Search results for: multi-modality brain stimulation

Authors: Govindan Sudha, Mathumitha Subramaniam, Alamelu Govindasamy, Sasikala Gunasekaran

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The aim of this study was to investigate the protective effect of Hypsizygus ulmarius polysaccharides (HUP) on reducing oxidative stress, cognitive impairment and neurotoxicity in D-galactose induced aging mice. Mice were subcutaneously injected with D-galactose (150 mg/kg per day) for 6 weeks and were administered HUP simultaneously. Aged mice receiving vitamin E (100 mg/kg) served as positive control. Chronic administration of D-galactose significantly impaired cognitive performance oxidative defence and mitochondrial enzymes activities as compared to control group. The results showed that HUP (200 and 400 mg/kg) treatment significantly improved the learning and memory ability in Morris water maze test. Biochemical examination revealed that HUP significantly increased the decreased activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST), mitochondrial enzymes-NADH dehydrogenase, malate dehydrogenase (MDH), isocitrate dehydrogenase (ICDH), Na+K+, Ca2+, Mg2+ATPase activities, elevated the lowered total anti-oxidation capability (TAOC), glutathione (GSH), vitamin C and decreased the raised acetylcholinesterase (AChE) activities, malondialdehyde (MDA), hydroperoxide (HPO), protein carbonyls (PCO), advanced oxidation protein products (AOPP) levels in brain of aging mice induced by D-gal in a dose-dependent manner. In conclusion, present study highlights the potential role of HUP against D-galactose induced cognitive impairment, biochemical and mitochondrial dysfunction in mice. In vitro studies on the effect of HUP on scavenging DPPH, ABTS, DMPD, OH radicals, reducing power, B-carotene bleaching and lipid peroxidation inhibition confirmed the free radical scavenging and antioxidant activity of HUP. The results suggest that HUP possesses anti-aging efficacy and may have potential in treatment of neurodegenerative diseases.

Keywords: aging, antioxidants, mushroom, neurotoxicity

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Authors: Jeanne Gallee, Sofia Vallila-Rohter

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Technology-based applications are increasingly being utilized in aphasia rehabilitation as a means of increasing intensity of treatment and improving accessibility to treatment. These interactive therapies, often available on tablets, lead individuals to complete language and cognitive rehabilitation tasks that draw upon skills such as the ability to name items, recognize semantic features, count syllables, rhyme, and categorize objects. Tasks involve visual and auditory stimulus cues and provide feedback about the accuracy of a person’s response. Research has begun to examine the efficacy of tablet-based therapies for aphasia, yet much remains unknown about how individuals interact with these therapy applications. Thus, the current study aims to examine the efficacy of a tablet-based therapy program for anomia, further examining how strategy training might influence the way that individuals with aphasia engage with and benefit from therapy. Individuals with aphasia are enrolled in one of two treatment paradigms: traditional therapy or strategy therapy. For ten weeks, all participants receive 2 hours of weekly in-house therapy using Constant Therapy, a tablet-based therapy application. Participants are provided with iPads and are additionally encouraged to work on therapy tasks for one hour a day at home (home logins). For those enrolled in traditional therapy, in-house sessions involve completing therapy tasks while a clinician researcher is present. For those enrolled in the strategy training group, in-house sessions focus on limiting cue use in order to maximize lexical retrieval attempts and naming opportunities. The strategy paradigm is based on the principle that retrieval attempts may foster long-term naming gains. Data have been collected from 7 participants with aphasia (3 in the traditional therapy group, 4 in the strategy training group). We examine cue use, latency of responses and accuracy through the course of therapy, comparing results across group and setting (in-house sessions vs. home logins).

Keywords: aphasia, speech-language pathology, traumatic brain injury, language

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Authors: Balkibekova Venera Serikpaevna

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Background: Autism Spectrum Disorder (ASD) poses significant challenges in both diagnosis and treatment. Existing therapeutic interventions often target specific symptoms, necessitating the exploration of alternative approaches. This study investigates the RITM (Rhythm Integration Tapping Music) developed by Balkibekova, aiming to create imitation, social engagement and a wide range of emotions through brain development. Methods: A randomized controlled trial was conducted with 100 participants diagnosed with ASD, aged 1 to 4 years. Participants were randomly assigned to either the RITM therapy group or a control group receiving standard care. The RITM therapy, rooted in tapping rhythm to music such as: marche on the drums, waltz on bells, lullaby on musical triangle, dancing on tambourine, polka on wooden spoons. Therapy sessions were conducted over a 3 year period, with assessments at baseline, midpoint, and post-intervention. Results: Preliminary analyses reveal promising outcomes in the RITM therapy group. Participants demonstrated significant improvements in social interactions, speech understanding, birth of speech, and adaptive behaviors compared to the control group. Careful examination of subgroup analyses provides insights into the differential effectiveness of the RITM approach across various ASD profiles. Conclusions: The findings suggest that RITM therapy, as developed by Balkibekova, holds promise as intervention for ASD. The integrative nature of the approach, addressing multiple domains simultaneously, may contribute to its efficacy. Further research is warranted to validate these preliminary results and explore the long-term impact of RITM therapy on individuals with ASD. This abstract presents a snapshot of the research, emphasizing the significance, methodology, key findings, and implications of the RITM therapy method for consideration in an autism conference.

Keywords: RITM therapy, tapping rhythm, autism, mirror neurons, bright emotions, social interactions, communications

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Authors: Katie Emerson, Sara Perez-Ojalvo, Jim Komorowski, Danielle Greenberg

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The purpose of this study was to evaluate arginase activity levels in response to combinations of an inositol-stabilized arginine silicate (ASI; Nitrosigine®), L-arginine, and Inositol. Arginine acts as a vasodilator that promotes increased blood flow resulting in enhanced delivery of oxygen and nutrients to the brain and other tissues. ASI alone has been shown to improve performance on cognitive tasks. Arginase, found in human serum, catalyzes the conversion of arginine to ornithine and urea, completing the last step in the urea cycle. Decreasing arginase levels maintains arginine and results in increased nitric oxide production. This study aimed to determine the most effective combination of ASI, L-arginine and inositol for minimizing arginase levels and therefore maximize ASI’s effect on cognition. Serum was taken from untreated healthy donors by separation from clotted factors. Arginase activity of serum in the presence or absence of test products was determined (QuantiChrom™, DARG-100, Bioassay Systems, Hayward CA). The remaining ultra-filtrated serum units were harvested and used as the source for the arginase enzyme. ASI alone or combined with varied levels of Inositol were tested as follows: ASI + inositol at 0.25 g, 0.5 g, 0.75 g, or 1.00 g. L-arginine was also tested as a positive control. All tests elicited changes in arginase activity demonstrating the efficacy of the method used. Adding L-arginine to serum from untreated subjects, with or without inositol only had a mild effect. Adding inositol at all levels reduced arginase activity. Adding 0.5 g to the standardized amount of ASI led to the lowest amount of arginase activity as compared to the 0.25g 0.75g or 1.00g doses of inositol or to L-arginine alone. The outcome of this study demonstrates an interaction of the pairing of inositol with ASI on the activity of the enzyme arginase. We found that neither the maximum nor minimum amount of inositol tested in this study led to maximal arginase inhibition. Since the inhibition of arginase activity is desirable for product formulations looking to maintain arginine levels, the most effective amount of inositol was deemed preferred. Subsequent studies suggest this moderate level of inositol in combination with ASI leads to cognitive improvements including reaction time, executive function, and concentration.

Keywords: arginine, inositol, arginase, cognitive benefits

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Authors: M. Zareh, H. Mohammadi, B. Naser

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Atherosclerotic plaque rupture is the main trigger of heart attack and brain stroke which are the leading cause of death in developed countries. Better understanding of rupture-prone plaque can help clinicians detect vulnerable plaques- rupture prone or instable plaques- and apply immediate medical treatment to prevent these life-threatening cardiovascular events. Therefore, there are plenty of studies addressing disclosure of vulnerable plaques properties. Necrotic core and fibrous tissue are two major tissues constituting atherosclerotic plaque; using histopathological and numerical approaches, many studies have demonstrated that plaque rupture is strongly associated with a large necrotic core and a thin fibrous cap, two morphological characteristic which can be acquired by two-dimensional imaging of atherosclerotic plaque present in coronary and carotid arteries. Plaque rupture is widely considered as a mechanical failure inside plaque tissue; this failure occurs when the stress within plaque excesses the strength of tissue material; hence, finite element method, a strong numerical approach, has been extensively applied to estimate stress distribution within plaques with different compositions which is then used for assessment of various vulnerability characteristics including plaque morphology, material properties and blood pressure. This study aims to evaluate significance of three-dimensional morphology on vulnerability degree of atherosclerotic plaque. To reach this end, different two-dimensional geometrical models of atherosclerotic plaques are considered based on available data and named Main 2D Models (M2M). Then, for each of these M2Ms, two three-dimensional idealistic models are created. These two 3D models represent two possible three-dimensional morphologies which might exist for a plaque with similar 2D morphology to one of M2Ms. Finite element method is employed to estimate stress, von-Mises stress, within each 3D models. Results indicate that for each M2Ms stress can significantly varies due to possible 3D morphological changes in that plaque. Also, our results show that an atherosclerotic plaque with thick cap may experience rupture if it has a critical 3D morphology. This study highlights the effect of 3D geometry of plaque on its instability degree and suggests that 3D morphology of plaque might be necessary to more effectively and accurately assess atherosclerotic plaque vulnerability.

Keywords: atherosclerotic plaque, plaque rupture, finite element method, 3D model

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Authors: Misty Attwood, Helgi Schioth

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Transmembrane proteins are important components in many essential cell processes such as signal transduction, cell-cell signalling, transport of solutes, structural adhesion activities, and protein trafficking. Due to their involvement in diverse critical activities, transmembrane proteins are implicated in different disease pathways and hence are the focus of intense interest in understanding functional activities, their pathogenesis in disease, and their potential as pharmaceutical targets. Further, as the structure and function of proteins are correlated, investigating a group of proteins with the same tertiary structure, i.e., the same number of transmembrane regions, may give understanding about their functional roles and potential as therapeutic targets. In this in silico bioinformatics analysis, we identify and comprehensively characterize the previously unstudied group of proteins with five transmembrane-spanning regions (5TM). We classify nearly 60 5TM proteins in which 31 are members of ten families that contain two or more family members and all members are predicted to contain the 5TM architecture. Furthermore, nine singlet proteins that contain the 5TM architecture without paralogues detected in humans were also identifying, indicating the evolution of single unique proteins with the 5TM structure. Interestingly, more than half of these proteins function in localization activities through movement or tethering of cell components and more than one-third are involved in transport activities, particularly in the mitochondria. Surprisingly, no receptor activity was identified within this family in sharp contrast with other TM families. Three major 5TM families were identified and include the Tweety family, which are pore-forming subunits of the swelling-dependent volume regulated anion channel in astrocytes; the sidoreflexin family that acts as mitochondrial amino acid transporters; and the Yip1 domain family engaged in vesicle budding and intra-Golgi transport. About 30% of the proteins have enhanced expression in the brain, liver, or testis. Importantly, 60% of these proteins are identified as cancer prognostic markers, where they are associated with clinical outcomes of various tumour types, indicating further investigation into the function and expression of these proteins is important. This study provides the first comprehensive analysis of proteins with 5TM regions and provides details of the unique characteristics and application in pharmaceutical development.

Keywords: 5TM, cancer prognostic marker, drug targets, transmembrane protein

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Authors: Aurora Sheehy, Caitlin Prince

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Within current orthodox medical protocols, trauma and mental health issues are deemed to reside within the realm of cognitive or psychological therapists and are marginalised in these areas, in part due to limited drugs option available, mostly manipulating neurotransmitters or sedating patients to reduce symptoms. By contrast, this research presents examples from the clinical practice of how trauma can be assessed and treated physiologically. Adverse Childhood Experiences (ACEs) are a tally of different types of abuse and neglect. It has been used as a measurable and reliable predictor of the likelihood of the development of autoimmune disease. It is a direct way to demonstrate reliably the health impact of traumatic life experiences. A second assessment tool is Allostatic Load, which refers to the cumulative effects that chronic stress has on mental and physical health. It records the decline of an individual’s physiological capacity to cope with their experience. It uses a specific grouping of serum testing and physical measures. It includes an assessment of neuroendocrine, cardiovascular, immune and metabolic systems. Allostatic load demonstrates the health impact that trauma has throughout the body. It forms part of an initial intake assessment in clinical practice and could also be used in research to evaluate treatment. Examining medicinal plants for their physiological, neurological and somatic effects through the lens of Polyvagal theory offers new opportunities for trauma treatments. In situations where Polyvagal theory recommends activities and exercises to enable parasympathetic activation, many herbs that affect Effector Memory T (TEM) cells also enact these responses. Traditional or Indigenous European herbs show the potential to support the polyvagal tone, through multiple mechanisms. As the ventral vagal nerve reaches almost every major organ, plants that have actions on these tissues can be understood via their polyvagal actions, such as monoterpenes as agents to improve respiratory vagal tone, cyanogenic glycosides to reset polyvagal tone, volatile oils rich in phenyl methyl esters improve both sympathetic and parasympathetic tone, bitters activate gut function and can strongly promote parasympathetic regulation. Auricular Acupuncture uses a system of somatotopic mapping of the auricular surface overlaid with an image of an inverted foetus with each body organ and system featured. Given that the concha of the auricle is the only place on the body where the Vagus Nerve neurons reach the surface of the skin, several investigators have evaluated non-invasive, transcutaneous electrical nerve stimulation (TENS) at auricular points. Drawn from an interdisciplinary evidence base and developed through clinical practice, these assessment and treatment tools are examples of practitioners in the field innovating out of necessity for the best outcomes for patients. This paper draws on case studies to direct future research.

Keywords: polyvagal, auricular acupuncture, trauma, herbs

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Authors: Argyris B. Karapetsas, Rozi M. Laskaraki, Aikaterini A. Karapetsa, Maria Bampou, Valentini N. Vamvaka

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The main aim of the current protocol is the contribution of neuropsychology in both assessment and rehabilitation settings for children with dyslexia. Objectives: The purpose of this study was to evaluate the significant role of neuropsychological assessment including both Psychometric and electrophysiological tests as well as to investigate the effectiveness of an Auditory Training program, designed via Music designed for children with Developmental Dyslexia (DD). Materials: In our study, participated 45 third-, and fourth-grade students with DD and a matched control group (n=45). Method: At the first phase of the protocol, children underwent a clinical assessment, including both electrophysiological, i.e. Event Related Potentials (ERPs) esp. P300 waveform, and psychometric tests, being conducted in Laboratory of Neuropsychology, at University of Thessaly, in Volos, Greece. Assessment’s results confirmed statistically significant lower performance for children with DD for all tests, compared to the typical readers of the control group. After evaluation, a subgroup of children with DD participated in a Rehabilitation Program including digitized musical auditory training activities. Results: The electrophysiological recordings after the intervention revealed shorter, almost similar, P300 latency values for children with DD to those of the control group, indicating the beneficial effects of the Intervention, thus enabling children develop reading skills and become successful readers. Discussion: Similar research data confirm the crucial role of neuropsychology in both diagnosis and treatment of common disorders, observed in children. Indeed, as for DD, there is growing evidence that brain activity dysfunction does occur, as it is confirmed by neuropsychological assessment and also musical auditory training may have remedial effects. Conclusions: The outcomes of the current study suggest that due to the neurobiological origin of DD, neuropsychology may give the means in both neuropsychological assessment and rehabilitation, enabling professionals to cope with cerebral dysfunction and recovery more efficiently.

Keywords: diagnosis, dyslexia, ERPs, Music, neuropsychology, rehabilitation

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Authors: Sunil Kumar, Uday C. Ghoshal

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Background and aims: Serotonin (5-hydroxtryptamine, 5-HT) is an important factor in gut function, playing key roles in intestinal peristalsis and secretion, and in sensory signaling in the brain-gut axis. Removal from its sites of action is mediated by a specific protein called the serotonin reuptake transporter (SERT). Polymorphisms in the promoter region of the SERT gene have effects on transcriptional activity, resulting in altered 5-HT reuptake efficiency. Functional polymorphisms may underlie disturbance in gut function in individuals suffering with disorders such as irritable bowel syndrome (IBS). The aim of this study was to assess the potential association between SERT polymorphisms and the diarrhea predominant IBS (D-IBS) phenotype Subjects: A total of 36 northern Indian female patients and 55 female northern Indian healthy controls (HC) were subjected to genotyping. Methods: Leucocyte DNA of all subjects was analyzed by polymerase chain reaction based technologies for SERT polymorphisms, specifically the insertion/deletion polymorphism in the promoter (SERT-P). Statistical analysis was performed to assess association of SERT polymorphism allele with the D-IBS phenotype. Results: The frequency of distribution of SERT-P gene was comparable between female patients with IBS and HC (p = 0.086). However, frequency of SERT-P deletion/deletion genotype was significantly higher in female patients with D-IBS compared to C-IBS and A-IBS [17/19 (89.5%) vs. 4/12 (33.3%) vs. 1/5 (20%), p=0.001, respectively]. The mucosal level of serotonin was higher in D-IBS compared to C-IBS and A-IBS [Median, range (159.26, 98.78–212.1) vs. 110.4, 67.87–143.53 vs. 92.34, 78.8–166.3 pmol/mL, p=0.001, respectively]. The mucosal level of serotonin was higher in female patients with IBS with SERT-P deletion/deletion genotype compared deletion/insertion and insertion/insertion [157.65, 67.87–212.1 vs. 110.4, 78.1–143.32 vs. 100.5, 69.1–132.03 pmol/mL, p=0.001, respectively]. Patients with D-IBS with deletion/deletion genotype more often reported symptoms of abdominal pain, discomfort (p=0.025) and bloating (p=0.039). Symptoms development following lactose ingestion was strongly associated with D-IBS and SERT-P deletion/deletion genotype (p=0.004). Conclusions: Significant association was observed between D-IBS and the SERT-P deletion/deletion genotype, suggesting that the serotonin transporter is a potential candidate gene for D-IBS in women.

Keywords: serotonin, SERT, inflammatory bowel disease, genetic polymorphism

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Authors: Ecem Deniz Kırkpantur, Ozge Ecmel Onur, Tuba Cimilli Ozturk, Ebru Unal Akoglu

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Moyamoya disease is a unique chronic progressive cerebrovascular disease characterized by bilateral stenosis or occlusion of the arteries around the circle of Willis with prominent arterial collateral circulation. The occurrence of Moyamoya disease is related to immune, genetic and other factors. There is no curative treatment for Moyamoya disease. Secondary prevention for patients with symptomatic Moyamoya disease is largely centered on surgical revascularization techniques. We present here a 62-year old male presented with headache and vision loss for 2 days. He was previously diagnosed with hypertension and glaucoma. On physical examination, left eye movements were restricted medially, both eyes were hyperemic and their movements were painful. Other neurological and physical examination were normal. His vital signs and laboratory results were within normal limits. Computed tomography (CT) showed dilated vascular structures around both lateral ventricles and atherosclerotic changes inside the walls of internal carotid artery (ICA). Magnetic resonance imaging (MRI) and angiography (MRA) revealed dilated venous vascular structures around lateral ventricles and hyper-intense gliosis in periventricular white matter. Ischemic gliosis around the lateral ventricles were present in the Digital Subtracted Angiography (DSA). After the neurology, ophthalmology and neurosurgery consultation, the patient was diagnosed with Moyamoya disease, pulse steroid therapy was started for vision loss, and super-selective DSA was planned for further investigation. Moyamoya disease is a rare condition, but it can be an important cause of stroke in both children and adults. It generally affects anterior circulation, but posterior cerebral circulation may also be affected, as well. In the differential diagnosis of acute vision loss, occipital stroke related to Moyamoya disease should be considered. Direct and indirect surgical revascularization surgeries may be used to effectively revascularize affected brain areas, and have been shown to reduce risk of stroke.

Keywords: headache, Moyamoya disease, stroke, visual loss

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Authors: Mylene T. Caytap-Milan

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This study was materialized with the purpose of determining the anxieties of students towards spoken English, sources of the specified anxiety, coping mechanisms to counter the apprehensions, and teacher management to reduce the anxiety within the classroom. Being qualitative in nature, interview as the data gathering tool was utilized with an audio-recorder. Participants of the study included thirteen teachers and students of speech classes in a state university in Region I, Philippines. Data elicited were transcribed in verbatim, confirmed by the participants, coded and categorized, and themed accordingly. A triangulation method was applied to establish the stronger validity of the data. Findings confirmed teachers’ and students’ awareness of the existence of Anxiety in speaking English (ASE). Based on the data gathered from the teachers, the following themes on students’ ASE were identified: (1) No Brain and Mouth Coordination, (2) Center of Attention, and (3) Acting Out Loud. However, the following themes were formulated based on the responses made by the students themselves: (1) The Common Feeling, (2) The Incompetent Me, and (3) The Limelight. With regard the sources of students’ ASE according to teachers are the following: (1) It Began at Home, (2) It Continued in School, (3) It’s not for me at all. On the other hand, the sources of students’ ASE according to students themselves are: (1) It Comes from Within, (2) It wasn’t Nursed Well, and (3) They’re Looking for Errors. In terms of coping with ASE, students identified the following mechanisms, which were themed into: (1) Acceptance, (2) Application, and (3) Apathy. Moreover, to reduce the ASE phenomenon within the classroom, the teachers demonstrate the following roles according to themes: (1) The Compass, (2) The Counselor, (3) The Referee, (4) The Polyglot, and (5) The English Nazi. Based on the findings, the following conclusions were drawn: (1) ASE can both serve positive and negative influences to the English speaking skills of students, (2) ASE can be reduced with teachers’ provision of more English speaking opportunities and with students’ initiative of personal training, (3) ASE can be reduced when English is introduced and practiced by children at an early age, and (4) ASE is inevitable in the affective domain thus teachers are encouraged to apply psychological positivism in the classroom. Studies related to the present undertaking may refer to the succeeding recommendations: (1) experiment on activities that will reduce anxiety ASE, (2) involve a psychologist for more critical but reliable results and recommendations, and (3) conduct the study among high school and primary students.

Keywords: coping mechanisms, sources, speaking anxiety, teacher management

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Authors: Lali Shanshiashvili, Marika Chikviladze, Nino Mamulashvili, Maia Sepashvili, Nana Narmania, David Mikeladze

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Purpose: During demyelinating inflammatory diseases and after the damage of the myelin sheet, myelin-derived proteins, including myelin basic protein (MBP), are secreted into the extracellular space. MBP shows extensive post-translational modifications, including the deimination of arginine residues. Deiminated MBP is structurally less ordered, susceptible to proteolytic attack, and more immunogenic than the unmodified one. It is hypothesized that MBP could change the inflammatory response in astrocytes. Methods: MBP was isolated and purified from bovine brain white matter. Primary astrocyte cultures were prepared from whole brains of 2-day-old Wistar rats. For evaluation of glutamate uptake/release in astrocytes following treatment of cells with MBP charge isomers, Glutamate Assay Kit was used. The expression of EAAT-2 (excitatory amino acid transporters), peroxisome proliferator-activated receptor gamma (PPAR- γ), inhibitor of nuclear factor kappa B (IkB), and high mobility group protein B1 (HMGB1) in astrocytes were assayed by Western Blot analysis. Results: This study investigated the action of deiminated isomer (C8) on the cultured primary astrocytes and compared its effects with the effects of unmodified C1 isomers. The study found that C8 and C1 MBP differently act on the uptake and release of glutamate in astrocytes: nonmodified C1 MBP increases the uptake of glutamate and does not change the release, whereas C8 decreases the release of glutamate but does not alter the uptake. Nevertheless, both isomers increased the expression of PPAR-γ and EAAT2 in the same intensity. However, immunostaining and Western Blots of cell lysates showed a decrease of IkB and increased expression of HMGB1 after the treatment of astrocytes by C8. Moreover, in the presence of C8, astrocytes release more nitric oxide than unmodified C1 isomers. Conclusion: These data suggest that the deiminated isomer of MBP evokes an inflammatory response and enhances the ability of astrocytes to release proinflammatory mediators through activation of NF-kB after the breakdown of myelin sheets. Acknowledgment: This research was supported by the SRNSF Georgia RF17_534 grant.

Keywords: myelin basic protein, glutamate, deimination, astrocytes, inflammation

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Authors: Eun Jae Ko, In Young Sung, Eui Soo Joeng

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Cognitive impairment is commonly encountered problem in children with various clinical diseases, including Down syndrome, autism spectrum disorder, brain injury, and others. Cognitive impairment limits participation in education and society, and this further hinders development in cognition. However, young children with cognitive impairment tend not to respond well to traditional cognitive treatments, therefore alternative treatment choices are need. As a cognitive training program, touch screen technology can easily be applied to very young children by involving visual and auditory support. Injini was developed as tablet computer based cognitive rehabilitation program for young children or individuals with severe cognitive impairment, which targeted on cognitive ages of 18 to 36 months. The aim of this study was to evaluate the efficacy of a tablet computer based cognitive rehabilitation program (Injini) for children with cognitive impairment. 38 children between cognitive ages of 18 to 36 months confirmed by cognitive evaluations were recruited and randomly assigned to the intervention group (n=20) and the control group (n=18). The intervention group received tablet computer based cognitive rehabilitation program (Injini) for 30 minutes per session, twice a week, over a period of 12 weeks, in addition to the traditional rehabilitation program. The control group received traditional rehabilitation program only. Mental score of Bayley Scales of Infant Development II (BSID II), Pediatric Evaluation of Disability Inventory (PEDI), Laboratory Temperament Assessment Battery (Lab-TAB), Early Childhood Behavior Questionnaire (ECBQ), and Goal Attainment Scale (GAS) were evaluated before and after 12 weeks of therapeutic intervention. When comparing the baseline characteristics, there was no significant difference between the two groups in the measurements of cognitive function. After 12 weeks of treatment, both group showed improvements in all measurements. However, in comparison of improvements after treatment, the intervention group showed more improvements in the mental score of BSID II, social function domain of PEDI, observation domain of Lab-TAB, and GAS, as compared to the control group. Application of the tablet computer based cognitive rehabilitation program (Injini) would be beneficial for improvement of cognitive function in young children with cognitive impairment.

Keywords: cognitive therapy, computer-assisted therapy, early intervention, tablets

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Authors: Banu Hatice Gürcüm, Pınar Arslan, Mahmut Yalçın

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Fashion designers create lots of dresses, suits, shoes, and other clothing and accessories, which are purchased every year by consumers. Fashion trends, sketches of designs, accessories affect the apparel goods, but colors make the finishing touches to an outfit. In all fields of apparel men's, women's, and children's wear, including casual wear, suits, sportswear, formal wear, outerwear, maternity, and intimate apparel, color sells. Thus, specialization in color in apparel is a basic concern each season. The perception of color is the key to sales for every sector in textile business. Mechanism of color perception, cognition in brain and color emotion are unique subjects, which scientists have been investigating for many years. The parameters of color may not be corresponding to visual scales since human emotions induced by color are completely subjective. However, with a very few exception each manufacturer concern their top selling colors for each season through seasonal sales reports of apparel companies. This paper examines sensory and instrumental methods for quantifying color of fabrics and investigates the relationship between fabric color and sale numbers. 5 top selling colors for each season from 10 leading apparel companies in the same segment are taken. The compilation is based according to the sales of the companies for 5 to 10 years. The research’s main concern is the corelation with the magnitude of seasonal color selling figures and the CIE chromaticity coordinates. The colors are chosen from the globally accepted Pantone Textile Color System and the three-dimentional measurement system CIE L*a*b* (CIELAB) is used, L* representing the degree of lightness of color, a* the degree of color ranging from magenta to green, and b* the degree of color ranging from blue to yellow. The objective of this paper is to demonstrate the feasibility of relating color perceptance to a laboratory instrument yielding measurements in the CIELAB system. Our approach is to obtain a total of a hundred reference fabrics to be measured on a laboratory spectrophotometer calibrated to the CIELAB color system. Relationships between the CIE tristimulus (X, Y, Z) and CIELAB (L*, a*, b*) are examined and are reported herein.

Keywords: CIELAB, CIE tristimulus, color preference, fashion

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Authors: Francesca Lombardi, Francesca Rosaria Augello, Benedetta Cinque, Maria Grazia Cifone, Paola Palumbo

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Glioblastoma multiforme (GBM) is a high-grade primary brain tumor refractory to current forms of treatment. The survival benefits of patients with GBM remain unsatisfactory due to the intrinsic or acquired resistance to temozolomide (TMZ), an alkylating agent, used as the first-line chemotherapeutic drug to treat GBM patients. Its cytotoxic effect is visualized by the induction of O6-methylguanine (O6MeG) within DNA. Cyclooxygenase-2 (COX-2), an inflammation-associated enzyme, has been implicated in tumorigenesis and progression of GBM, its inhibition shows anticancer activities. In the present study, it was verified if the combination of a COX-2 selective inhibitor, NS398, with TMZ could counteract the TMZ resistance. In particular, the effect of NS398 mixed with TMZ was investigated in the GBM TMZ-resistant cell line, T98G. Cells were pretreated with NS398 (100µM, 24 hours) and then exposed to TMZ alone (200µM), NS398 alone, or both for 72 hours, after which cell growth rate and cycle phases, as well as apoptosis level, were evaluated. Coadministration of NS398 and TMZ caused a significant decrease in cell growth and a progressive increase of dead cells detected by trypan blue staining. Moreover, a significant level of apoptotic cell percentage and alteration of cell cycle phases were observed in T98G treated with TMZ-NS398 combination when compared to untreated cells or TMZ-treated cells. TMZ-resistant tumors, as GBM, express elevated levels of DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). The mixture drastically reduced MGMT expression in the TMZ-resistant cell line T98G, known to express high levels of MGMT basically. Moreover, while TMZ alone did not influence the COX-2 protein expression, the combination successfully reduced it. In conclusion, these results demonstrated that NS398 enhanced the efficacy of TMZ through cell number reduction, apoptosis induction, and decreased MGMT levels, suggesting the ability of drug combination to reduce the chemoresistance. This drug combination deserves attention and could be considered as a promising therapeutic strategy for GBM patients.

Keywords: COX-2, COX-2 inhibitor, glioblastoma, NS398, T98G, temozolomide

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Authors: Li Shihao, Dieter Trau

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Bilirubin is a yellow substance that is made when the body breaks down old red blood cells. High levels of bilirubin can cause jaundice, a condition that makes the newborn's skin and the white part of the eyes look yellow. Jaundice is a serial-killer in developing countries in Southeast Asia such as Myanmar and most parts of Africa where jaundice screening is largely unavailable. Worldwide, 60% of newborns experience infant jaundice. One in ten will require therapy to prevent serious complications and lifelong neurologic sequelae. Limitations of current solutions: - Blood test: Blood tests are painful may largely unavailable in poor areas of developing countries, and also can be costly and unsafe due to the insufficient investment and lack of access to health care systems. - Transcutaneous jaundice-meter: 1) can only provide reliable results to caucasian newborns, due to skin pigmentations since current technologies measure bilirubin by the color of the skin. Basically, the darker the skin is, the harder to measure, 2) current jaundice meters are not affordable for most underdeveloped areas in Africa like Kenya and Togo, 3) fat tissue under the skin also influences the accuracy, which will give overestimated results, 4) current jaundice meters are not reliable after treatment (phototherapy) because bilirubin levels underneath the skin will be reduced first, while overall levels may be quite high. Thus, there is an urgent need for a low-cost non-invasive device, which can be effective not only for caucasian babies but also Asian and African newborns, to save lives at the most vulnerable time and prevent any complications like brain damage. Instead of measuring bilirubin on skin, we proposed a new method to do the measurement on the sclera, which can avoid the difference of skin pigmentations and ethnicities, due to the necessity for the sclera to be white regardless of racial background. This is a novel approach for measuring bilirubin by an optical method of light reflection off the white part of the eye. Moreover, the device is connected to a smart device, which can provide a user-friendly interface and the ability to record the clinical data continuously A disposable eye cap will be provided avoiding contamination and fixing the distance to the eye.

Keywords: Jaundice, bilirubin, non-invasive, sclera

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Authors: Salman Abdul Majeed, Vidur Solanki, Ruqiya Shama Tareen

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BACKGROUND: The COVID-19 pandemic has affected the way of living as we have known for all strata of society. While disease containment measures imposed by governmental agencies have been instrumental in controlling the spread of the virus, it has had profound collateral impacts on all populations. However, the disruption caused in the lives of one segment of population has been far more damaging than most others: the emotional wellbeing of our child and adolescent populations. This impact was even more pronounced in children who already suffered from neurodevelopmental or psychiatric disorders. In particular, school closures have not only led to profound social isolation, but also negative impacts on normal developmental opportunities and interruptions in mental health services obtained through school systems. It is too soon to understand the full impacts of quarantine, isolation, stress of social detachment and fear of pandemic, but we have started to see the devastating impact on C&A already. This review intends to shed light on the current understanding of psychiatric wellbeing of C&A during COVID-19 pandemic. METHOD: Literature search utilizing key words COVID-19 and children, quarantine and children, social isolation, Loneliness, pandemic stress and children, and mental health of children, disease containment measures was carried out. Over 200 articles were identified, out of which 81 articles were included in this review article. RESULTS: The disruption caused by COVID-19 in the lives of C&A is much more damaging and its impact is far reaching. The C&A ED visits for possible suicide attempts have jumped to 22.3% in 2020 and 39.1% during 2021. One study utilizing T1-weighted structural images, computed the thickness of cortical and subcortical structures including amygdala, hippocampus, and nucleus accumbens. The Peri-COVID group showed reduced cortical and subcortical thickness and more advanced brain aging compared to pre pandemic studies. CONCLUSION: Mental health resources for C&A remain under funded, neglected, and inaccessible to population that needs it most. Children with ongoing mental health disorders were impacted worst, along with those with predisposed biopsychosocial risk factors.

Keywords: COVID-19 and children, quarantine and children, social isolation, Loneliness, pandemic stress and children, disease containment measures, mental health of children

Procedia PDF Downloads 43

Authors: Piotr Podlipniak

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Social consolidation has often been indicated as an adaptive function of music which led to the evolution of music faculty. According to many scholars this function is possible thanks to musical rhythm that enables sensorimotor synchronization to a musical beat. The ability to synchronize to music allows performing music collectively which enhances social cohesion. However, the collective performance of music consists also in spectral synchronization that depends on musical pitch structure. Similarly to rhythmic synchronization, spectral synchronization is a result of ‘brain states alignment’ between people who collectively listen to or perform music. In order to successfully synchronize pitches performers have to adequately expect the pitch structure. The most common form of music which predominates among all human societies is tonal music. In fact tonality understood in the broadest sense as such an organization of musical pitches in which some pitch is more important than others is the only kind of musical pitch structure that has been observed in all currently known musical cultures. The perception of such a musical pitch structure elicits specific emotional reactions which are often described as tensions and relaxations. These facts provoke some important questions. What is the evolutionary reason that people use pitch structure as a form of vocal communication? Why different pitch structures elicit different emotional states independent of extra-musical context? It is proposed in the current presentation that in the course of evolution pitch structure became a human specific tool of communication the function of which is to induce emotional states such as uncertainty and cohesion. By the means of eliciting these emotions during collective music performance people are able to unconsciously give cues concerning social acceptance. This is probably one of the reasons why in all cultures people collectively perform tonal music. It is also suggested that tonal pitch structure had been invented socially before it became an evolutionary innovation of Homo sapiens. It means that a predisposition to tonally organize pitches evolved by the means of ‘Baldwin effect’ – a process in which natural selection transforms the learned response of an organism into the instinctive response. The hypothetical evolutionary scenario of the emergence of tonal pitch structure will be proposed. In this scenario social forces such as a need for closer cooperation play the crucial role.

Keywords: emotion, evolution, tonality, social consolidation

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Authors: Obinna Afamefuna Echi

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Background: The global increase in the elderly population is anticipated to reach significant levels by 2050, presenting extensive economic, social, and healthcare challenges. Age-related cognitive decline, alterations in brain anatomy, and systemic inflammation are profound concerns that diminish the quality of life and increase susceptibility to diseases like Alzheimer's and cardiovascular diseases. Resistance training is presently studied for its potential neuroprotective and anti-inflammatory benefits in older adults. Objectives: This study aimed to explore the effects of different resistance training modalities on neurotrophic factors, inflammatory markers, and cognitive functions in the elderly. Methods: A controlled trial was conducted with 60 male participants aged 60-75, assigned to either 12 weeks of high-intensity blood flow restriction training (BFRT), muscle damaging resistance training (MDRT), or a non-exercising control group. Cognitive function, neurotrophic factors such as BDNF, and inflammatory markers including IL-6 and TNF were measured before and after the intervention period. Setting: Participants were recruited from Kaunas, Lithuania, with sessions facilitated at the Lithuanian Sports University and health assessments conducted at the Lithuanian University of Health Sciences. Results: Preliminary data suggested did not show significant improvements in BDNF levels and cognitive functions in the BFRT and MDRT groups compared to controls. However, there was a notable reduction in inflammatory markers, indicating potential health benefits beyond cognitive enhancement. Conclusion: The incorporation of resistance training can be a strategic intervention to mitigate age-associated cognitive decline and systemic inflammation, thereby enhancing overall health and quality of life in older adults. The results advocate for wider adoption and further study of resistance training as a preventive measure in ageing populations. Funding: The Lithuanian Sports University, the Research Council of Lithuania and the Lithuanian University of Health Sciences.

Keywords: ageing, resistance training, BDNF, cognitive function

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Authors: Ricardo de Oliveira Orsi, Aline Astolfi, Daniel Diego Mendes, Isabella Cristina de Castro Lippi, Jaine da Luz Scheffer, Yan Souza Lima, Juliana Lunardi, Giovanna do Padro Ribeiro, Samir Moura Kadri

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NECTAR Brazilian group (Center of Education, Science, and Technology in Rational Beekeeping) conducted studies on the pesticides honey bees effects using the transcriptome sequencing (RNA-Seq) analyzes for gene expression studies. In this way, we analyzed the effects of Pyraclostrobin and Fipronil on the honey bees with 21 old-days (forager) in laboratory conditions. For this, frames containing sealed brood were removed from the beehives and maintenance on the stove (32°C and 75% humidity) until the bees were born. So, newly emerged workers were marked on the pronotum with a non-toxic pen and reintroduced into their original hives. After 21 days, 120 marked bees were collected with an entomological forces and immediately stored in Petri dishes, perforated to ensure ventilation, and kept fasted for 3 hours. These honeybees were exposed to food contaminated or not with the sublethal dose of Pyraclostrobin (850 ppb/bee) or Fipronil (2.5 ppb/bee). After four hours of exposure, 15 bees from each treatment were referred to transcriptome analysis. Total RNA analysis was extracted from the brain pools (03 brains per pool) using the TRIzol® reagent protocol according to the manufacturer's instructions. cDNA libraries were constructed, and the FASTQC program was used to check adapter content and assess the quality of raw reads. Differential expression analysis was performed with the DESeq2 package. Genes that had an adjusted value of less than 0.05 were considered to be significantly up-regulated. Regarding the Pyraclostrobin, alterations were observed in the pattern of 17 gene related to of antioxidant system, cellular respiration, glucose metabolism, and regulation of juvenile hormone and the hormone insulin. Glyphosate altered the 10 gene related to the digestive system, exoskeleton composition, vitamin E transport, and antioxidant system. The results indicate that the necessity of studies using the sublethal doses to evaluate the pesticides uses and risks on crops and its effects on the honey bees.

Keywords: beekeeping, honey bees, pesticides, transcriptome

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Authors: Vaishali Patil, Neeraj Masand

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In older people, Alzheimer’s disease (AD) is turning out to be a lethal disease. According to the amyloid hypothesis, aggregation of the amyloid β–protein (Aβ), particularly its 42-residue variant (Aβ42), plays direct role in the pathogenesis of AD. Aβ is generated through sequential cleavage of amyloid precursor protein (APP) by β–secretase (BACE) and γ–secretase (GS). Thus in the treatment of AD, γ-secretase modulators (GSMs) are potential disease-modifying as they selectively lower pathogenic Aβ42 levels by shifting the enzyme cleavage sites without inhibiting γ–secretase activity. This possibly avoids known adverse effects observed with complete inhibition of the enzyme complex. Virtual screening, via drug-like ADMET filter, QSAR and molecular docking analyses, has been utilized to identify novel γ–secretase modulators with sulphonamide nucleus. Based on QSAR analyses and docking score, some novel analogs have been synthesized. The results obtained by in silico studies have been validated by performing in vivo analysis. In the first step, behavioral assessment has been carried out using Scopolamine induced amnesia methodology. Later the same series has been evaluated for neuroprotective potential against the oxidative stress induced by Scopolamine. Biochemical estimation was performed to evaluate the changes in biochemical markers of Alzheimer’s disease such as lipid peroxidation (LPO), Glutathione reductase (GSH), and Catalase. The Scopolamine induced amnesia model has shown increased Acetylcholinesterase (AChE) levels and the inhibitory effect of test compounds in the brain AChE levels have been evaluated. In all the studies Donapezil (Dose: 50µg/kg) has been used as reference drug. The reduced AChE activity is shown by compounds 3f, 3c, and 3e. In the later stage, the most potent compounds have been evaluated for Aβ42 inhibitory profile. It can be hypothesized that this series of alkyl-aryl sulphonamides exhibit anti-AD activity by inhibition of Acetylcholinesterase (AChE) enzyme as well as inhibition of plaque formation on prolong dosage along with neuroprotection from oxidative stress.

Keywords: gamma-secretase inhibitors, Alzzheimer's disease, sulphonamides, QSAR

Procedia PDF Downloads 227

Authors: Mina Salamatmanesh, Elizabeth Fitzpatrick, Tim Ramsay, Josee Lagacé, Lindsey Sikora, JoAnne Whittingham

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Introduction: Hearing loss (HL) is one of the most common disorders that presents at birth and in early childhood. Universal newborn hearing screening (UNHS) has been adopted based on the assumption that with early identification of HL, children will have access to optimal amplification and intervention at younger ages, therefore, taking advantage of the brain’s maximal plasticity. One particular challenge for parents in the early years is achieving consistent hearing aid (HA) use which is critical to the child’s development and constitutes the first step in the rehabilitation process. This study examined the consistency of hearing aid use in young children based on data logging information documented during audiology sessions in the first three years after hearing aid fitting. Methodology: The first 100 children who were diagnosed with bilateral HL before 72 months of age since 2003 to 2015 in a pediatric audiology clinic and who had at least two hearing aid follow-up sessions with available data logging information were included in the study. Data from each audiology session (age of child at the session, average hours of use per day (for each ear) in the first three years after HA fitting) were collected. Clinical characteristics (degree of hearing loss, age of HA fitting) were also documented to further understanding of factors that impact HA use. Results: Preliminary analysis of the results of the first 20 children shows that all of them (100%) have at least one data logging session recorded in the clinical audiology system (Noah). Of the 20 children, 17(85%) have three data logging events recorded in the first three years after HA fitting. Based on the statistical analysis of the first 20 cases, the median hours of use in the first follow-up session after the hearing aid fitting in the right ear is 3.9 hours with an interquartile range (IQR) of 10.2h. For the left ear the median is 4.4 and the IQR is 9.7h. In the first session 47% of the children use their hearing aids ≤5 hours, 12% use them between 5 to 10 hours and 22% use them ≥10 hours a day. However, these children showed increased use by the third follow-up session with a median (IQR) of 9.1 hours for the right ear and 2.5, and of 8.2 hours for left ear (IQR) IQR is 5.6 By the third follow-up session, 14% of children used hearing aids ≤5 hours, while 38% of children used them ≥10 hours. Based on the primary results, factors like age and level of HL significantly impact the hours of use. Conclusion: The use of data logging information to assess the actual hours of HA provides an opportunity to examine the: a) challenges of families of young children with HAs, b) factors that impact use in very young children. Data logging when used collaboratively with parents, can be a powerful tool to identify problems and to encourage and assist families in maximizing their child’s hearing potential.

Keywords: hearing loss, hearing aid, data logging, hours of use

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Authors: Natalie Riley, Anita Quigley, Robert M. I. Kapsa, George W. Greene

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As the fields of medicine and bionics grow rapidly in technological advancement, the future and success of it depends on the ability to effectively interface between the artificial and the biological worlds. The biggest obstacle when it comes to implantable, electronic medical devices, is maintaining a ‘clean’, low noise electrical connection that allows for efficient sharing of electrical information between the artificial and biological systems. Implant fouling occurs with the adhesion and accumulation of proteins and various cell types as a result of the immune response to protect itself from the foreign object, essentially forming an electrical insulation barrier that often leads to implant failure over time. Lubricin (LUB) functions as a major boundary lubricant in articular joints, a unique glycoprotein with impressive anti-adhesive properties that self-assembles to virtually any substrate to form a highly ordered, ‘telechelic’ polymer brush. LUB does not passivate electroactive surfaces which makes it ideal, along with its innate biocompatibility, as a coating for implantable bionic electrodes. It is the aim of the study to investigate LUB’s anti-fouling properties and its potential as a safe, bioinspired material for coating applications to enhance the performance and longevity of implantable medical devices as well as reducing the frequency of implant replacement surgeries. Native, bovine-derived LUB (N-LUB) and recombinant LUB (R-LUB) were applied to gold-coated mylar surfaces. Fibroblast, chondrocyte and neural cell types were cultured and grown on the coatings under both passive and electrically stimulated conditions to test the stability and anti-adhesive property of the LUB coating in the presence of an electric field. Lactate dehydrogenase (LDH) assays were conducted as a directly proportional cell population count on each surface along with immunofluorescent microscopy to visualize cells. One-way analysis of variance (ANOVA) with post-hoc Tukey’s test was used to test for statistical significance. Under both passive and electrically stimulated conditions, LUB significantly reduced cell attachment compared to bare gold. Comparing the two coating types, R-LUB reduced cell attachment significantly compared to its native counterpart. Immunofluorescent micrographs visually confirmed LUB’s antiadhesive property, R-LUB consistently demonstrating significantly less attached cells for both fibroblasts and chondrocytes. Preliminary results investigating neural cells have so far demonstrated that R-LUB has little effect on reducing neural cell attachment; the study is ongoing. Recombinant LUB coatings demonstrated impressive anti-adhesive properties, reducing cell attachment in fibroblasts and chondrocytes. These findings and the availability of recombinant LUB brings into question the results of previous experiments conducted using native-derived LUB, its potential not adequately represented nor realized due to unknown factors and impurities that warrant further study. R-LUB is stable and maintains its anti-fouling property under electrical stimulation, making it suitable for electroactive surfaces.

Keywords: anti-fouling, bioinspired, cell attachment, lubricin

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Authors: Sarayu Vanga, Jorge Galeano-Cabral, Kaya Wei

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Cerebral hypoxia refers to a condition in which there is a decrease in oxygen supply to the brain. Patients suffering from this condition experience a decrease in their body temperature. While there isn't any cure to treat cerebral hypoxia as of date, certain procedures are utilized to help aid in the treatment of the condition. Regulating the body temperature is an example of one of those procedures. Hypoxia is well known to reduce the body temperature of mammals, although the neural origins of this response remain uncertain. In order to speed recovery from this condition, it is necessary to maintain a stable body temperature. In this study, we present an approach to regulating body temperature for patients who suffer from cerebral hypoxia or other similar conditions. After a thorough literature study, we propose the use of thermoelectric blankets, which are temperature-controlled thermal blankets based on thermoelectric devices. These blankets are capable of heating up and cooling down the patient to stabilize body temperature. This feature is possible through the reversible effect that thermoelectric devices offer while behaving as a thermal sensor, and it is an effective way to stabilize temperature. Thermoelectricity is the direct conversion of thermal to electrical energy and vice versa. This effect is now known as the Seebeck effect, and it is characterized by the Seebeck coefficient. In such a configuration, the device has cooling and heating sides with temperatures that can be interchanged by simply switching the direction of the current input in the system. This design integrates various aspects, including a humidifier, ventilation machine, IV-administered medication, air conditioning, circulation device, and a body temperature regulation system. The proposed design includes thermocouples that will trigger the blanket to increase or decrease a set temperature through a medical temperature sensor. Additionally, the proposed design allows an efficient way to control fluctuations in body temperature while being cost-friendly, with an expected cost of 150 dollars. We are currently working on developing a prototype of the design to collect thermal and electrical data under different conditions and also intend to perform an optimization analysis to improve the design even further. While this proposal was developed for treating cerebral hypoxia, it can also aid in the treatment of other related conditions, as fluctuations in body temperature appear to be a common symptom that patients have for many illnesses.

Keywords: body temperature regulation, cerebral hypoxia, thermoelectric, blanket design

Procedia PDF Downloads 121

Authors: A. Newman-Tancredi, R. Depoortère, P. Gruca, E. Litwa, M. Lason, M. Papp

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The N-methyl-D-aspartic acid (NMDA) receptor antagonist, ketamine, can elicit rapid-acting antidepressant (RAAD) effects in treatment-resistant patients, but it requires parenteral co-administration with a classical antidepressant under medical supervision. In addition, ketamine can also produce serious side effects that limit its long-term use, and there is much interest in identifying RAADs based on ketamine’s mechanism of action but with safer profiles. Ketamine elicits GABAergic interneuron inhibition, glutamatergic neuron stimulation, and, notably, activation of serotonin 5-HT1A receptors in the prefrontal cortex (PFC). Direct activation of the latter receptor subpopulation with selective ‘biased agonists’ may therefore be a promising strategy to identify novel RAADs and, consistent with this hypothesis, the prototypical cortical biased agonist, NLX-101, exhibited robust RAAD-like activity in the chronic mild stress model of depression (CMS). The present study compared the effects of a novel, selective 5-HT1A receptor-biased agonist, NLX-204, with those of ketamine and NLX-101. Materials and methods: CMS procedure was conducted on Wistar rats; drugs were administered either intraperitoneally (i.p.) or by bilateral intracortical microinjection. Ketamine: 10 mg/kg i.p. or 10 µg/side in PFC; NLX-204 and NLX-101: 0.08 and 0.16 mg/kg i.p. or 16 µg/side in PFC. In addition, interaction studies were carried out with systemic NLX-204 or NLX-101 (each at 0.16 mg/kg i.p.) in combination with intracortical WAY-100635 (selective 5-HT1A receptor antagonist; 2 µg/side) or muscimol (GABA-A receptor agonist, 12.5 ng/side). Anhedonia was assessed by CMS-induced decrease in sucrose solution consumption; anxiety-like behavior was assessed using the Elevated Plus Maze (EPM), and cognitive impairment was assessed by the Novel Object Recognition (NOR) test. Results: A single administration of NLX-204 was sufficient to reverse the CMS-induced deficit in sucrose consumption, similarly to ketamine and NLX-101. NLX-204 also reduced CMS-induced anxiety in the EPM and abolished CMS-induced NOR deficits. These effects were maintained (EPM and NOR) or enhanced (sucrose consumption) over a subsequent 2-week period of treatment. The anti-anhedonic response of the drugs was also maintained for several weeks Following treatment discontinuation, suggesting that they had sustained effects on neuronal networks. A single PFC administration of NLX-204 reversed deficient sucrose consumption, similarly to ketamine and NLX-101. Moreover, the anti-anhedonic activities of systemic NLX-204 and NLX 101 were abolished by coadministration with intracortical WAY-100635 or muscimol. Conclusions: (i) The antidepressant-like activity of NLX-204 in the rat CMS model was as rapid as that of ketamine or NLX-101, supporting targeting cortical 5-HT1A receptors with selective, biased agonists to achieve RAAD effects. (ii)The anti-anhedonic activity of systemic NLX-204 was mimicked by local administration of the compound in the PFC, confirming the involvement of cortical circuits in its RAAD-like effects. (iii) Notably, the effects of systemic NLX-204 and NLX-101 were abolished by PFC administration of muscimol, indicating that they act by (indirectly) eliciting a reduction in cortical GABAergic neurotransmission. This is consistent with ketamine’s mechanism of action and suggests that there are converging NMDA and 5-HT1A receptor signaling cascades in PFC underlying the RAAD-like activities of ketamine and NLX-204. Acknowledgements: The study was financially supported by NCN grant no. 2019/35/B/NZ7/00787.

Keywords: depression, ketamine, serotonin, 5-HT1A receptor, chronic mild stress

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Authors: Dugeree Otgongerel, Kyong Jin Cho, Yu-Han Kim, Sangmee Ahn Jo

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Excessive activation of glutamate receptor is thought to be involved in retinal ganglion cell (RGC) death after ischemia- reperfusion damage. Glutamate carboxypeptidase II (GCPII) is an enzyme responsible for the synthesis of glutamate. Several studies showed that inhibition of GCPII prevents or reduces cellular damage in brain diseases. Thus, in this study, we examined the expression of GCPII in rat retina and the role of GCPII in acute high IOP ischemia-reperfusion damage of eye by using a GCPII inhibitor, 2-(phosphonomethyl) pentanedioic acid (2-PMPA). Animal model of ischemia-reperfusion was induced by raising the intraocular pressure for 60 min and followed by reperfusion for 3 days. Rats were randomly divided into four groups: either intra-vitreous injection of 2-PMPA (11 or 110 ng per eye) or PBS after ischemia-reperfusion, 2-PMPA treatment without ischemia-reperfusion and sham-operated normal control. GCPII immunoreactivity in normal rat retina was detected weakly in retinal nerve fiber layer (RNFL) and retinal ganglionic cell layer (RGL) and also inner plexiform layer (IPL) and outer plexiform layer (OPL) strongly where are co-stained with an anti-GFAP antibody, suggesting that GCPII is expressed mostly in Muller and astrocytes. Immunostaining with anti-BRN antibody showed that ischemia- reperfusion caused RGC death (31.5 %) and decreased retinal thickness in all layers of damaged retina, but the treatment of 2-PMPA twice at 0 and 48 hour after reperfusion blocked these retinal damages. GCPII level in RNFL layer was enhanced after ischemia-reperfusion but was blocked by PMPA treatment. This result was confirmed by western blot analysis showing that the level of GCPII protein after ischemia- reperfusion increased by 2.2- fold compared to control, but this increase was blocked almost completely by 110 ng PMPA treatment. Interestingly, GFAP immunoreactivity in the retina after ischemia- reperfusion followed by treatment with PMPA showed similar pattern to GCPII, increase after ischemia-reperfusion but reduction to the normal level by PMPA treatment. Our data demonstrate that increase of GCPII protein level after ischemia-reperfusion injury is likely to cause glial activation and/or retinal cell death which are mediated by glutamate, and GCPII inhibitors may be useful in treatment of retinal disorders in which glutamate excitotoxicity is pathogenic.

Keywords: glutamate carboxypepptidase II, glutamate excitotoxicity, ischemia-reperfusion, retinal ganglion cell

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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: 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: Turky Al-Qahtani, Roustem Miftahof

Abstract:

Introduction: Under common assumptions of excitabi-lity, morphological (cellular) homogeneity, and spatial structural anomalies added as required, it has been shown that biological systems are able to display travelling wave dynamics. Being not self-sustainable, existence depends on the electrophysiological state of transmembrane ion channels and it requires an extrinsic/intrinsic periodic source. However, organs in the body are highly multicellular, heterogeneous, and their functionality is the outcome of electro-mechanical conjugation, rather than excitability only. Thus, peristalsis in the gut relies on spatiotemporal myoelectrical pattern formations between the mechanical, represented by smooth muscle cells (SM), and the control, comprised of a chain of primary sensory and motor neurones, components. Synaptically linked through the afferent and efferent pathways, they form a functional unit (FU) of the gut. Aims: These are: i) to study numerically the complex dynamics, and ii) to investigate the possibility of self-sustained myoelectrical activity in the FU. Methods: The FU recreates the following sequence of physiological events: deformation of mechanoreceptors of located in SM; generation and propagation of electrical waves of depolarisation - spikes - along the axon to the soma of the primary neurone; discharge of the primary neurone and spike propagation towards the motor neurone; burst of the motor neurone and transduction of spikes to SM, subsequently producing forces of contraction. These are governed by a system of nonlinear partial and ordinary differential equations being a modified version of the Hodgkin-Huxley model and SM fibre mechanics. In numerical experiments; the source of excitation is mechanical stretches of SM at a fixed amplitude and variable frequencies. Results: Low frequency (0.5 < v < 2 Hz) stimuli cause the propagation of spikes in the neuronal chain and, finally, the generation of active forces by SM. However, induced contractions are not sufficient to initiate travelling wave dynamics in the control system. At frequencies, 2 < v < 4 Hz, multiple low amplitude and short-lasting contractions are observed in SM after the termination of stretching. For frequencies (0.5 < v < 4 Hz), primary and sensory neurones demonstrate strong connectivity and coherent electrical activity. Significant qualitative and quantitative changes in dynamics of myoelectical patterns with a transition to a self-organised mode are recorded with the high degree of stretches at v = 4.5 Hz. Increased rates of deformation lead to the production of high amplitude signals at the mechanoreceptors with subsequent self-sustained excitation within the neuronal chain. Remarkably, the connection between neurones weakens resulting in incoherent firing. Further increase in a frequency of stimulation (v > 4.5 Hz) has a detrimental effect on the system. The mechanical and control systems become disconnected and exhibit uncoordinated electromechanical activity. Conclusion: To our knowledge, the existence of periodic activity in a multicellular, functionally heterogeneous biological system with mechano-electrical dynamics, such as the FU, has been demonstrated for the first time. These findings support the notion of possible peristalsis in the gut even in the absence of intrinsic sources - pacemaker cells. Results could be implicated in the pathogenesis of intestinal dysrythmia, a medical condition associated with motor dysfunction.

Keywords: complex dynamics, functional unit, the gut, dysrythmia

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