within each path on their perception. The model analysis results indicate significant differences in EEG data across different paths and movement modes. Additionally, typical mountainous spatial characteristics, such as openness, green view index, and elevation difference, are identified as key factors influencing participants' EEG data. Higher levels of natural sound and green view index were shown to effectively alleviate participants' stress perception in mountain stairway spaces. The findings reveal the intrinsic connections between environment, behavior, and perception in stairway spaces of mountain city parks, providing a theoretical basis for optimizing the design of stairway spaces in mountain cities.

Keywords: audio-visual perception, EEG monitoring, mountain city park, real environment, stairway space

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Authors: Man-Yun Liu, Emily Chia-Yu Su

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Alzheimer's disease (AD) is the public health crisis of the 21st century. AD is a degenerative brain disease and the most common cause of dementia, a costly disease on the healthcare system. Unfortunately, the cause of AD is poorly understood, furthermore; the treatments of AD so far can only alleviate symptoms rather cure or stop the progress of the disease. Currently, there are several ways to diagnose AD; medical imaging can be used to distinguish between AD, other dementias, and early onset AD, and cerebrospinal fluid (CSF). Compared with other diagnostic tools, blood (plasma) test has advantages as an approach to population-based disease screening because it is simpler, less invasive also cost effective. In our study, we used blood biomarkers dataset of The Alzheimer’s disease Neuroimaging Initiative (ADNI) which was funded by National Institutes of Health (NIH) to do data analysis and develop a prediction model. We used independent analysis of datasets to identify plasma protein biomarkers predicting early onset AD. Firstly, to compare the basic demographic statistics between the cohorts, we used SAS Enterprise Guide to do data preprocessing and statistical analysis. Secondly, we used logistic regression, neural network, decision tree to validate biomarkers by SAS Enterprise Miner. This study generated data from ADNI, contained 146 blood biomarkers from 566 participants. Participants include cognitive normal (healthy), mild cognitive impairment (MCI), and patient suffered Alzheimer’s disease (AD). Participants’ samples were separated into two groups, healthy and MCI, healthy and AD, respectively. We used the two groups to compare important biomarkers of AD and MCI. In preprocessing, we used a t-test to filter 41/47 features between the two groups (healthy and AD, healthy and MCI) before using machine learning algorithms. Then we have built model with 4 machine learning methods, the best AUC of two groups separately are 0.991/0.709. We want to stress the importance that the simple, less invasive, common blood (plasma) test may also early diagnose AD. As our opinion, the result will provide evidence that blood-based biomarkers might be an alternative diagnostics tool before further examination with CSF and medical imaging. A comprehensive study on the differences in blood-based biomarkers between AD patients and healthy subjects is warranted. Early detection of AD progression will allow physicians the opportunity for early intervention and treatment.

Keywords: Alzheimer's disease, blood-based biomarkers, diagnostics, early detection, machine learning

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Authors: Marco Frieslaar, Bing Chu, Eric Rogers

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Stroke is a devastating illness that is the second biggest cause of death in the world (after heart disease). Where it does not kill, it leaves survivors with debilitating sensory and physical impairments that not only seriously harm their quality of life, but also cause a high incidence of severe depression. It is widely accepted that early intervention is essential for recovery, but current rehabilitation techniques largely favor hospital-based therapies which have restricted access, expensive and specialist equipment and tend to side-step the emotional challenges. In addition, there is insufficient funding available to provide the long-term assistance that is required. As a consequence, recovery rates are poor. The relatively unexplored solution is to develop therapies that can be harnessed in the home and are formulated from technologies that already exist in everyday life. This would empower individuals to take control of their own improvement and provide choice in terms of when and where they feel best able to undertake their own healing. This research seeks to identify how effective post-stroke, rehabilitation therapy can be applied to upper limb mobility, within the physical context of a home rather than a hospital. This is being achieved through the design and construction of an automation scheme, based on iterative learning control and the Riener muscle model, that has the ability to adapt to the user and react to their level of fatigue and provide tangible physical recovery. It utilizes a SMART Phone and laptop to construct an iterative learning control (ILC) system, that monitors upper arm movement in three dimensions, as a series of exercises are undertaken. The equipment generates functional electrical stimulation to assist in muscle activation and thus improve directional accuracy. In addition, it monitors speed, accuracy, areas of motion weakness and similar parameters to create a performance index that can be compared over time and extrapolated to establish an independent and objective assessment scheme, plus an approximate estimation of predicted final outcome. To further extend its assessment capabilities, nerve conduction velocity readings are taken by the software, between the shoulder and hand muscles. This is utilized to measure the speed of response of neuron signal transfer along the arm and over time, an online indication of regeneration levels can be obtained. This will prove whether or not sufficient training intensity is being achieved even before perceivable movement dexterity is observed. The device also provides the option to connect to other users, via the internet, so that the patient can avoid feelings of isolation and can undertake movement exercises together with others in a similar position. This should create benefits not only for the encouragement of rehabilitation participation, but also an emotional support network potential. It is intended that this approach will extend the availability of stroke recovery options, enable ease of access at a low cost, reduce susceptibility to depression and through these endeavors, enhance the overall recovery success rate.

Keywords: home-based therapy, iterative learning control, Riener muscle model, SMART phone, stroke rehabilitation

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Authors: Thaminda Liyanage, Chamila Shamika Kurukulasuriya

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Introduction: Morbid obesity has been successfully treated with bariatric surgery for over 60 years. Although operative procedures have improved and associated complications have reduced substantially, surgery still carries the risk of post-operative malabsorption, malnutrition and a range of gastrointestinal disorders. Overweight by itself can impair libido in both sexes and cause erectile dysfunction in males by inducing a state of hypogonadotropic hypogonadism, proportional to the degree of obesity. Impact of weight reduction on libido and sexual activity remains controversial, however it is broadly accepted that weight loss improves sexual drive. Zinc deficiency, subsequent to malabsorption, may lead to impaired testosterone synthesis in men while excessive and/or rapid weight loss in females may result in reversible amenorrhoea leading to sub-fertility. Methods: We describe a 37 year old male, 6 years post Roux-en-Y gastric bypass surgery, who presented with erectile dysfunction, loss of libido, worsening fatigue and generalized weakness for 4 months. He also complained of constipation and frequent muscle cramps but denied having headache, vomiting or visual disturbances. Patient had lost 38 kg of body weight post gastric bypass surgery over four years {135kg (BMI 42.6 kg/m2) to 97 kg (BMI 30.6 kg/m2)} and the weight had been stable for past two years. He had no recognised co-morbidities at the time of the surgery and noted marked improvement in general wellbeing, physical fitness and psychological confident post surgery, up until four months before presentation. Clinical examination revealed dry pale skin with normal body hair distribution, no thyroid nodules or goitre, normal size testicles and normal neurological examination with no visual field defects or diplopia. He had low serum testosterone, follicular stimulating hormone (FSH), luteinizing hormone (LH), T3, T4, thyroid stimulating hormone (TSH), insulin like growth factor 1 (IGF-1) and 24-hour urine cortisol levels. Serum cortisol demonstrated an appropriate rise to ACTH stimulation test but growth hormone (GH) failed increase on insulin tolerance test. Other biochemical and haematological studies were normal, except for low zinc and folate with minimally raised liver enzymes. MRI scan of the head confirmed a solid pituitary mass with no mass effect on optic chiasm. Results: In this patient clinical, biochemical and radiological findings were consistent with anterior pituitary dysfunction. However, there were no features of raised intracranial pressure or neurological compromise. He was commenced on appropriate home replacement therapy and referred for neurosurgical evaluation. Patient reported marked improvement in his symptoms, specially libido and erectile dysfunction, on subsequent follow up visits. Conclusion: Sexual dysfunction coupled with non specific constitutional symptoms has multiple aetiologies. Clinical symptoms out of proportion to nutritional deficiencies post bariatric surgery should be thoroughly investigated. Close long term follow up is crucial for overall success.

Keywords: obesity, bariatric surgery, erectile dysfunction, loss of libido

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Authors: Deeba N. Baig, Ateeqa Ijaz, Saloome Rafiq

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Camel is a religious and culturally significant animal in Asian and African regions. In Pakistan Dromedary and Bactrian are common camel breeds. Other than the transportation use, it is a pivotal source of milk and meat. The quality of its milk and meat is predominantly dependent on the geographical location and variety of vegetation available for the diet. Camel milk (CM) is highly nutritious because of its reduced cholesterol and sugar contents along with enhanced minerals and vitamins level. The absence of beta-lactoglobulin (like human milk), makes CM a safer alternative for infants and children having Cow Milk Allergy (CMA). In addition to this, it has a unique probiotic profile both in raw and fermented form. Number of Lactic acid bacteria (LAB) including lactococcus, lactobacillus, enterococcus, streptococcus, weissella, pediococcus and many other bacteria have been detected. From these LAB Lactobacilli, Bifidobacterium and Enterococcus are widely used commercially for fermentation purpose. CM has high therapeutic value as its effectiveness is known against various ailments like fever, arthritis, asthma, gastritis, hepatitis, Jaundice, constipation, postpartum care of women, anti-venom, dropsy etc. It also has anti-diabetic, anti-microbial, antitumor potential along with its robust efficacy in the treatment of auto-immune disorders. Recently, the role of CM has been explored in brain-gut axis for the therapeutics of neurodevelopmental disorders. In this connection, a lot of grey area was available to explore the probiotics and therapeutics latent in the CM available in Pakistan. Thus, current study was designed to explore the predominant probiotic flora and antimicrobial potential of CM from different local breeds of Pakistan. The probiotics have been identified through biochemical, physiological and ribo-typing methods. In addition to this, bacteriocins (antimicrobial-agents) were screened through PCR-based approach. Results of this study revealed that CM from different breeds of camel depicted a number of similar probiotic candidates along with the range of limited variability. However, the nucleotide sequence analysis of selected anti-listerial bacteriocins exposed least variability. As a conclusion, the CM has sufficient probiotic availability and significant anti-microbial potential.

Keywords: bacteriocins, camel milk, probiotics potential, therapeutics

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Authors: Panagiota A. Kotsoni, George S. Ypsilandis

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Learning an L2 is a demanding process for all students and in particular for those with learning disabilities (LD) who demonstrate an inability to catch up with their classmates’ progress in a given period of time. This area of study, i.e. examining children with learning disabilities in L2 has not (yet) attracted the growing interest that is registered in L1 and thus remains comparatively neglected. It is this scientific field that this study wishes to contribute to. The longitudinal purpose of this study is to locate effective Supportive Feedback Strategies (SFS) and add to the quality of learning in second language vocabulary in both typically developing (TD) and LD children. Specifically, this study aims at investigating and comparing the performance of TD with LD children on two different types of SFSs related to vocabulary short and long-term retention. In this study two different SFSs have been examined to a total of ten (10) unknown vocabulary items. Both strategies provided morphosyntactic clarifications upon new contextualized vocabulary items. The traditional SFS (direct) provided the information only in one hypertext page with a selection on the relevant item. The experimental SFS (engaging) provided the exact same split information in three successive hypertext pages in the form of a hybrid dialogue asking from the subjects to move on to the next page by selecting the relevant link. It was hypothesized that this way the subjects would engage in their own learning process by actively asking for more information which would further lead to their better retention. The participants were fifty-two (52) foreign language learners (33 TD and 19 LD) aged from 9 to 12, attending an English language school at the level of A1 (CEFR). The design of the study followed a typical pre-post-post test procedure after an hour and after a week. The results indicated statistically significant group differences with TD children performing significantly better than the LD group in both short and long-term memory measurements and in both SFSs. As regards the effectiveness of one SFS over another the initial hypothesis was not supported by the evidence as the traditional SFS was more effective compared to the experimental one in both TD and LD children. This difference proved to be statistically significant only in the long-term memory measurement and only in the TD group. It may be concluded that the human brain seems to adapt to different SFS although it shows a small preference when information is provided in a direct manner.

Keywords: learning disabilities, memory, second/foreign language acquisition, supportive feedback

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Authors: John McDowall, Lucy Lightfoot

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Stigma constitutes a significant barrier to the recovery and social integration of individuals affected by mental illness. Although there is some debate in the literature regarding the definition and utility of stigma as a concept, it is widely accepted that it comprises three components: stereotypical beliefs, prejudicial reactions, and discrimination. Stereotypical beliefs describe the cognitive knowledge-based component of stigma, referring to beliefs (often negative) about members of a group that is based on cultural and societal norms (e.g. ‘People with anxiety are just weak’). Prejudice refers to the affective/evaluative component of stigma and describes the endorsement of negative stereotypes and the resulting negative emotional reactions (e.g. ‘People with anxiety are just weak, and they frustrate me’). Discrimination refers to the behavioural component of stigma, which is arguably the most problematic, as it exerts a direct effect on the stigmatized person and may lead people to behave in a hostile or avoidant way towards them (i.e. refusal to hire them). Research exploring anti-stigma initiatives focus primarily on an educational approach, with the view that accurate information will replace misconceptions and decrease stigma. Many approaches take a biogenetic stance, emphasising brain and biochemical deficits - the idea being that ‘mental illness is an illness like any other.' While this approach tends to effectively reduce blame, it has also demonstrated negative effects such as increasing prognostic pessimism, the desire for social distance and perceptions of stereotypes. In the present study 144 participants were split into three groups and read one of three vignettes presenting causal explanations for Generalised Anxiety Disorder (GAD): One explanation emphasized biogenetic factors as being important in the etiology of GAD, another emphasised psychosocial factors (e.g. aversive life events, poverty, etc.), and a third stressed the adaptive features of the disorder from an evolutionary viewpoint. A variety of measures tapping the various components of stigma were administered following the vignettes. No difference in stigma measures as a function of causal explanation was found. People who had contact with mental illness in the past were significantly less stigmatising across a wide range of measures, but this did not interact with the type of causal explanation.

Keywords: generalised anxiety disorder, discrimination, prejudice, stigma

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Authors: Siti Aisya Gany, Swee Ching Tan, Sook Yee Gan

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Diminished antioxidant defense or increased production of reactive oxygen species in the biological system can result in oxidative stress which may lead to various neurodegenerative diseases including Alzheimer’s disease (AD). Microglial activation also contributes to the progression of AD by producing several pro-inflammatory cytokines, nitric oxide (NO), and prostaglandin E2 (PGE2). Oxidative stress and inflammation have been reported to be possible pathophysiological mechanisms underlying AD. In addition, the cholinergic hypothesis postulates that memory impairment in patient with AD is also associated with the deficit of cholinergic function in the brain. Although a number of drugs have been approved for the treatment of AD, most of these synthetic drugs have diverse side effects and yield relatively modest benefits. Marine algae have great potential in pharmaceutical and biomedical applications as they are valuable sources of bioactive properties such as anti-coagulation, anti-microbial, anti-oxidative, anti-cancer and anti-inflammatory. Hence, this study aimed to provide an overview of the properties of Malaysian seaweeds (Padina australis, Sargassum polycystum and Caulerpa racemosa) in inhibiting oxidative stress, neuroinflammation and cholinesterase enzymes. All tested samples significantly exhibit potent DPPH and moderate Superoxide anion radical scavenging ability (P<0.05). Hexane and methanol extracts of S. polycystum exhibited the most potent radical scavenging ability with IC50 values of 0.1572 ± 0.004 mg/ml and 0.8493 ± 0.02 for DPPH and ABTS assays, respectively. Hexane extract of C. racemosa gave the strongest superoxide radical inhibitory effect (IC50 of 0.3862± 0.01 mg/ml). Most seaweed extracts significantly inhibited the production of cytokine (IL-6, IL-1 β, TNFα) and NO in a concentration-dependent manner without causing significant cytotoxicity to the lipopolysaccharide (LPS)-stimulated microglia cells (P<0.05). All extracts suppressed cytokine and NO level by more than 80% at the concentration of 0.4mg/ml. In addition, C. racemosa and S. polycystum also showed anti-acetylcholinesterase activities with the IC50 values ranging from 0.086-0.115 mg/ml. Moreover, C. racemosa and P. australis were also found to be active against butyrylcholinesterase with IC50 values ranging from 0.118-0.287 mg/ml.

Keywords: anti-cholinesterase, anti-oxidative, neuroinflammation, seaweeds

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Authors: Alexander Vandesompele, Joni Dambre

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The diversity in dendritic arborization, as first illustrated by Santiago Ramon y Cajal, has always suggested a role for dendrites in the functionality of neurons. In the past decades, thanks to new recording techniques and optical stimulation methods, it has become clear that dendrites are not merely passive electrical components. They are observed to integrate inputs in a non-linear fashion and actively participate in computations. Regardless, in simulations of neural networks dendritic structure and functionality are often overlooked. Especially in a machine learning context, when designing artificial neural networks, point neuron models such as the leaky-integrate-and-fire (LIF) model are dominant. These models mimic the integration of inputs at the neuron soma, and ignore the existence of dendrites. In this work, the LIF point neuron model is extended with a simple form of dendritic computation. This gives the LIF neuron increased capacity to discriminate spatiotemporal input sequences, a dendritic functionality as observed in another study. Simulations of the spiking neurons are performed using the Bindsnet framework. In the common LIF model, incoming synapses are independent. Here, we introduce a dependency between incoming synapses such that the post-synaptic impact of a spike is not only determined by the weight of the synapse, but also by the activity of other synapses. This is a form of short term plasticity where synapses are potentiated or depressed by the preceding activity of neighbouring synapses. This is a straightforward way to prevent inputs from simply summing linearly at the soma. To implement this, each pair of synapses on a neuron is assigned a variable,representing the synaptic relation. This variable determines the magnitude ofthe short term plasticity. These variables can be chosen randomly or, more interestingly, can be learned using a form of Hebbian learning. We use Spike-Time-Dependent-Plasticity (STDP), commonly used to learn synaptic strength magnitudes. If all neurons in a layer receive the same input, they tend to learn the same through STDP. Adding inhibitory connections between the neurons creates a winner-take-all (WTA) network. This causes the different neurons to learn different input sequences. To illustrate the impact of the proposed dendritic mechanism, even without learning, we attach five input neurons to two output neurons. One output neuron isa regular LIF neuron, the other output neuron is a LIF neuron with dendritic relationships. Then, the five input neurons are allowed to fire in a particular order. The membrane potentials are reset and subsequently the five input neurons are fired in the reversed order. As the regular LIF neuron linearly integrates its inputs at the soma, the membrane potential response to both sequences is similar in magnitude. In the other output neuron, due to the dendritic mechanism, the membrane potential response is different for both sequences. Hence, the dendritic mechanism improves the neuron’s capacity for discriminating spa-tiotemporal sequences. Dendritic computations improve LIF neurons even if the relationships between synapses are established randomly. Ideally however, a learning rule is used to improve the dendritic relationships based on input data. It is possible to learn synaptic strength with STDP, to make a neuron more sensitive to its input. Similarly, it is possible to learn dendritic relationships with STDP, to make the neuron more sensitive to spatiotemporal input sequences. Feeding structured data to a WTA network with dendritic computation leads to a significantly higher number of discriminated input patterns. Without the dendritic computation, output neurons are less specific and may, for instance, be activated by a sequence in reverse order.

Keywords: dendritic computation, spiking neural networks, point neuron model

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Authors: Noman Shahzad, Amyn Pardhan, Hasnain Zafar

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Introduction: Though short term survival advantage of damage control laparotomy in management of critically ill trauma patients is established, there is little known about the long-term quality of life of these patients. Facial closure rate after damage control laparotomy is reported to be 20-70 percent. Abdominal wall reconstruction in those who failed to achieve facial closure is challenging and can potentially affect quality of life of these patients. Methodology: We conducted retrospective matched cohort study. Adult patients who underwent damage control laparotomy from Jan 2007 till Jun 2013 were identified through medical record. Patients who had concomitant disabling brain injury or limb injuries requiring amputation were excluded. Age, gender and presentation time matched non exposure group of patients who underwent laparotomy for trauma but no damage control were identified for each damage control laparotomy patient. Quality of life assessment was done via telephonic interview at least one year after the operation, using Urdu version of EuroQol Group Quality of Life (QOL) questionnaire EQ5D after permission. Wilcoxon signed rank test was used to compare QOL scores and McNemar test was used to compare individual parameters of QOL questionnaire. Study was approved by institutional ethical review committee. Results: Out of 32 patients who underwent damage control laparotomy during study period, 20 fulfilled the selection criteria for which 20 matched controls were selected. Median age of patients (IQ Range) was 33 (26-40) years. Facial closure rate in damage control laparotomy group was 40% (8/20). One third of those who did not achieve facial closure (4/12) underwent abdominal wall reconstruction. Self-reported QOL score of damage control laparotomy patients was significantly worse than non-damage control group (p = 0.032). There was no statistically significant difference in two groups regarding individual QOL measures. Significantly, more patients in damage control group were requiring use of abdominal binder, and more patients in damage control group had to either change their job or had limitations in continuing previous job. Our study was not adequately powered to detect factors responsible for worse QOL in damage control group. Conclusion: Quality of life of damage control patients is worse than their age and gender matched patients who underwent trauma laparotomy but not damage control. Adequately powered studies need to be conducted to explore factors responsible for this finding for potential improvement.

Keywords: damage control laparotomy, laparostomy, quality of life

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Authors: Elena Bellini, Daniele Mugnaini, Michele Boschetto

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People with an Autistic Spectrum Disorder and an Intellectual Disability who need to attend a Hospital Emergency Waiting Room frequently present high levels of discomfort and challenging behaviors due to stress-related hyperarousal, sensory sensitivity, novelty-anxiety, communication and self-regulation difficulties. Increased agitation and acting out also disturb the diagnostic and therapeutic processes, and the emergency room climate. Architectural design disciplines aimed at reducing distress in hospitals or creating autism-friendly environments are called for to find effective answers to this particular need. A growing number of researchers are considering the physical environment as an important point of intervention for people with autism. It has been shown that providing the right setting can help enhance confidence and self-esteem and can have a profound impact on their health and wellbeing. Environmental psychology has evaluated the perceived quality of care, looking at the design of hospital rooms, paths and circulation, waiting rooms, services and devices. Furthermore, many studies have investigated the influence of the hospital environment on patients, in terms of stress-reduction and therapeutic intervention’ speed, but also on health professionals and their work. Several services around the world are organizing autism-friendly hospital environments which involve the architecture and the specific staff training. In Italy, the association Spes contra spem has promoted and published, in 2013, the ‘Chart of disabled people in the hospital’. It stipulates that disabled people should have equal rights to accessible and high-quality care. There are a few Italian examples of therapeutic programmes for autistic people as the Dama project in Milan and the recent experience of Children and Autism Foundation in Pordenone. Careggi’s Emergency Waiting Room in Florence has been built to satisfy this challenge. This project of research comes from a collaboration between the technical staff of Careggi Hospital, the Center for autism PAMAPI and some architects expert in the sensory environment. The methodology of focus group involved architects, psychologists and professionals through a transdisciplinary research, centered on the links between the spatial characteristics and clinical state of people with ASD. The relationship between architectural space and quality of life is studied to pay maximum attention to users’ needs and to support the medical staff in their work by a specific program of training. The result of this research is a sum of criteria used to design the emergency waiting room, that will be illustrated. A protected room, with a clear space design, maximizes comprehension and predictability. The multisensory environment is thought to help sensory integration and relaxation. Visual communication through Ipad allows an anticipated understanding of medical procedures, and a specific technological system supports requests, choices and self-determination in order to fit sensory stimulation to personal preferences, especially for hypo and hypersensitive people. All these characteristics should ensure a better regulation of the arousal, less behavior problems, improving treatment accessibility, safety, and effectiveness. First results about patient-satisfaction levels will be presented.

Keywords: accessibility of care, autism-friendly architecture, personalized therapeutic process, sensory environment

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Authors: Hebah M. Musalem, Jeylan El-Mansoury, Lin M. Tuleimat, Selwa Alhazza, Abdul-Aziz A. Al Zoba

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Background: Amblyopia is a condition that affects the visual system triggering a decrease in visual acuity without a known underlying pathology. It is due to abnormal vision development in childhood or infancy. Most importantly, vision loss is preventable or reversible with the right kind of intervention in most of the cases. Strabismus, sensory defects, and anisometropia are all well-known causes of amblyopia. However, ocular misalignment in Strabismus is considered the most common form of amblyopia worldwide. The risk of developing amblyopia increases in premature children, developmentally delayed or children who had brain lesions affecting the visual pathway. The prevalence of amblyopia varies between 2 to 5 % in the world according to the literature. Objective: To determine the different causes of Amblyopia in pediatric patients seen in ophthalmology clinic of a tertiary care center, i.e. King Faisal Specialist Hospital and Research Center (KFSH&RC). Methods: This is a hospital based, random retrospective, based on reviewing patient’s files in the Ophthalmology Department of KFSH&RC in Riyadh city, Kingdom of Saudi Arabia. Inclusion criteria: amblyopic pediatric patients who attended the clinic from 2015 to 2016, who are between 6 months and 18 years old. Exclusion Criteria: patients above 18 years of age and any patient who is uncooperative to obtain an accurate vision or a proper refraction. Detailed ocular and medical history are recorded. The examination protocol includes a full ocular exam, full cycloplegic refraction, visual acuity measurement, ocular motility and strabismus evaluation. All data were organized in tables and graphs and analyzed by statistician. Results: Our preliminary results will be discussed on spot by our corresponding author. Conclusions: We focused on this study on utilizing various examination techniques which enhanced our results and highlighted a distinguished correlation between amblyopia and its’ causes. This paper recommendation emphasizes on critical testing protocols to be followed among amblyopic patient, especially in tertiary care centers.

Keywords: amblyopia, amblyopia causes, amblyopia diagnostic criterion, amblyopia prevalence, Saudi Arabia

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Authors: Anoop T. R., Otman Basir, Robert F. Hess, Eileen E. Birch, Brooke A. Koritala, Reed M. Jost, Becky Luu, David Stager, Ben Thompson

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Strabismus refers to a misalignment of the eyes. Early detection and treatment of strabismus in childhood can prevent the development of permanent vision loss due to abnormal development of visual brain areas. We developed a two-stage method for strabismus detection and classification based on photographs of the face. The first stage detects the presence or absence of strabismus, and the second stage classifies the type of strabismus. The first stage comprises face detection using Haar cascade, facial landmark estimation, face alignment, aligned face landmark detection, segmentation of the eye region, and detection of strabismus using VGG 16 convolution neural networks. Face alignment transforms the face to a canonical pose to ensure consistency in subsequent analysis. Using facial landmarks, the eye region is segmented from the aligned face and fed into a VGG 16 CNN model, which has been trained to classify strabismus. The CNN determines whether strabismus is present and classifies the type of strabismus (exotropia, esotropia, and vertical deviation). If stage 1 detects strabismus, the eye region image is fed into stage 2, which starts with the estimation of pupil center coordinates using mask R-CNN deep neural networks. Then, the distance between the pupil coordinates and eye landmarks is calculated along with the angle that the pupil coordinates make with the horizontal and vertical axis. The distance and angle information is used to characterize the degree and direction of the strabismic eye misalignment. This model was tested on 100 clinically labeled images of children with (n = 50) and without (n = 50) strabismus. The True Positive Rate (TPR) and False Positive Rate (FPR) of the first stage were 94% and 6% respectively. The classification stage has produced a TPR of 94.73%, 94.44%, and 100% for esotropia, exotropia, and vertical deviations, respectively. This method also had an FPR of 5.26%, 5.55%, and 0% for esotropia, exotropia, and vertical deviation, respectively. The addition of one more feature related to the location of corneal light reflections may reduce the FPR, which was primarily due to children with pseudo-strabismus (the appearance of strabismus due to a wide nasal bridge or skin folds on the nasal side of the eyes).

Keywords: strabismus, deep neural networks, face detection, facial landmarks, face alignment, segmentation, VGG 16, mask R-CNN, pupil coordinates, angle deviation, horizontal and vertical deviation

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Authors: Thanthrige Thiunuwan Priyathilaka, Don Anushka Sandaruwan Elvitigala, Bong-Soo Lim, Hyung-Bok Jeong, Jehee Lee

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Toll like receptors (TLRs) are a phylogeneticaly conserved family of pattern recognition receptors, which participates in the host immune responses against various pathogens and pathogen derived mitogen. TLR21, a non-mammalian type, is almost restricted to the fish species even though those can be identified rarely in avians and amphibians. Herein, this study was carried out to identify and characterize TLR21 from rock bream (Oplegnathus fasciatus) designated as RbTLR21, at transcriptional and genomic level. In this study, the full length cDNA and genomic sequence of RbTLR21 was identified using previously constructed cDNA sequence database and BAC library, respectively. Identified RbTLR21 sequence was characterized using several bioinformatics tools. The quantitative real time PCR (qPCR) experiment was conducted to determine tissue specific expressional distribution of RbTLR21. Further, transcriptional modulation of RbTLR21 upon the stimulation with Streptococcus iniae (S. iniae), rock bream iridovirus (RBIV) and Edwardsiella tarda (E. tarda) was analyzed in spleen tissues. The complete coding sequence of RbTLR21 was 2919 bp in length which can encode a protein consisting of 973 amino acid residues with molecular mass of 112 kDa and theoretical isoelectric point of 8.6. The anticipated protein sequence resembled a typical TLR domain architecture including C-terminal ectodomain with 16 leucine rich repeats, a transmembrane domain, cytoplasmic TIR domain and signal peptide with 23 amino acid residues. Moreover, protein folding pattern prediction of RbTLR21 exhibited well-structured and folded ectodomain, transmembrane domain and cytoplasmc TIR domain. According to the pair wise sequence analysis data, RbTLR21 showed closest homology with orange-spotted grouper (Epinephelus coioides) TLR21with 76.9% amino acid identity. Furthermore, our phylogenetic analysis revealed that RbTLR21 shows a close evolutionary relationship with its ortholog from Danio rerio. Genomic structure of RbTLR21 consisted of single exon similar to its ortholog of zebra fish. Sevaral putative transcription factor binding sites were also identified in 5ʹ flanking region of RbTLR21. The RBTLR 21 was ubiquitously expressed in all the tissues we tested. Relatively, high expression levels were found in spleen, liver and blood tissues. Upon induction with rock bream iridovirus, RbTLR21 expression was upregulated at the early phase of post induction period even though RbTLR21 expression level was fluctuated at the latter phase of post induction period. Post Edwardsiella tarda injection, RbTLR transcripts were upregulated throughout the experiment. Similarly, Streptococcus iniae induction exhibited significant upregulations of RbTLR21 mRNA expression in the spleen tissues. Collectively, our findings suggest that RbTLR21 is indeed a homolog of TLR21 family members and RbTLR21 may be involved in host immune responses against bacterial and DNA viral infections.

Keywords: rock bream, toll like receptor 21 (TLR21), pattern recognition receptor, genomic characterization

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Authors: Bahar Hazal Yalçınkaya, Bayram Yılmaz, Mustafa Özilgen

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Brain information transmission in the neuronal network occurs in the form of electrical signals. Neural work transmits information between the neurons or neurons and target cells by moving charged particles in a voltage field; a fraction of the energy utilized in this process is dissipated via entropy generation. Exergy loss and entropy generation models demonstrate the inefficiencies of the communication along the dendritic trees. In this study, neurons of 4 different animals were analyzed with one dimensional cable model with N=6 identical dendritic trees and M=3 order of symmetrical branching. Each branch symmetrically bifurcates in accordance with the 3/2 power law in an infinitely long cylinder with the usual core conductor assumptions, where membrane potential is conserved in the core conductor at all branching points. In the model, exergy loss and entropy generation rates are calculated for each branch of equivalent cylinders of electrotonic length (L) ranging from 0.1 to 1.5 for four different dendritic branches, input branch (BI), and sister branch (BS) and two cousin branches (BC-1 & BC-2). Thermodynamic analysis with the data coming from two different cat motoneuron studies show that in both experiments nearly the same amount of exergy is lost while generating nearly the same amount of entropy. Guinea pig vagal motoneuron loses twofold more exergy compared to the cat models and the squid exergy loss and entropy generation were nearly tenfold compared to the guinea pig vagal motoneuron model. Thermodynamic analysis show that the dissipated energy in the dendritic tress is directly proportional with the electrotonic length, exergy loss and entropy generation. Entropy generation and exergy loss show variability not only between the vertebrate and invertebrates but also within the same class. Concurrently, single action potential Na⁺ ion load, metabolic energy utilization and its thermodynamic aspect contributed for squid giant axon and mammalian motoneuron model. Energy demand is supplied to the neurons in the form of Adenosine triphosphate (ATP). Exergy destruction and entropy generation upon ATP hydrolysis are calculated. ATP utilization, exergy destruction and entropy generation showed differences in each model depending on the variations in the ion transport along the channels.

Keywords: ATP utilization, entropy generation, exergy loss, neuronal information transmittance

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Authors: Dalia El Hadi, Alaa Bou Ghannam, Hala Mostafa, Hana Mansour, Ibrahim Hashim, Soubhi Tahhan, Tharwat El Zahran

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Introduction: Neuro-ophthalmological emergencies require prompt assessment and management to avoid vision or life-threatening sequelae. Some would require neuroimaging. Most commonly used are the CT and MRI of the Brain. They can be over-used when not indicated. Their yield remains dependent on multiple factors relating to the clinical scenario. Methods: A retrospective cross-sectional study was conducted by reviewing the electronic medical records of patients presenting to the Emergency Department (ED) with isolated neuro-ophthalmologic complaints. For each patient, data were collected on the clinical presentation, whether neuroimaging was performed (and which type), and the result of neuroimaging. Analysis of the performed neuroimaging was made, and its yield was determined. Results: A total of 211 patients were reviewed. The complaints or symptoms at presentation were: blurry vision, change in the visual field, transient vision loss, floaters, double vision, eye pain, eyelid droop, headache, dizziness and others such as nausea or vomiting. In the ED, a total of 126 neuroimaging procedures were performed. Ninety-four imagings (74.6%) were normal, while 32 (25.4%) had relevant abnormal findings. Only 2 symptoms were significant for abnormal imaging: blurry vision (p-value= 0.038) and visual field change (p-value= 0.014). While 4 physical exam findings had significant abnormal imaging: visual field defect (p-value= 0.016), abnormal pupil reactivity (p-value= 0.028), afferent pupillary defect (p-value= 0.018), and abnormal optic disc exam (p-value= 0.009). Conclusion: Risk indicators for abnormal neuroimaging in the setting of neuro-ophthalmological emergencies are blurred vision or changes in the visual field on history taking. While visual field irregularities, abnormal pupil reactivity with or without afferent pupillary defect, or abnormal optic discs, are risk factors related to physical testing. These findings, when present, should sway the ED physician towards neuroimaging but still individualizing each case is of utmost importance to prevent time-consuming, resource-draining, and sometimes unnecessary workup. In the end, it suggests a well-structured patient-centered algorithm to be followed by ED physicians.

Keywords: emergency department, neuro-ophthalmology, neuroimaging, risk indicators

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Authors: Scott Andersen

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Perhaps simply and rather unadornedly, consciousness is having multiple goals for action and the continuously adjudication of such goals to implement action, referred to as the Maps of Meaning (MoM) Consciousness Theory. The MoM theory triangulates through three parallel corollaries, action (behavior), mechanism (morphology/pathophysiology), and goals (teleology). (1) An organism’s consciousness contains a fluid, nested goals. These goals are not intentionality, but intersectionality, embodiment meeting the world. i.e., Darwinian inclusive fitness or randomization, then survival of the fittest. These goals form via gradual descent under inclusive fitness, the goals being the abstraction of a ‘match’ between the evolutionary environment and organism. Human consciousness implements the brain efficiency hypothesis, genetics, epigenetics, and experience crystallize efficiencies, not necessitating best or objective but fitness, i.e., perceived efficiency based on one’s adaptive environment. These efficiencies are objectively arbitrary, but determine the operation and level of one’s consciousness, termed extreme thrownness. Since inclusive fitness drives efficiencies in physiologic mechanism, morphology and behavior (action) and originates one’s goals, embodiment is necessarily entangled to human consciousness as its the intersection of mechanism or action (both necessitating embodiment) occurring in the world that determines fitness. Perception is the operant process of consciousness and is the consciousness’ de facto goal adjudication process. Goal operationalization is fundamentally efficiency-based via one’s unique neuronal mapping as a byproduct of genetics, epigenetics, and experience. Perception involves information intake and information discrimination, equally underpinned by efficiencies of inclusive fitness via extreme thrownness. Perception isn’t a ‘frame rate,’ but Bayesian priors of efficiency based on one’s extreme thrownness. Consciousness and human consciousness is a modular (i.e., a scalar level of richness, which builds up like building blocks) and dimensionalized (i.e., cognitive abilities become possibilities as emergent phenomena at various modularities, like stratified factors in factor analysis). The meta dimensions of human consciousness seemingly include intelligence quotient, personality (five-factor model), richness of perception intake, and richness of perception discrimination, among other potentialities. Future consciousness research should utilize factor analysis to parse modularities and dimensions of human consciousness and animal models.

Keywords: consciousness, perception, prospection, embodiment

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Authors: Yogesh Rai, Saurabh Singh, Sanjay Pandey, Dhananjay K. Sah, B. G. Roy, B. S. Dwarakanath, Anant N. Bhatt

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One of the most common signatures of highly malignant gliomas is their capacity to metabolize more glucose to lactic acid than normal brain tissues, even under normoxic conditions (Warburg effect), indicating that aerobic glycolysis is constitutively upregulated through stable genetic or epigenetic changes. However, oxidative phosphorylation (OxPhos) is also required to maintain the mitochondrial membrane potential for tumor cell survival. In the process of tumorigenesis, tumor cells during fastest growth rate exhibit both high glycolytic and high OxPhos. Therefore, metabolically reprogrammed cancer cells with combination of both aerobic glycolysis and altered OxPhos develop a robust metabolic phenotype, which confers a selective growth advantage. In our study, we grew the high glycolytic BMG-1 (glioma) cells with continuous exposure of mitochondrial uncoupler 2, 4, dinitro phenol (DNP) for 10 passages to obtain a phenotype of high glycolysis with enhanced altered OxPhos. We found that OxPhos modified BMG (OPMBMG) cells has similar growth rate and cell cycle distribution but high mitochondrial mass and functional enzymatic activity than parental cells. In in-vitro studies, OPMBMG cells showed enhanced invasion, proliferation and migration properties. Moreover, it also showed enhanced angiogenesis in matrigel plug assay. Xenografted tumors from OPMBMG cells showed reduced latent period, faster growth rate and nearly five folds reduction in the tumor take in nude mice compared to BMG-1 cells, suggesting that robust metabolic phenotype facilitates tumor formation and growth. OPMBMG cells which were found radio-resistant, showed enhanced radio-sensitization by 2-DG as compared to the parental BMG-1 cells. This study suggests that metabolic reprogramming in cancer cells enhances the potential of migration, invasion and proliferation. It also strengthens the cancer cells to escape the death processes, conferring resistance to therapeutic modalities. Our data also suggest that combining metabolic inhibitors like 2-DG with conventional therapeutic modalities can sensitize such metabolically aggressive cancer cells more than the therapies alone.

Keywords: 2-DG, BMG, DNP, OPM-BMG

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Authors: Viviane A. O. Silva, Angela M. Costa, Glaucia N. M. Hajj, Ana Preto, Aline Tansini, Martin Roffé, Peter Jordan, Rui M. Reis

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Autophagy is a recycling and degradative system suggested to be a major cell death pathway in cancer cells. Autophagy pathway is interconnected with the endocytosis pathways sharing the same ultimate lysosomal destination. Lysosomes are crucial regulators of cell homeostasis, responsible to downregulate receptor signalling and turnover. It seems highly likely that derailed endocytosis can make major contributions to several hallmarks of cancer. WNK2, a member of the WNK (with-no-lysine [K]) subfamily of protein kinases, had been found downregulated by its promoter hypermethylation, and has been proposed to act as a specific tumour-suppressor gene in brain tumors. Although some contradictory studies indicated WNK2 as an autophagy modulator, its role in cancer cell death is largely unknown. There is also growing evidence for additional roles of WNK kinases in vesicular traffic. Aim: To evaluate the role of WNK2 in autophagy and endocytosis on glioma context. Methods: Wild-type (wt) A172 cells (WNK2 promoter-methylated), and A172 transfected either with an empty vector (Ev) or with a WNK2 expression vector, were used to assess the cellular basal capacities to promote autophagy, through western blot and flow-cytometry analysis. Additionally, we evaluated the effect of WNK2 on general endocytosis trafficking routes by immunofluorescence. Results: The re-expression of ectopic WNK2 did not interfere with autophagy-related protein light chain 3 (LC3-II) expression levels as well as did not promote mTOR signaling pathway alteration when compared with Ev or wt A172 cells. However, the restoration of WNK2 resulted in a marked increase (8 to 92,4%) of Acidic Vesicular Organelles formation (AVOs). Moreover, our results also suggest that WNK2 cells promotes delay in uptake and internalization rate of cholera toxin B and transferrin ligands. Conclusions: The restoration of WNK2 interferes in vesicular traffic during endocytosis pathway and increase AVOs formation. This results also suggest the role of WNK2 in growth factor receptor turnover related to cell growth and homeostasis and associates one more time, WNK2 silencing contribution in genesis of gliomas.

Keywords: autophagy, endocytosis, glioma, WNK2

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Authors: Tracey Lion-Cachet

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Eating disorders typically manifest in adolescence and are notoriously difficult to treat. There are two notable reasons for this. Firstly, research consistently demonstrates that early intervention is a critical mediator of prognosis, with early intervention leading to a better prognosis. However, because eating disorders do not originate as full-syndrome diagnoses but rather as prodromal cases, they often go undetected; by the time symptoms meet diagnostic criteria, they have become recalcitrant. Another interrelated issue is motivation to change. Research demonstrates that in the early stages of an eating disorder, adolescents are highly resistant to change, and motivation increases only once symptoms have shifted from egosyntonic to egodystonic in nature. The purpose of this project was to design a prevention model based on the social psychology paradigm of Entertainment-Education, which embeds messages within the genre of film as a means of affecting change. The resulting project was a narrative screenplay targeting teenagers/young adults from diverse backgrounds. The goals of the project were to create a film script that, if ultimately made into a film, could serve to: 1) interrupt symptom progression and improve prognosis through early intervention; 2) incorporate techniques from third-wave cognitive behavioral treatment models, acceptance and commitment therapy (ACT) and rational recovery (RR), with a focus on the effects of mindfulness as a means of informing recovery; 3) target issues to do with motivation to change by shifting the perception of eating disorders from culturally specific psychiatric illnesses to habit-based brain wiring issues. Nine licensed clinicians were asked to evaluate two excerpts taken from the final script. They subsequently provided feedback on a Likert-scale, which assessed whether the script had achieved its goals. Overall, evaluators agreed that the project’s etiological and intervention models have the potential to inspire change and serve as an effective means of prevention and treatment of eating disorders. However, one-third of the evaluators did not find the content developmentally appropriate. This is a notable limitation to the study and will need to be addressed in the larger script before the final project can potentially be targeted to a teenage and young adult audience.

Keywords: adolescents, eating disorders, pediatrics, entertainment-education, mindfulness-based intervention, prevention

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Authors: Fatimah Abd Elghani, Raymonde Szargel, Vered Shani, Hazem Safory, Haya Hamza, Mor Savyon, Ruth Rott, Rina Bandopadhyay, Simone Engelender

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Background: PINK1 is a mitochondrial kinase mutated in some familial cases of Parkinson’s disease. Down regulation of PINK1 results in abnormal mitochondrial morphology and altered membrane potential. Although PINK1 has a predicted mitochondrial import sequence, it’s cellular, and submitochondrial localization remains unclear, in part because it is rapidly degraded. In this work, we investigated the mechanisms involved in PINK1 degradation and how this may affect PINK1 stability and function, with implications for mitochondrial function in PD. In addition, pharmacological inhibition of proteasome activity was shown to lead to PINK1 accumulation, indicating that PINK1 degradation depends on the ubiquitin-proteasome system (UPS). Methods: Using co-immunoprecipitation assays, we identified E3 ubiquitin ligase SIAH1 as a PINK1-interacting protein in HEK293 cells as well as on rat brain tissues. In addition, we determined the effect of SIAH 1, SIAH2 and Parkin on PINK1 steady-state levels by Western blot analysis, and checked their possibility to ubiquitinate and mediate PINK1 degradation through the proteasome carried out in vivo ubiquitination experiments. Results: We have obtained results showing that SIAH-1 interacts with and ubiquitinates PINK1. The ubiquitination promoted by SIAH-1 leads to the proteasomal degradation of PINK1. We confirmed these findings by knocking down SIAH-1 and observing important accumulation of PINK1 in cells. Besides, we found that SIAH-1 decreases PINK1 steady-state levels but not the E3 ligase Parkin. We also investigated the interaction of SIAH-1 with PINK1 disease mutants and its ability to promote their ubiquitination and degradation. Although, no clear difference in the ability of SIAH-1 to promote the degradation of PINK1 disease mutants was observed. It is possible that dysfunction of proteasomal activity in the disease may lead to the accumulation and aggregation of ubiquitinated PINK1 in patients with PINK1 mutations, with possible implications to the pathogenesis of PD. Conclusions: Here, we demonstrated that SIAH-1 ubiquitinates and promotes the degradation of PINK1. In addition, SIAH-1 represents now a target that may help the improvement of mitophagy in PD. Further investigations needed to understand how mitophagy is regulated by PINK1-SIAH-1 axis to provide targets for future therapeutics.

Keywords: PD, Parkinson's disease, PINK1, PTEN-induced kinase1, SIAH, seven in absentia homolog, SN, substantia nigra

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Authors: Aleksandra Chałupnik, Zuzanna Chilimoniuk, Joanna Borowik, Aleksandra Borkowska, Anna Torres

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Background: Precocious puberty is the occurrence of secondary sexual characteristics in girls before the age of 8. The diverse etiology of premature puberty is crucial to determine whether it is true precocious puberty, depending on the activation of the hypothalamic-pituitary-gonadal axis, or pseudo-precocious, which is independent of the activation of this axis. Whatever the cause, premature action of the sex hormones leads to the common symptoms of various forms of puberty. These include the development of sexual characteristics, acne, acceleration of growth rate and acceleration of skeletal maturation. Due to the possible genetic basis of the disorders, an interdisciplinary search for the cause is needed. Case report: The case report concerns a patient of a pediatric gynecology clinic who, at the age of two years, developed advanced thelarhe (M3) and started recurrent vaginal bleeding. In August 2019, gonadotropin suppression initially and after LHRH stimulation and high estradiol levels were reported at the Endocrinology Department. Imaging examinations showed a cyst in the right ovary projection. The bone age was six years. The entire clinical picture indicated pseudo- (peripheral) precocious in the course of ovarian autonomic cyst. In the follow-up ultrasound performed in September, the image of the cyst was stationary and normalization of estradiol levels and clinical symptoms was noted. In December 2019, cyst regression and normal gonadotropin and estradiol concentrations were found. In June 2020, white mucus tinged with blood on the underwear, without any other disturbing symptoms, was observed for several days. Two consecutive USG examinations carried out in the same month confirmed the change in the right ovary, the diameter of which was 25 mm with a very high level of estradiol. Germinal tumor markers were normal. On the Tanner scale, the patient scored M2P1. The labia and hymen had puberty features. The correct vaginal entrance was visible. Another active vaginal bleeding occurred in the first week of July 2020. The considered laparoscopic treatment was abandoned due to the lack of oncological indications. Treatment with Tamoxifen was recommended in July 2020. In the initiating period of treatment, no maturation progression, and even reduction of symptoms, no acceleration of growth and a marked reduction in the size of the cysts were noted. There was no bleeding. After the size of the cyst and hormonal activity increased again, the treatment was changed to Anastrozole, the effect of which led to a reduction in the size of the cyst. Conclusions: The entire clinical picture indicates alleged (peripheral) puberty. Premature puberty in girls, which is manifested as enlarged mammary glands with high levels of estrogens secreted by autonomic ovarian cysts and prepubertal levels of gonadotropins, may indicate McCune-Albright syndrome. Vaginal bleeding may also occur in this syndrome. Cancellation of surgical treatment of the cyst made it impossible to perform a molecular test that would allow to confirm the diagnosis. Taking into account the fact that cysts are often one of the first symptoms of McCune-Albrigt syndrome, it is important to remember about multidisciplinary care for the patient and careful search for skin and bone changes or other hormonal disorders.

Keywords: McCune Albrigth's syndrome, ovarian cyst, pediatric gynaecology, precocious puberty

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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

Abstract:

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

Procedia PDF Downloads 119

Authors: Pauline Nyssen, Ange Mouithys-Mickalad, Maryse Hoebeke

Abstract:

Inflammation is a complex physiological phenomenon involving chemical and enzymatic mechanisms. Polymorphonuclear neutrophil leukocytes (PMNs) play an important role by producing reactive oxygen species (ROS) and releasing myeloperoxidase (MPO), a pro-oxidant enzyme. Released both in the phagolysosome and the extracellular medium, MPO produces during its peroxidase and halogenation cycles oxidant species, including hypochlorous acid, involved in the destruction of pathogen agents, like bacteria or viruses. Inflammatory pathologies, like rheumatoid arthritis, atherosclerosis induce an excessive stimulation of the PMNs and, therefore, an uncontrolled release of ROS and MPO in the extracellular medium, causing severe damages to the surrounding tissues and biomolecules such as proteins, lipids, and DNA. The treatment of chronic inflammatory pathologies remains a challenge. For many years, MPO has been used as a target for the development of effective treatments. Numerous studies have been focused on the design of new drugs presenting more efficient MPO inhibitory properties. However, some designed inhibitors can be toxic. An alternative consists of assessing the potential inhibitory action of clinically-known molecules, having antioxidant activity. Propofol, 2,6-diisopropyl phenol, which is used as an intravenous anesthetic agent, meets these requirements. Besides its anesthetic action employed to induce a sedative state during surgery or in intensive care units, propofol and its injectable form Diprivan indeed present antioxidant properties and act as ROS and free radical scavengers. A study has also evidenced the ability of propofol to inhibit the formation of the neutrophil extracellular traps fibers, which are important to trap pathogen microorganisms during the inflammation process. The aim of this study was to investigate the potential inhibitory action mechanism of propofol and Diprivan on MPO activity. To go into the anti-inflammatory action of propofol in-depth, two of its oxidative derivatives, 2,6-diisopropyl-1,4-p-benzoquinone (PPFQ) and 3,5,3’,5’-tetra isopropyl-(4,4’)-diphenoquinone (PPFDQ), were studied regarding their inhibitory action. Specific immunological extraction followed by enzyme detection (SIEFED) and molecular modeling have evidenced the low anti-catalytic action of propofol. Stopped-flow absorption spectroscopy and direct MPO activity analysis have proved that propofol acts as a reversible MPO inhibitor by interacting as a reductive substrate in the peroxidase cycle and promoting the accumulation of redox compound II. Overall, Diprivan exhibited a weaker inhibitory action than the active molecule propofol. In contrast, PPFQ seemed to bind and obstruct the enzyme active site, preventing the trigger of the MPO oxidant cycles. PPFQ induced a better chlorination cycle inhibition at basic and neutral pH in comparison to propofol. PPFDQ did not show any MPO inhibition activity. The three interest molecules have also demonstrated their inhibition ability on an important step of the inflammation pathway, the PMNs superoxide anions production, thanks to EPR spectroscopy and chemiluminescence. In conclusion, propofol presents an interesting immunomodulatory activity by acting as a reductive substrate in the peroxidase cycle of MPO, slowing down its activity, whereas PPFQ acts more as an anti-catalytic substrate. Although PPFDQ has no impact on MPO, it can act on the inflammation process by inhibiting the superoxide anions production by PMNs.

Keywords: Diprivan, inhibitor, myeloperoxidase, propofol, spectroscopy

Procedia PDF Downloads 152