Search results for: Howard Weeks

Authors: Sakshi Chopra, Ashima Nehra, Sumit Sinha, Harsimarpreet Kaur, Ravindra Mohan Pandey

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Background: Cognitive rehabilitation aims to retrain brain injured individuals with cognitive deficits to restore or compensate lost functions. As illiterates or people with low literacy levels represent a significant proportion of the world, specific rehabilitation modules for such populations are indispensable. Literacy is significantly associated with all neuropsychological measures and retraining programs widely use written or spoken techniques which essentially require the patient to read or write. So, the aim of the study was to develop and standardize a literacy free neuropsychological rehabilitation program for improving cognitive functioning in patients with mild and moderate Traumatic Brain Injury (TBI). Several studies have pointed out to the impairments seen in memory, executive functioning, and attention and concentration post-TBI, so the rehabilitation program focussed on these domains. Visual item memorization, stick constructions, symbol cancellations, and colouring techniques were used to construct the retraining program. Methodology: The development of the program consisted of planning, preparing, analyzing, and revising the different modules. The construction focussed on areas of retraining immediate and delayed visual memory, planning ability, focused and divided attention, concentration, and response inhibition (to control irritability and aggression). A total of 98 home based retraining modules were prepared in the 4 domains (42 for memory, 42 for executive functioning, 7 for attention and concentration, and 7 for response inhibition). The standardization was done on 20 healthy controls to review, select and edit items. For each module, the time, errors made and errors per second were noted down, to establish the difficulty level of each module and were arranged in increasing level of difficulty over a period of 6 weeks. The retraining tasks were then administered on 11 brain injured individuals (5 after Mild TBI and 6 after Moderate TBI). These patients were referred from the Trauma Centre to Clinical Neuropsychology OPD, All India Institute of Medical Sciences, New Delhi, India. Results: The time was taken, errors made and errors per second were analysed for all domains. Education levels were divided into illiterates, up to 10 years, 10 years to graduation and graduation and above. Mean and standard deviations were calculated. Between group and within group analysis was done using the t-test. The performance of 20 healthy controls was analyzed and only a significant difference was observed on the time taken for the attention tasks and all other domains had non-significant differences in performance between different education levels. Comparing the errors, time taken between patient and control group, there was a significant difference in all the domains at the 0.01 level except the errors made on executive functioning, indicating that the tool can successfully differentiate between healthy controls and patient groups. Conclusions: Apart from the time taken for symbol cancellations, the entire cognitive rehabilitation program is literacy free. As it taps the major areas of impairment post-TBI, it could be a useful tool to rehabilitate the patient population with low literacy levels across the world. The next step is already underway to test its efficacy in improving cognitive functioning in a randomized clinical controlled trial.

Keywords: cognitive rehabilitation, illiterates, India, traumatic brain injury

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Authors: Vijay Samuel, Tina Thekkekkara, Shoma Ganguly

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There is no reported Hanta Seoul virus infection in children in the UK so far, making it quite challenging for clinicians in diagnosing, predicting and prognosticating the outcome of the infection to patients and parents. We report a case of a ten-year-old girl who presented with pyrexia associated with headache, photophobia and abdominal pain. The family had recently acquired two pet rats six weeks ago. She appeared flushed with peri-oral pallor, coated the strawberry tongue, inflamed tonsils and bilateral cervical lymphadenopathy. Her liver and splenic edges were palpable. Investigations showed that she was thrombocytopenic with deranged renal and liver functions. An ultrasound abdomen demonstrated a mildly enlarged spleen, peripancreatic lymph node and an acalculous cholecystitis. In view of her clinical presentation, a diagnosis of leptospirosis was considered and she was commenced on intravenous benzylpenicillin. The following day she became oliguric, developed significant proteinuria and her renal function deteriorated. Following conservative management, her urine output gradually improved along with her renal function, proteinuria and thrombocytopaenia. Serology for leptospirosis and various other viruses were negative. Following discussion with the Rare and Imported Pathogens Laboratory at Porton hanta virus serology was requested and found to be strongly positive for Seoul hanta virus. Following discharge she developed palpitations, fatigue, severe headache and cognitive difficulties including memory loss and difficulties in spelling, reading and mathematics. Extensive investigations including ECG, MRI brain and CSF studies were performed and revealed no significant abnormalities. Since 2012, there have been six cases of acute kidney injury due to Hantavirus infection in the UK. Two cases were from the Humber region and were exposure to wild rats and the other four were exposed to specially bred pet fancy rats. Hanta virus infections can cause mild flu like symptoms but two clinical syndromes are associated with severe disease including haemorrhagic fever with renal syndrome, which may be associated with thrombocytopenia and Hantavirus cardiopulmonary syndrome. Neuropsychological impairments reported following hantavirus pulmonary syndrome and following Puumala virus infection have been reported. Minor white matter lesions were found in about half of the patients investigated with MRI brain. Seoul virus has a global distribution owing to the dispersal of its carrier host rats, through global trade. Several ports in the region could explain the possible establishment of Seoul virus in local populations of rats in the Yorkshire and Humber region. The risk of infection for occupationally exposed groups is 1-3% compared to 32.9% for specialist pet rat owners. The report highlight’s the importance of routinely asking about pets in the family. We hope to raise awareness of the emergence of hantavirus infection in the UK, particularly in the Yorkshire and Humber region. Clinicians should consider hantavirus infection as a potential cause of febrile illness causing renal impairment in children. Awareness of the possible neuro-cognitive sequele would help the clinicians offer appropriate information and support to children and their families. Contacting Rare and Imported Pathogens Laboratory at Porton is a useful resource for clinicians in UK when they consider unusual infections.

Keywords: Seoul hantavirus in child Porton, UK Acute kidney injury

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Authors: Chia-Pei Chen, Yu-Ju Chen, Yu-Juei Hsu

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The prevalence and incidence of end-stage renal disease in Taiwan ranks the highest in the world. According to the statistical survey of the Ministry of Health and Welfare in 2019, kidney disease is the ninth leading cause of death in Taiwan. It leads to autonomic dysfunction, inflammatory response and symptom distress, and further increases the damage to the structure and function of the kidneys, leading to increased demand for renal replacement therapy and risks of cardiovascular disease, which also has medical costs for the society. If we can intervene in a feasible manual to effectively regulate the autonomic nerve function of CKD patients, reduce the inflammatory response and symptom distress. To prolong the progression of the disease, it will be the main goal of caring for CKD patients. This study aims to test the effect of heart rate variability biofeedback (HRVBF) on improving autonomic nerve function (Heart Rate Variability, HRV), inflammatory response (Interleukin-6 [IL-6], C reaction protein [CRP] ), symptom distress (Piper fatigue scale, Pittsburgh Sleep Quality Index [PSQI], and Beck Depression Inventory-II [BDI-II] ) in patients with chronic kidney disease. This study was experimental research, with a convenience sampling. Participants were recruited from the nephrology clinic at a medical center in northern Taiwan. With signed informed consent, participants were randomly assigned to the HRVBF or control group by using the Excel BINOMDIST function. The HRVBF group received four weekly hospital-based HRVBF training, and 8 weeks of home-based self-practice was done with StressEraser. The control group received usual care. We followed all participants for 3 months, in which we repeatedly measured their autonomic nerve function (HRV), inflammatory response (IL-6, CRP), and symptom distress (Piper fatigue scale, PSQI, and BDI-II) on their first day of study participation (baselines), 1 month, and 3 months after the intervention to test the effects of HRVBF. The results were analyzed by SPSS version 23.0 statistical software. The data of demographics, HRV, IL-6, CRP, Piper fatigue scale, PSQI, and BDI-II were analyzed by descriptive statistics. To test for differences between and within groups in all outcome variables, it was used by paired sample t-test, independent sample t-test, Wilcoxon Signed-Rank test and Mann-Whitney U test. Results: Thirty-four patients with chronic kidney disease were enrolled, but three of them were lost to follow-up. The remaining 31 patients completed the study, including 15 in the HRVBF group and 16 in the control group. The characteristics of the two groups were not significantly different. The four-week hospital-based HRVBF training combined with eight-week home-based self-practice can effectively enhance the parasympathetic nerve performance for patients with chronic kidney disease, which may against the disease-related parasympathetic nerve inhibition. In the inflammatory response, IL-6 and CRP in the HRVBF group could not achieve significant improvement when compared with the control group. Self-reported fatigue and depression significantly decreased in the HRVBF group, but they still failed to achieve a significant difference between the two groups. HRVBF has no significant effect on improving the sleep quality for CKD patients.

Keywords: heart rate variability biofeedback, autonomic nerve function, inflammatory response, symptom distress, chronic kidney disease

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Authors: Shereen Ismail Fawaz, Shin-Ichi Izumi, Nouran Mohamed Salah, Heba G. Saber, Ibrahim Mohamed Roushdi

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Background: Multiple sclerosis (MS) is a chronic, inflammatory, mainly demyelinating disease of the central nervous system, more common in young adults. Cerebellar involvement is one of the most disabling lesions in MS and is usually a sign of disease progression. It plays a major role in the planning, initiation, and organization of movement via its influence on the motor cortex and corticospinal outputs. Therefore, it contributes to controlling movement, motor adaptation, and motor learning, in addition to its vast connections with other major pathways controlling balance, such as the cerebellopropriospinal pathways and cerebellovestibular pathways. Hence, trying to stimulate the cerebellum by facilitatory protocols will add to our motor control and balance function. Non-invasive brain stimulation, both repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), has recently emerged as effective neuromodulators to influence motor and nonmotor functions of the brain. Anodal tDCS has been shown to improve motor skill learning and motor performance beyond the training period. Similarly, rTMS, when used at high frequency (>5 Hz), has a facilitatory effect on the motor cortex. Objective: Our aim was to determine the effect of high-frequency rTMS over the cerebellum in improving balance and functional ambulation of multiple sclerosis patients with Ataxia. Patients and methods: This was a randomized single-blinded placebo-controlled prospective trial on 40 patients. The active group (N=20) received real rTMS sessions, and the control group (N=20) received Sham rTMS using a placebo program designed for this treatment. Both groups received 12 sessions of high-frequency rTMS over the cerebellum, followed by an intensive exercise training program. Sessions were given three times per week for four weeks. The active group protocol had a frequency of 10 Hz rTMS over the cerebellar vermis, work period 5S, number of trains 25, and intertrain interval 25s. The total number of pulses was 1250 pulses per session. The control group received Sham rTMS using a placebo program designed for this treatment. Both groups of patients received an intensive exercise program, which included generalized strengthening exercises, endurance and aerobic training, trunk abdominal exercises, generalized balance training exercises, and task-oriented training such as Boxing. As a primary outcome measure the Modified ICARS was used. Static Posturography was done with: Patients were tested both with open and closed eyes. Secondary outcome measures included the expanded Disability Status Scale (EDSS) and 8 Meter walk test (8MWT). Results: The active group showed significant improvements in all the functional scales, modified ICARS, EDSS, and 8-meter walk test, in addition to significant differences in static Posturography with open eyes, while the control group did not show such differences. Conclusion: Cerebellar high-frequency rTMS could be effective in the functional improvement of balance in MS patients with ataxia.

Keywords: brain neuromodulation, high frequency rTMS, cerebellar stimulation, multiple sclerosis, balance rehabilitation

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Authors: Ngoc-Nguyen Nguyen, Hsiu-Ling Chen, Thanh-Truc Lai Huynh

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In foreign language learning, vocabulary acquisition has consistently posed challenges to learners, especially for those at lower levels. Conventional approaches often fail to promote vocabulary learning and ensure engaging experiences alike. The emergence of mobile learning, particularly the integration of chatbot systems, has offered alternative ways to facilitate this practice. Chatbots have proven effective in educational contexts by offering interactive learning experiences in a constructivist manner. These tools have caught attention in the field of mobile-assisted language learning (MALL) in recent years. This research is conducted in an English for Specific Purposes (ESP) course at the A2 level of the CEFR, designed for non-English majors. Participants are first-year Vietnamese students aged 18 to 20 at a university. This quasi-experimental study follows a pretest-posttest control group design over five weeks, with two classes randomly assigned as the experimental and control groups. The experimental group engages in chatbot-assisted spaced practice with SRL components, while the control group uses the same spaced practice without SRL. The two classes are taught by the same lecturer. Data are collected through pre- and post-tests, cognitive load surveys, and semi-structured interviews. The combination of self-regulated learning (SRL) and distributed practice, grounded in the spacing effect, forms the basis of the present study. SRL elements, which concern goal setting and strategy planning, are integrated into the system. The spaced practice method, similar to those used in widely recognized learning platforms like Duolingo and Anki flashcards, spreads out learning over multiple sessions. This study’s design features quizzes progressively increasing in difficulty. These quizzes are aimed at targeting both the Recognition-Recall and Comprehension-Use dimensions for a comprehensive acquisition of vocabulary. The mobile-based chatbot system is built using Golang, an open-source programming language developed by Google. It follows a structured flow that guides learners through a series of 4 quizzes in each week of teacher-led learning. The quizzes start with less cognitively demanding tasks, such as multiple-choice questions, before moving on to more complex exercises. The integration of SRL elements allows students to self-evaluate the difficulty level of vocabulary items, predict scores achieved, and choose appropriate strategy. This research is part one of a two-part project. The initial findings will determine the development of an upgraded chatbot system in part two, where adaptive features in response to the integration of SRL components will be introduced. The research objectives are to assess the effectiveness of the chatbot-assisted approach, based on the combination of spaced practice and SRL, in improving vocabulary acquisition and managing cognitive load, as well as to understand students' perceptions of this learning tool. The insights from this study will contribute to the growing body of research on mobile-assisted language learning and offer practical implications for integrating chatbot systems with spaced practice into educational settings to enhance vocabulary learning.

Keywords: mobile learning, mobile-assisted language learning, MALL, chatbots, vocabulary learning, spaced practice, spacing effect, self-regulated learning, SRL, self-regulation, EFL, cognitive load

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Authors: Hsin-Yu Lee, Ming-Zhong Li, Wen-Hsi Chiu, Su-Fen Cheng, Shwu-Wen Lin

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Background: The use of medical terminology is essential to professional nurses on clinical practice. However, most nursing students consider traditional lecture-based teaching of medical terminology as boring and overly conceptual and lack motivation to learn. It is thus an issue to be discussed on how to enhance nursing students’ self-directed learning and improve learning outcomes of medical terminology. Digital game-based learning is a learner-centered way of learning. Past literature showed that the most common game-based learning for language education has been immersive games and teaching games. Thus, this study selected role-playing games (RPG) and digital puzzle games for observation and comparison. It is interesting to explore whether digital game-based learning has positive impact on nursing students’ learning of medical terminology and whether students can adapt well on this type of learning. Results can be used to provide references for institutes and teachers on teaching medical terminology. These instructions give you guidelines for preparing papers for the conference. Use this document as a template if you are using Microsoft Word. Otherwise, use this document as an instruction set. The electronic file of your paper will be formatted further at WASET. Define all symbols used in the abstract. Do not cite references in the abstract. Do not delete the blank line immediately above the abstract; it sets the footnote at the bottom of this column. Page margins are 1,78 cm top and down; 1,65 cm left and right. Each column width is 8,89 cm and the separation between the columns is 0,51 cm. Objective: The purpose of this research is to explore respectively the impact of RPG and puzzle game on nursing students’ self-directed learning and technology acceptance. The study further discusses whether different game types bring about different influences on students’ self-directed learning and technology acceptance. Methods: A quasi-experimental design was adopted in this study so that repeated measures between two groups could be conveniently conducted. 103 nursing students from a nursing college in Northern Taiwan participated in the study. For three weeks of experiment, the experiment group (n=52) received “traditional teaching + RPG” while the control group (n=51) received “traditional teaching + puzzle games”. Results: 1. On self-directed learning: For each game type, there were significant differences for the delayed tests of both groups as compared to the pre and post-tests of each group. However, there were no significant differences between the two game types. 2. On technology acceptance: For the experiment group, after the intervention of RPG, there were no significant differences concerning technology acceptance. For the control group, after the intervention of puzzle games, there were significant differences regarding technology acceptance. Pearson-correlation coefficient and path analysis conducted on the results of the two groups revealed that the dimension were highly correlated and reached statistical significance. Yet, the comparison of technology acceptance between the two game types did not reach statistical significance. Conclusion and Recommend: This study found that through using different digital games on learning, nursing students have effectively improved their self-directed learning. Students’ technology acceptances were also high for the two different digital game types and each dimension was significantly correlated. The results of the experimental group showed that through the scenarios of RPG, students had a deeper understanding of medical terminology, which reached the ‘Understand’ dimension of Bloom’s taxonomy. The results of the control group indicated that digital puzzle games could help students memorize and review medical terminology, which reached the ‘Remember’ dimension of Bloom’s taxonomy. The findings suggest that teachers of medical terminology could use digital games to assist their teaching according to their goals on cognitive learning. Adequate use of those games could help improve students’ self-directed learning and further enhance their learning outcome on medical terminology.

Keywords: digital game-based learning, medical terminology, nursing education, self-directed learning, technology acceptance model

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Authors: Sara J. Mills, Sally Howell

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The field of special education has long struggled to bridge the research to practice gap. There is ample evidence from research of effective strategies for students with special needs, but these strategies are not routinely implemented in schools in ways that yield positive results for students. In recent years, the field of special education has turned its focus to implementation science. That is, discovering effective methods of implementing evidence-based practices in school settings. Teacher training is a critical factor in implementation. This study aimed to successfully implement Schema-Based Instruction (SBI) for math problem solving in four classrooms in a special primary school serving students with language deficits, including students with Autism Spectrum Disorders (ASD) and Intellectual Disabilities (ID). Using an action research design that allowed for adjustments and modification to be made over the year-long study, two cohorts of teachers across the school were trained and supported in six-week learning cycles to implement SBI in their classrooms. The learning cycles included a one-day training followed by six weeks of one-on-one or team coaching and three fortnightly cohort group meetings. After the first cohort of teachers completed the learning cycle, modifications and adjustments were made to lesson materials in an attempt to improve their effectiveness with the second cohort. Fourteen teachers participated in the study, including master special educators (n=3), special education instructors (n=5), and classroom assistants (n=6). Thirty-one students participated in the study (21 boys and 10 girls), ranging in age from 5 to 12 years (M = 9 years). Twenty-one students had a diagnosis of ASD, 20 had a diagnosis of mild or moderate ID, with 13 of these students having both ASD and ID. The remaining students had diagnosed language disorders. To evaluate the effectiveness of the implementation approach, both student and teacher data was collected. Student data included pre- and post-tests of math word problem solving. Teacher data included fidelity of treatment checklists and pre-post surveys of teacher attitudes and efficacy for teaching problem solving. Finally, artifacts were collected throughout the learning cycle. Results from cohort 1 and cohort 2 revealed similar outcomes. Students improved in the number of word problems they answered correctly and in the number of problem-solving steps completed independently. Fidelity of treatment data showed that teachers implemented SBI with acceptable levels of fidelity (M = 86%). Teachers also reported increases in the amount of time spent teaching problem solving, their confidence in teaching problem solving and their perception of students’ ability to solve math word problems. The artifacts collected during instruction indicated that teachers made modifications to allow their students to access the materials and to show what they knew. These findings are in line with research that shows student learning can improve when teacher professional development is provided over an extended period of time, actively involves teachers, and utilizes a variety of learning methods in classroom contexts. Further research is needed to evaluate whether these gains in teacher instruction and student achievement can be maintained over time once the professional development is completed.

Keywords: implementation science, mathematics problem solving, research-to-practice gap, schema based instruction

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Authors: Elham Abbas Aljaaly, Nahlaa Abdulwahab Khalifa

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The active method of disease prevention is seen as the most affordable and sustainable action to deal with risks of non-communicable diseases such as obesity. This eight-week project aimed to pilot the feasibility and acceptability of a school-based programme, which is proposed to prevent and modify overweight status and possible related risk factors among student girls 'at the intermediate level' in Jeddah city. The programme was conducted through comprehensible approach targeting physical environment and school policies (nutritional/exercise/behavioural approach). The programme was designed to cultivate the personal and environmental awareness in schools for girls. This was applied by promoting healthy eating and physical activity through policies, physical education, healthier options for school canteens, and the creation of school health teams. The prevention programme was applied on 68 students (who agreed to participate) from grades 7th, 8th and 9th. A pre and post assessment questionnaire was employed on 66 students. The questionnaires were designed to obtain information on students' knowledge about health, nutrition and physical activity. Survey questions included information about nutrients, food consumption patterns, food intake and lifestyle. Physical education included training sessions for new opportunities for physical activities to be performed during school or after school hours. A running competition 'to enhance students’ performance for physical activities' was also conducted during the school visit. A visit to the school canteen was conducted to check, observe, record and assess all available food/beverage items and meals. The assessment method was a subjective method for the type of food/beverages if high in saturated fat, salt and sugar (HFSS) or non-HFSS. The school canteen administrators were encouraged to provide healthy food/beverage items and a sample healthy canteen was provided for implementation. Two healthy options were introduced to the school canteen. A follow up for students’ preferences for the introduced options and the purchasing power were assessed. Thirty-eight percent of young girls (n=26) were not participating in any form of physical activities inside or outside school. Skipping breakfast was stated by 42% (n=28) of students with no daily consumption (19%, n=13) for fruit/vegetables. Significant changes were noticed in students’ (n=66) overall responses to the pre and post questions (P value=.001). All students had participated in the conducted running competition sessions and reported satisfaction and enjoyment about the sessions. No absence was reported by the research team for attending physical education and activity sessions throughout the delivered programme. The purchasing power of the introduced healthy options of 'Salad and oatmeal' was increased to 18% in 8 weeks at the school canteen, and slightly affected the purchase for other less healthy options. The piloted programme indorsed better health and nutrition knowledge, healthy eating and lifestyle attitude, which could help young girls to obtain sustainable changes. It is expected that the outcomes of the programme will be a cornerstone for the futuristic national study that will assist policy makers and participants to build a knowledgeable health promotion scenario and make sure that school students have access to healthy foods, physical exercise and healthy lifestyle.

Keywords: adolescents, diet, exercise, behaviours, overweight/obesity, prevention-intervention programme, Saudi Arabia, schoolgirls

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Authors: Kashima Arora, Monika Tomar, Vinay Gupta

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Biosensors have found potential applications ranging from environmental testing and biowarfare agent detection to clinical testing, health care, and cell analysis. This is driven in part by the desire to decrease the cost of health care and to obtain precise information more quickly about the health status of patient by the development of various biosensors, which has become increasingly prevalent in clinical testing and point of care testing for a wide range of biological elements. Uric acid is an important byproduct in human body and a number of pathological disorders are related to its high concentration in human body. In past few years, rapid growth in the development of new materials and improvements in sensing techniques have led to the evolution of advanced biosensors. In this context, metal oxide thin film based matrices due to their bio compatible nature, strong adsorption ability, high isoelectric point (IEP) and abundance in nature have become the materials of choice for recent technological advances in biotechnology. In the past few years, wide band-gap metal oxide semiconductors including ZnO, SnO₂ and CeO₂ have gained much attention as a matrix for immobilization of various biomolecules. Tin oxide (SnO₂), wide band gap semiconductor (Eg =3.87 eV), despite having multifunctional properties for broad range of applications including transparent electronics, gas sensors, acoustic devices, UV photodetectors, etc., it has not been explored much for biosensing purpose. To realize a high performance miniaturized biomolecular electronic device, rf sputtering technique is considered to be the most promising for the reproducible growth of good quality thin films, controlled surface morphology and desired film crystallization with improved electron transfer property. Recently, iron oxide and its composites have been widely used as matrix for biosensing application which exploits the electron communication feature of Fe, for the detection of various analytes using urea, hemoglobin, glucose, phenol, L-lactate, H₂O₂, etc. However, to the authors’ knowledge, no work is being reported on modifying the electronic properties of SnO₂ by implanting with suitable metal (Fe) to induce the redox couple in it and utilizing it for reagentless detection of uric acid. In present study, Fe implanted SnO₂ based matrix has been utilized for reagentless uric acid biosensor. Implantation of Fe into SnO₂ matrix is confirmed by energy-dispersive X-Ray spectroscopy (EDX) analysis. Electrochemical techniques have been used to study the response characteristics of Fe modified SnO₂ matrix before and after uricase immobilization. The developed uric acid biosensor exhibits a high sensitivity to about 0.21 mA/mM and a linear variation in current response over concentration range from 0.05 to 1.0 mM of uric acid besides high shelf life (~20 weeks). The Michaelis-Menten kinetic parameter (Km) is found to be relatively very low (0.23 mM), which indicates high affinity of the fabricated bioelectrode towards uric acid (analyte). Also, the presence of other interferents present in human serum has negligible effect on the performance of biosensor. Hence, obtained results highlight the importance of implanted Fe:SnO₂ thin film as an attractive matrix for realization of reagentless biosensors towards uric acid.

Keywords: Fe implanted tin oxide, reagentless uric acid biosensor, rf sputtering, thin film

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Authors: Dilek Ozturk, Narin Ozturk, Zeliha Pala Kara, Engin Kaptan, Serap Sancar Bas, Nurten Ozsoy, Alper Okyar

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Most physiological processes oscillate in a rhythmic manner in mammals including metabolism and energy homeostasis, locomotor activity, hormone secretion, immune and endocrine system functions. Endocrine body rhythms are tightly regulated by the circadian timing system. The hypothalamic-pituitary-thyroid (HPT) axis is under circadian control at multiple levels from hypothalamus to thyroid gland. Since circadian timing system controls a variety of biological functions in mammals, circadian rhythms of biological functions may modify the drug tolerability/toxicity depending on the dosing time. Selective mTOR (mammalian target of rapamycin) inhibitor everolimus is an immunosuppressant and anticancer agent that is active against many cancers. It was also found to be active in medullary thyroid cancer. The aim of this study was to investigate the dosing time-dependent toxicity of everolimus on the thyroid gland and hormones in mice. Healthy C57BL/6J mice were synchronized with 12h:12h Light-Dark cycle (LD12:12, with Zeitgeber Time 0 – ZT0 – corresponding to Light onset). Everolimus was administered to male (5 mg/kg/day) and female mice (15 mg/kg/day) orally at ZT1-rest period- and ZT13-activity period- for 4 weeks; body weight loss, clinical signs and possible changes in serum thyroid hormone levels (TSH and free T4) were examined. Histological alterations in the thyroid gland were evaluated according to the following criteria: follicular size, colloid density and viscidity, height of the follicular epithelium and the presence of necrotic cells. The statistical significance between differences was analyzed with ANOVA. Study findings included everolimus-related diarrhea, decreased activity, decreased body weight gains, alterations in serum TSH levels, and histopathological changes in thyroid gland. Decreases in mean body weight gains were more evident in mice treated at ZT1 as compared to ZT13 (p < 0.001, for both sexes). Control tissue sections of thyroid glands exhibited well-organized histoarchitecture when compared to everolimus-treated groups. Everolimus caused histopathological alterations in thyroid glands in male (5 mg/kg, slightly) and female mice (15 mg/kg; p < 0.01 for both ZT as compared to their controls) irrespective of dosing-time. TSH levels were slightly decreased upon everolimus treatment at ZT13 in both males and females. Conversely, increases in TSH levels were observed when everolimus treated at ZT1 in both males (5 mg/kg; p < 0.05) and females (15 mg/kg; slightly). No statistically significant alterations in serum free T4 levels were observed. TSH and free T4 is clinically important thyroid hormones since a number of disease states have been linked to alterations in these hormones. Serum free T4 levels within the normal ranges in the presence of abnormal serum TSH levels in everolimus treated mice may suggest subclinical thyroid disease which may have repercussions on the cardiovascular system, as well as on other organs and systems. Our study has revealed the histological damage on thyroid gland induced by subacute everolimus administration, this effect was irrespective of dosing time. However, based on the body weight changes and clinical signs upon everolimus treatment, tolerability for the drug was best following dosing at ZT13 in both male and females. Yet, effects of everolimus on thyroid functions may deserve further studies regarding their clinical importance and chronotoxicity.

Keywords: circadian rhythm, chronotoxicity, everolimus, thyroid gland, thyroid hormones

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Authors: Agnes Simone

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A 52-year-old male with unknown psychiatric and medical history was brought to the Psychiatric Emergency Room by ambulance directly from jail. He had been detained for three weeks for possession of a firearm while intoxicated. On initial evaluation, the patient was unable to provide a reliable history. He presented with odd jerking movements of his extremities and catatonic features, including mutism and stupor. His vital signs were stable. Patient was transferred to the medical emergency department for work-up of altered mental status. Due to suspicion for opioid overdose, the patient was given naloxone (Narcan) with no improvement. Laboratory work-up included complete blood count, comprehensive metabolic panel, thyroid stimulating hormone, vitamin B12, folate, magnesium, rapid plasma reagin, HIV, blood alcohol level, aspirin, and Tylenol blood levels, urine drug screen, and urinalysis, which were all negative. CT head and chest X-Ray were also negative. With this negative work-up, the medical team concluded there was no organic etiology and requested inpatient psychiatric admission. Upon re-evaluation by psychiatry, it was evident that the patient continued to have an altered mental status. Of note, the medical team did not include substance withdrawal in the differential diagnosis due to stable vital signs and a negative urine drug screen. The psychiatry team decided to check California's prescription drug monitoring program (CURES) and discovered that the patient was prescribed benzodiazepine alprazolam (Xanax) 2mg BID, a sedative-hypnotic, and hydrocodone/acetaminophen 10mg/325mg (Norco) QID, an opioid. After a thorough chart review, his daughter's contact information was found, and she confirmed his benzodiazepine and opioid use, with recent escalation and misuse. It was determined that the patient was experiencing alprazolam withdrawal, given this collateral information, his current symptoms, negative urine drug screen, and recent abrupt discontinuation of medications while incarcerated. After admission to the medical unit and two doses of alprazolam 2mg, the patient's mental status, alertness, and orientation improved, but he had no memory of the events that led to his hospitalization. He was discharged with a limited supply of alprazolam and a close follow-up to arrange a taper. Accompanying this case report, a qualitative review of presentations with alprazolam withdrawal was completed. This case and the review highlights: (1) Alprazolam withdrawal can occur at low doses and within just one week of use. (2) Alprazolam withdrawal can present without any vital sign instability. (3) Alprazolam withdrawal does not respond to short-acting benzodiazepines but does respond to certain long-acting benzodiazepines due to its unique chemical structure. (4) Alprazolam withdrawal is distinct from and more severe than other benzodiazepine withdrawals. This case highlights (1) the importance of physician utilization of drug-monitoring programs. This case, in particular, relied on California's drug monitoring program. (2) The importance of obtaining collateral information, especially in cases in which the patient is unable to provide a reliable history. (3) The importance of including substance intoxication and withdrawal in the differential diagnosis even when there is a negative urine drug screen. Toxidrome of withdrawal can be delayed. (4) The importance of discussing addiction and withdrawal risks of medications with patients.

Keywords: addiction risk of benzodiazepines, alprazolam withdrawal, altered mental status, benzodiazepines, drug monitoring programs, sedative-hypnotics, substance use disorder

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Authors: Thomas Rockstuhl, Kok Yee Ng, Guido Gianasso, Soon Ang

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Two meta-analyses show that intercultural experience is not related to intercultural adaptation or performance in international assignments. These findings have prompted calls for a deeper grounding of research on international experience in the phenomenon of global work. Two issues, in particular, may limit current understanding of the relationship between international experience and global work performance. First, intercultural experience is too broad a construct that may not sufficiently capture the essence of global work, which to a large part involves sensemaking and managing intercultural conflicts. Second, the psychological mechanisms through which intercultural experience affects performance remains under-explored, resulting in a poor understanding of how experience is translated into learning and performance outcomes. Drawing on recognition primed decision-making (RPD) research, the current study advances a cognitive processing model to highlight the importance of intercultural conflict familiarity. Compared to intercultural experience, intercultural conflict familiarity is a more targeted construct that captures individuals’ previous exposure to dealing with intercultural conflicts. Drawing on RPD theory, we argue that individuals’ intercultural conflict familiarity enhances their ability to make accurate judgments and generate effective responses when intercultural conflicts arise. In turn, the ability to make accurate situation judgements and effective situation responses is an important predictor of global work performance. A relocation program within a multinational enterprise provided the context to test these hypotheses using a time-lagged, multi-source field study. Participants were 165 employees (46% female; with an average of 5 years of global work experience) from 42 countries who relocated from country to regional offices as part a global restructuring program. Within the first two weeks of transfer to the regional office, employees completed measures of their familiarity with intercultural conflicts, cultural intelligence, cognitive ability, and demographic information. They also completed an intercultural situational judgment test (iSJT) to assess their situation judgment and situation response. The iSJT comprised four validated multimedia vignettes of challenging intercultural work conflicts and prompted employees to provide protocols of their situation judgment and situation response. Two research assistants, trained in intercultural management but blind to the study hypotheses, coded the quality of employee’s situation judgment and situation response. Three months later, supervisors rated employees’ global work performance. Results using multilevel modeling (vignettes nested within employees) support the hypotheses that greater familiarity with intercultural conflicts is positively associated with better situation judgment, and that situation judgment mediates the effect of intercultural familiarity on situation response quality. Also, aggregated situation judgment and situation response quality both predicted supervisor-rated global work performance. Theoretically, our findings highlight the important but under-explored role of familiarity with intercultural conflicts; a shift in attention from the general nature of international experience assessed in terms of number and length of overseas assignments. Also, our cognitive approach premised on RPD theory offers a new theoretical lens to understand the psychological mechanisms through which intercultural conflict familiarity affects global work performance. Third, and importantly, our study contributes to the global talent identification literature by demonstrating that the cognitive processes engaged in resolving intercultural conflicts predict actual performance in the global workplace.

Keywords: intercultural conflict familiarity, job performance, judgment and decision making, situational judgment test

Procedia PDF Downloads 178

Authors: Amin Masoumiganjgah, Luke Salmon, Julianne Burnton, Fahimeh Bagheri, Gavin Lenton, S. L. Ezekial Tan

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Introduction: The incidence of proximal biceps tenodesis and acute distal biceps repair is increasing, and rehabilitation protocols following both are variable. Golf is a popular sport within Australia, and the Gold Coast has become a Mecca for golfers, with more courses per capita than anywhere else in the world. Currently, there are no clear guidelines regarding return to golf play following biceps procedures. The aim of this study was to determine biceps brachii activation during the golf swing through electromyographic analysis, and subsequently, aid in rehabilitation guidelines and return to golf following tenodesis and repair. Methods: Subjects were amateur golfers with no previous upper limb surgery. Surface electromyography (EMG) and high-speed video recording were used to analyse activation of the left and right biceps brachii and the anterior deltoid during the golf swing. Each participant’s maximum voluntary contraction (MVC) was recorded, and they were then required to hit a golf ball aiming for specific distances of 2, 50, 100 and 150 metres at a driving range. Noraxon myoResearch and Matlab were used for data analysis. Mean % MVC was calculated for leading and trailing arms during the full swing and its’ 4 phases: back-swing, acceleration, early follow-through and late follow-through. Results: 12 golfers (2 female and 10 male), participated in the study. Median age was 27 (25 – 38), with all being right handed. Over all distances, the mean activation of the short and long head of biceps brachii was < 10% through the full swing. When breaking down the 50, 100 and 150m swing into phases, mean MVC activation was lowest in backswing (5.1%), followed by acceleration (9.7%), early follow-through (9.2%), and late follow-through (21.4%). There was more variation and slightly higher activation in the right biceps (trailing arm) in backswing, acceleration, and early follow-through; with higher activation in the leading arm in late follow-through (25.4% leading, 17.3% trailing). 2m putts resulted in low MVC values (3.1% ) with little variation across swing phases. There was considerable individual variation in results – one tense subject averaged 11.0% biceps MVC through the 2m putting stroke and others recorded peak mean MVC biceps activations of 68.9% at 50m, 101.3% at 100m, and 111.3% at 150m. Discussion: Previous studies have investigated the role of rotator cuff, spine, and hip muscles during the golf swing however, to our knowledge, this is the first study that investigates the activation of biceps brachii. Many rehabilitation programs following a biceps tenodesis or repair allow active range against gravity and restrict strengthening exercises until 6 weeks, and this does not appear to be associated with any adverse outcome. Previous studies demonstrate a range of < 10% MVC is similar to the unloaded biceps brachii during walking(1), active elbow flexion with the hand positioned either in pronation or supination will produce MVC < 20% throughout range(2) and elbow flexion with a 4kg dumbbell can produce mean MVC’s of around 40%(3). Our study demonstrates that increasing activation is associated with the leading arm, increasing shot distance and the late follow-through phase. Although the cohort mean MVC of the biceps brachii is <10% through the full swing, variability is high and biceps activation reach peak mean MVC’s of over 100% in different swing phases for some individuals. Given these EMG values, caution is advised when advising patients post biceps procedures to return to long distance golf shots, particularly when the leading arm is involved. Even though it would appear that putting would be as safe as having an unloaded hand out of a sling following biceps procedures, the variability of activation patterns across different golfers would lead us to caution against accelerated golf rehabilitation in those who may be particularly tense golfers. The 50m short iron shot was too long to consider as a chip shot and more work can be done in this area to determine the safety of chipping.

Keywords: electromyographic analysis, biceps brachii rupture, golf swing, tendon surgery

Procedia PDF Downloads 79

Authors: Chien Chin-Wen

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Collaborative teaching has different teaching models and station teaching is one type of collaborative teaching. Station teaching is not commonly practiced in elementary school English education and introduced in language teacher education programs in Taiwan. In station teaching, each teacher takes a small part of instructional content, working with a small number of students. Students rotate between stations where they receive the assignments and instruction from different teachers. The teachers provide the same content to each group, but the instructional method can vary based upon the needs of each group of students. This study explores thirty-four Taiwanese pre-service elementary school English teachers’ knowledge about station teaching and their competence demonstrated in designing activities for and delivering of station teaching in an English remedial education to six sixth graders in a local elementary school in northern Taiwan. The participants simultaneously enrolled in this Elementary School English Teaching Materials and Methods class, a part of an elementary school teacher education program in a northern Taiwan city. The instructor (Jennifer, pseudonym) in this Elementary School English Teaching Materials and Methods class collaborated with an English teacher (Olivia, pseudonym) in Maureen Elementary School (pseudonym), an urban elementary school in a northwestern Taiwan city. Of Olivia’s students, four male and two female sixth graders needed to have remedial English education. Olivia chose these six elementary school students because they were in the lowest 5 % of their class in terms of their English proficiency. The thirty-four pre-service English teachers signed up for and took turns in teaching these six sixth graders every Thursday afternoon from four to five o’clock for twelve weeks. While three participants signed up as a team and taught these six sixth graders, the last team consisted of only two pre-service teachers. Each team designed a 40-minute lesson plan on the given language focus (words, sentence patterns, dialogue, phonics) of the assigned unit. Data in this study included the KWLA chart, activity designs, and semi-structured interviews. Data collection lasted for four months, from September to December 2014. Data were analyzed as follows. First, all the notes were read and marked with appropriate codes (e.g., I don’t know, co-teaching etc.). Second, tentative categories were labeled (e.g., before, after, process, future implication, etc.). Finally, the data were sorted into topics that reflected the research questions on the basis of their relevance. This study has the following major findings. First of all, the majority of participants knew nothing about station teaching at the beginning of the study. After taking the course Elementary School English Teaching Materials and Methods and after designing and delivering the station teaching in an English remedial education program to six sixth graders, they learned that station teaching is co-teaching, and that it includes activity designs for different stations and students’ rotating from station to station. They demonstrated knowledge and skills in activity designs for vocabulary, sentence patterns, dialogue, and phonics. Moreover, they learned to interact with individual learners and guided them step by step in learning vocabulary, sentence patterns, dialogue, and phonics. However, they were still incompetent in classroom management, time management, English, and designing diverse and meaningful activities for elementary school students at different English proficiency levels. Hence, language teacher education programs are recommended to integrate station teaching to help pre-service teachers be equipped with eight knowledge and competences, including linguistic knowledge, content knowledge, general pedagogical knowledge, curriculum knowledge, knowledge of learners and their characteristics, pedagogical content knowledge, knowledge of education content, and knowledge of education’s ends and purposes.

Keywords: co-teaching, competence, knowledge, pre-service teachers, station teaching

Procedia PDF Downloads 427

Authors: Dmitriy Berillo, Areej K. A. Al-Jwaid, Jonathan L. Caplin, Andrew Cundy, Irina Savina

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Chlorophenols (CPs) are used as a precursor in the production of higher CPs and dyestuffs, and as a preservative. Contamination by CPs of the ground water is located in the range from 0.15-100mg/L. The EU has set maximum concentration limits for pesticides and their degradation products of 0.1μg/L and 0.5μg/L, respectively. People working in industries which produce textiles, leather products, domestic preservatives, and petrochemicals are most heavily exposed to CPs. The International Agency for Research on Cancers categorized CPs as potential human carcinogens. Existing multistep water purification processes for CPs such as hydrogenation, ion exchange, liquid-liquid extraction, adsorption by activated carbon, forward and inverse osmosis, electrolysis, sonochemistry, UV irradiation, and chemical oxidation are not always cost effective and can cause the formation of even more toxic or mutagenic derivatives. Bioremediation of CPs derivatives utilizing microorganisms results in 60 to 100% decontamination efficiency and the process is more environmentally-friendly compared with existing physico-chemical methods. Microorganisms immobilized onto a substrate show many advantages over free bacteria systems, such as higher biomass density, higher metabolic activity, and resistance to toxic chemicals. They also enable continuous operation, avoiding the requirement for biomass-liquid separation. The immobilized bacteria can be reused several times, which opens the opportunity for developing cost-effective processes for wastewater treatment. In this study, we develop a bioremediation system for CPs based on macroporous materials, which can be efficiently used for wastewater treatment. Conditions for the preparation of the macroporous material from specific bacterial strains (Pseudomonas mendocina and Rhodococus koreensis) were optimized. The concentration of bacterial cells was kept constant; the difference was only the type of cross-linking agents used e.g. glutaraldehyde, novel polymers, which were utilized at concentrations of 0.5 to 1.5%. SEM images and rheology analysis of the material indicated a monolithic macroporous structure. Phenol was chosen as a model system to optimize the function of the cryogel material and to estimate its enzymatic activity, since it is relatively less toxic and harmful compared to CPs. Several types of macroporous systems comprising live bacteria were prepared. The viability of the cross-linked bacteria was checked using Live/Dead BacLight kit and Laser Scanning Confocal Microscopy, which revealed the presence of viable bacteria with the novel cross-linkers, whereas the control material cross-linked with glutaraldehyde(GA), contained mostly dead cells. The bioreactors based on bacteria were used for phenol degradation in batch mode at an initial concentration of 50mg/L, pH 7.5 and a temperature of 30°C. Bacterial strains cross-linked with GA showed insignificant ability to degrade phenol and for one week only, but a combination of cross-linking agents illustrated higher stability, viability and the possibility to be reused for at least five weeks. Furthermore, conditions for CPs degradation will be optimized, and the chlorophenol degradation rates will be compared to those for phenol. This is a cutting-edge bioremediation approach, which allows the purification of waste water from sustainable compounds without a separation step to remove free planktonic bacteria. Acknowledgments: Dr. Berillo D. A. is very grateful to Individual Fellowship Marie Curie Program for funding of the research.

Keywords: bioremediation, cross-linking agents, cross-linked microbial cell, chlorophenol degradation

Procedia PDF Downloads 212

Authors: T. Heikkinen, J. Oksman, T. Bragge, A. Nurmi, O. Kontkanen, T. Ahtoniemi

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Motor impairment is an inherent phenotypic feature of several chronic neurodegenerative diseases, and pharmacological therapies aimed to counterbalance the motor disability have a great market potential. Animal models of chronic neurodegenerative diseases display a number deteriorating motor phenotype during the disease progression. There is a wide array of behavioral tools to evaluate motor functions in rodents. However, currently existing methods to study motor functions in rodents are often limited to evaluate gross motor functions only at advanced stages of the disease phenotype. The most commonly applied traditional motor assays used in CNS rodent models, lack the sensitivity to capture fine motor impairments or improvements. Fine motor skill characterization in rodents provides a more sensitive tool to capture more subtle motor dysfunctions and therapeutic effects. Importantly, similar approach, kinematic movement analysis, is also used in clinic, and applied both in diagnosis and determination of therapeutic response to pharmacological interventions. The aim of this study was to apply kinematic gait analysis, a novel and automated high precision movement analysis system, to characterize phenotypic deficits in three different chronic neurodegenerative animal models, a transgenic mouse model (SOD1 G93A) for amyotrophic lateral sclerosis (ALS), and R6/2 and Q175KI mouse models for Huntington’s disease (HD). The readouts from walking behavior included gait properties with kinematic data, and body movement trajectories including analysis of various points of interest such as movement and position of landmarks in the torso, tail and joints. Mice (transgenic and wild-type) from each model were analyzed for the fine motor kinematic properties at young ages, prior to the age when gross motor deficits are clearly pronounced. Fine motor kinematic Evaluation was continued in the same animals until clear motor dysfunction with conventional motor assays was evident. Time course analysis revealed clear fine motor skill impairments in each transgenic model earlier than what is seen with conventional gross motor tests. Motor changes were quantitatively analyzed for up to ~80 parameters, and the largest data sets of HD models were further processed with principal component analysis (PCA) to transform the pool of individual parameters into a smaller and focused set of mutually uncorrelated gait parameters showing strong genotype difference. Kinematic fine motor analysis of transgenic animal models described in this presentation show that this method isa sensitive, objective and fully automated tool that allows earlier and more sensitive detection of progressive neuromuscular and CNS disease phenotypes. As a result of the analysis a comprehensive set of fine motor parameters for each model is created, and these parameters provide better understanding of the disease progression and enhanced sensitivity of this assay for therapeutic testing compared to classical motor behavior tests. In SOD1 G93A, R6/2, and Q175KI mice, the alterations in gait were evident already several weeks earlier than with traditional gross motor assays. Kinematic testing can be applied to a wider set of motor readouts beyond gait in order to study whole body movement patterns such as with relation to joints and various body parts longitudinally, providing a sophisticated and translatable method for disseminating motor components in rodent disease models and evaluating therapeutic interventions.

Keywords: Gait analysis, kinematic, motor impairment, inherent feature

Procedia PDF Downloads 354

Authors: Yung-Chih Kuo, Che-Yu Lin, Jay-Shake Li, Yung-I Lou

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Curcumin (CRM) and nerve growth factor (NGF) were entrapped in liposomes (LIP) with cardiolipin (CL) to downregulate the phosphorylation of mitogen-activated protein kinases for Alzheimer’s disease (AD) management. AD belongs to neurodegenerative disorder with a gradual loss of memory, yielding irreversible dementia. CL-conjugated LIP loaded with CRM (CRM-CL/LIP) and that with NGF (NGF-CL/LIP) were applied to AD models of SK-N-MC cells and Wistar rats with an insult of β-amyloid peptide (Aβ). Lipids comprising 1,2-dipalmitoyl-sn-glycero-3- phosphocholine (Avanti Polar Lipids, Alabaster, AL), 1',3'-bis[1,2- dimyristoyl-sn-glycero-3-phospho]-sn-glycerol (CL; Avanti Polar Lipids), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy(polyethylene glycol)-2000] (Avanti Polar Lipids), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol)-2000] (Avanti Polar Lipids) and CRM (Sigma–Aldrich, St. Louis, MO) were dissolved in chloroform (J. T. Baker, Phillipsburg, NJ) and condensed using a rotary evaporator (Panchum, Kaohsiung, Taiwan). Human β-NGF (Alomone Lab, Jerusalem, Israel) was added in the aqueous phase. Wheat germ agglutinin (WGA; Medicago AB, Uppsala, Sweden) was grafted on LIP loaded with CRM for (WGA-CRM-LIP) and CL-conjugated LIP loaded with CRM (WGA-CRM-CL/LIP) using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (Sigma–Aldrich) and N-hydroxysuccinimide (Alfa Aesar, Ward Hill, MA). The protein samples of SK-N-MC cells (American Type Tissue Collection, Rockville, MD) were used for sodium dodecyl sulfate (Sigma–Aldrich) polyacrylamide gel (Sigma–Aldrich) electrophoresis. In animal study, the LIP formulations were administered by intravenous injection via a tail vein of male Wistar rats (250–280 g, 8 weeks, BioLasco, Taipei, Taiwan), which were housed in the Animal Laboratory of National Chung Cheng University in accordance with the institutional guidelines and the guidelines of Animal Protection Committee under the Council of Agriculture of the Republic of China. We found that CRM-CL/LIP could inhibit the expressions of phosphorylated p38 (p-p38), p-Jun N-terminal kinase (p-JNK), and p-tau protein at serine 202 (p-Ser202) to retard the neuronal apoptosis. Free CRM and released CRM from CRM-LIP and CRM-CL/LIP were not in a straightforward manner to effectively inhibit the expression of p-p38 and p-JNK in the cytoplasm. In addition, NGF-CL/LIP enhanced the quantities of p-neurotrophic tyrosine kinase receptor type 1 (p-TrkA) and p-extracellular-signal-regulated kinase 5 (p-ERK5), preventing the Aβ-induced degeneration of neurons. The membrane fusion of NGF-LIP activated the ERK5 pathway and the targeting capacity of NGF-CL/LIP enhanced the possibility of released NGF to affect the TrkA level. Moreover, WGA-CRM-LIP improved the permeation of CRM across the blood–brain barrier (BBB) and significantly reduced the Aβ plaque deposition and malondialdehyde level and increased the percentage of normal neurons and cholinergic function in the hippocampus of AD rats. This was mainly because the encapsulated CRM was protected by LIP against a rapid degradation in the blood. Furthermore, WGA on LIP could target N-acetylglucosamine on endothelia and increased the quantity of CRM transported across the BBB. In addition, WGA-CRM-CL/LIP could be effective in suppressing the synthesis of acetylcholinesterase and reduced the decomposition of acetylcholine for better neurotransmission. Based on the in vitro and in vivo evidences, WGA-CRM-CL/LIP can rescue neurons from apoptosis in the brain and can be a promising drug delivery system for clinical AD therapy.

Keywords: Alzheimer’s disease, β-amyloid, liposome, mitogen-activated protein kinase

Procedia PDF Downloads 329

Authors: Aidan Ryan, Nahima Miah, Sahaj Kaur, Imogen Sutherland, Mohamed Saleh

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Pulmonary symptoms are a common presentation to the emergency department. Due to a lack of understanding of the underlying pathophysiology, chronic liver disease is not often considered a cause of dyspnea. We present three patients who were admitted with significant respiratory distress secondary to hepatopulmonary syndrome, portopulmonary hypertension, and hepatic hydrothorax. The first is a 27-year-old male with a 6-month history of progressive dyspnea. The patient developed a severe type 1 respiratory failure with a PaO₂ of 6.3kPa and was escalated to critical care, where he was managed with non-invasive ventilation to maintain oxygen saturation. He had an agitated saline contrast echocardiogram, which showed the presence of a possible shunt. A CT angiogram revealed significant liver cirrhosis, portal hypertension, and large para esophageal varices. Ultrasound of the abdomen showed coarse liver echo patter and enlarged spleen. Along with these imaging findings, his biochemistry demonstrated impaired synthetic liver function with an elevated international normalized ratio (INR) of 1.4 and hypoalbuminaemia of 28g/L. The patient was then transferred to a tertiary center for further management. Further investigations confirmed a shunt of 56%, and liver biopsy confirmed cirrhosis suggestive of alpha-1-antitripsyin deficiency. The findings were consistent with a diagnosis of hepatopulmonary syndrome, and the patient is awaiting a liver transplant. The second patient is a 56-year-old male with a 12-month history of worsening dyspnoea, jaundice, confusion. His medical history included liver cirrhosis, portal hypertension, and grade 1 oesophageal varices secondary to significant alcohol excess. On admission, he developed a type 1 respiratory failure with PaO₂ of 6.8kPa requiring 10L of oxygen. CT pulmonary angiogram was negative for pulmonary embolism but showed evidence of chronic pulmonary hypertension, liver cirrhosis, and portal hypertension. An echocardiogram revealed a grossly dilated right heart with reduced function, pulmonary and tricuspid regurgitation, and pulmonary artery pressures estimated at 78mmHg. His biochemical markers showed impaired synthetic liver function with an INR of 3.2, albumin of 29g/L, along with raised bilirubin of 148mg/dL. During his long admission, he was managed with diuretics with little improvement. After three weeks, he was diagnosed with portopulmonary hypertension and was commenced on terlipressin. This resulted in successfully weaning off oxygen, and he was discharged home. The third patient is a 61-year-old male who presented to the local ambulatory care unit for therapeutic paracentesis on a background of decompensated liver cirrhosis. On presenting, he complained of a 2-day history of worsening dyspnoea and a productive cough. Chest x-ray showed a large pleural effusion, increasing in size over the previous eight months, and his abdomen was visibly distended with ascitic fluid. Unfortunately, the patient deteriorated, developing a larger effusion along with an increase in oxygen demand, and passed away. Without underlying cardiorespiratory disease, in the presence of a persistent pleural effusion with underlying decompensated cirrhosis, he was diagnosed with hepatic hydrothorax. While each presented with dyspnoea, the cause and underlying pathophysiology differ significantly from case to case. By describing these complications, we hope to improve awareness and aid prompt and accurate diagnosis, vital for improving outcomes.

Keywords: dyspnea, hepatic hydrothorax, hepatopulmonary syndrome, portopulmonary syndrome

Procedia PDF Downloads 120

Authors: Nkechi V. Enwuru, Bullum Nkeki, Elizabeth A. Adekoya, Olumide A. Adebesin, Rebecca F. Peters, Victoria A. Aikhomu, Mendie E. U.

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Background: Probiotics are live microbial feed supplement beneficial for host. Probiotics and their postbiotic products have been used to prevent or treat various health conditions. However, the products cell viability is often low due to harsh conditions subjected during processing, handling, storage, and gastrointestinal transit. These strongly influence probiotics’ benefits; thus, viability is essential for probiotics to produce health benefits for the host. Microencapsulation is a promising technique with considerable effects on probiotic survival. The study is aimed to formulate a microencapsulated probiotic and evaluate its viability, antimicrobial efficacy, and cytotoxic activity of its postbiotic on the MCF-7 breast cancer cell line. Method: Human and animal raw milk were sampled for lactic acid bacteria. The isolated bacteria were identified using conventional and VITEK 2 systems. The identified lactic acid bacterium was encapsulated using spray-dried and extrusion methods. The free, encapsulated, and chitosan-coated encapsulated probiotics were tested for viability in simulated-gastric intestinal (SGI) fluid and different storage conditions at refrigerated (4oC) and room (25oC) temperatures. The disintegration time and weight uniformity of the spray-dried hard gelatin capsules were tested. The antimicrobial property of free and encapsulated probiotics was tested against enteric pathogenic isolates from antiretroviral therapy (ART) treated HIV-positive patients. The postbiotic of the free cells was extracted, and its cytotoxic effect on the MCF-7 breast cancer cell line was tested through an MTT assay. Result: The Lactobacillus plantarum was isolated from animal raw milk. Zero-size hard gelatin L. plantarum capsules with granules within a size range of 0.71–1.00 mm diameter was formulated. The disintegration time ranges from 2.14±0.045 to 2.91±0.293 minutes, while the average weight is 502.1mg. Simulated gastric solution significantly affected viability of both free and microcapsules. However, the encapsulated cells were more protected and viable due to impermeability in the microcapsules. Furthermore, the viability of free cells stored at 4oC and 25oC were less than 4 log CFU/g and 6 log CFU/g respectively after 12 weeks. However, the microcapsules stored at 4oC achieved the highest viability among the free and microcapsules stored at 25oC and the free cells stored at 4oC. Encapsulated cells were released in the simulated gastric fluid, viable and effective against the enteric pathogens tested. However, chitosan-coated calcium alginate encapsulated probiotics significantly inhibited Shigella flexneri, Candida albicans, and Escherichia coli. The Postbiotic Metabolites (PM) of L. plantarum produced a cytotoxic effect on the MCF-7 breast cancer cell line. The postbiotic showed significant cytotoxic activity similar to 5FU, a standard antineoplastic agent. The inhibition concentration of 50% growth (IC50) of postbiotic metabolite K3 is low and consistent with the IC50 of the positive control (Cisplatin). Conclusions: Lactobacillus plantarum postbiotic exhibited a cytotoxic effect on the MCF-7 breast cancer cell line and could be used as combined adjuvant therapy in breast cancer management. The microencapsulation technique protects the probiotics, improving their viability and delivery to the gastrointestinal tract. Chitosan enhances antibacterial efficacy; thus, chitosan-coated microencapsulated L. plantarum probiotics could be more effective and used as a combined therapy in HIV management of opportunistic enteric infection.

Keywords: probiotics, encapsulation, gastrointestinal conditions, antimicrobial effect, postbiotic, cytotoxicity effect

Procedia PDF Downloads 119

Authors: Sumeyra Karatas, Veysel Karatas, Reyhan Safak, Gamze Bulut-Ozturk, Ozgul Kartal

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Productive struggle entails a student's cognitive exertion to comprehend mathematical concepts and uncover solutions not immediately apparent. The significance of productive struggle in learning mathematics is accentuated by influential educational theorists, emphasizing its necessity for learning mathematics with understanding. Consequently, supporting productive struggle in learning mathematics is recognized as a high-leverage and effective mathematics teaching practice. In this study, the investigation into the role of productive struggle in learning mathematics led to the development of a comprehensive rubric for productive struggle pedagogy through an exhaustive literature review. The rubric consists of eight primary criteria and 37 sub-criteria, providing a detailed description of teacher actions and pedagogical choices that foster students' productive struggles. These criteria encompass various pedagogical aspects, including task design, tool implementation, allowing time for struggle, posing questions, scaffolding, handling mistakes, acknowledging efforts, and facilitating discussion/feedback. Utilizing this rubric, a team of researchers and teachers designed eight 90-minute lesson plans, employing a productive struggle pedagogy, for a two-week unit on solving systems of linear equations. Simultaneously, another set of eight lesson plans on the same topic, featuring identical content and problems but employing a traditional lecture-and-practice model, was designed by the same team. The objective was to assess the impact of supporting productive struggle on students' mathematics learning, defined by the strands of mathematical proficiency. This quasi-experimental study compares the control group, which received traditional lecture- and practice instruction, with the treatment group, which experienced a productive struggle in pedagogy. Sixty-six 10th and 11th-grade students from two algebra classes, taught by the same teacher at a high school, underwent either the productive struggle pedagogy or lecture-and-practice approach over two-week eight 90-minute class sessions. To measure students' learning, an assessment was created and validated by a team of researchers and teachers. It comprised seven open-response problems assessing the strands of mathematical proficiency: procedural and conceptual understanding, strategic competence, and adaptive reasoning on the topic. The test was administered at the beginning and end of the two weeks as pre-and post-test. Students' solutions underwent scoring using an established rubric, subjected to expert validation and an inter-rater reliability process involving multiple criteria for each problem based on their steps and procedures. An analysis of covariance (ANCOVA) was conducted to examine the differences between the control group, which received traditional pedagogy, and the treatment group, exposed to the productive struggle pedagogy, on the post-test scores while controlling for the pre-test. The results indicated a significant effect of treatment on post-test scores for procedural understanding (F(2, 63) = 10.47, p < .001), strategic competence (F(2, 63) = 9.92, p < .001), adaptive reasoning (F(2, 63) = 10.69, p < .001), and conceptual understanding (F(2, 63) = 10.06, p < .001), controlling for pre-test scores. This demonstrates the positive impact of supporting productive struggle in learning mathematics. In conclusion, the results revealed the significance of the role of productive struggle in learning mathematics. The study further explored the practical application of productive struggle through the development of a comprehensive rubric describing the pedagogy of supporting productive struggle.

Keywords: effective mathematics teaching practice, high school algebra, learning mathematics, productive struggle

Procedia PDF Downloads 51

Authors: Ipsita Pujari, Abitha Thomas, Vidhu S. Babu, K. Satyamoorthy

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Orchids are esteemed as celebrities in cut flower industry globally, due to their long-lasting fragrance and freshness. Apart from splendor, the unique metabolites endowed with pharmaceutical potency have made them one of the most hunted in plant kingdom. This had led to their trafficking, resulting in habitat loss, subsequently making them occupiers of IUCN red list as RET species. Many of the orchids especially wild varieties still remain undiscovered. In view to protect and conserve the wild germplasm, researchers have been inventing novel micropropagation protocols; thereby conserving Orchids. India is overflowing with exclusive wild cultivars of Orchids, whose pharmaceutical properties remain untapped and are not marketed owing to relatively small flowers. However, their germplasm is quite pertinent to be preserved for making unusual hybrids. Dendrobium genus is the second largest among Orchids exists in India and has highest demand attributable to enduring cut flowers and significant therapeutic uses in traditional medicinal system. Though the genus is quite endemic in Western Ghat regions of the country, many species are still anonymous with their unknown curative properties. A standard breeding cycle in Orchids usually takes five to seven years (Dendrobium hybrids taking a long juvenile phase of two to five years reaching maturity and flowering stage) and this extensive life cycle has always hindered the development of Dendrobium breeding. Dendrobium is reported with essential therapeutic plant bio-chemicals and ‘Moscatilin’ is one, found exclusive to this famous Dendrobium genus. Moscatilin is reported to have anti-mutagenic and anti-cancer properties, whose positive action has very recently been demonstrated against a range of cancers. Our preliminary study here established a simple and economic small-scale propagation protocol of Dendrobium ovatum describing in vitro production of Moscatilin. Subsequently for enhancing the content of Moscatilin, an efficient experimental related to the organization of transgenic (hairy) D. ovatum root cultures through infection of Agrobacterium rhizogenes 2364 strain on MS basal medium is being reported in the present study. Hairy roots generated on almost half of the explants used (spherules, in vitro plantlets and calli) maintained through suspension cultures, after 8 weeks of co-cultivation with Agrobacterium rhizogenes. GFP assay performed with isolated hairy roots has confirmed the integrative transformation which was further positively confirmed by PCR using rolB gene specific primers. Reverse phase-high performance liquid chromatography and mass spectrometry techniques were used for quantification and accurate identification of Moscatilin respectively from transgenic systems. A noticeable ~3 fold increase in contents were observed in transformed D. ovatum root cultures as compared to the simple in vitro culture, callus culture and callus regeneration plantlets. Role of elicitors e.g., Methyl jasmonate, Salicylic acid, Yeast extract and Chitosan were tested for elevating the Moscatilin content to obtain a comprehensive optimized protocol facilitating the in vitro production of valuable Moscatilin with larger yield. This study would provide evidence towards the in vitro assembly of Moscatilin within a short time-period through not a so-expensive technology for the first time. It also serves as an appropriate basis for bioreactor scale-up resulting in commercial bioproduction of Moscatilin.

Keywords: bioproduction, Dendrobium ovatum, hairy root culture, moscatilin

Procedia PDF Downloads 235

Authors: Dimitra C. Banti, Gesthimani Liona, Petros Samaras, Manasis Mitrakas

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Municipal and industrial wastewaters are often treated biologically, by the activated sludge process (ASP). The ASP not only requires large aeration and sedimentation tanks, but also generates large quantities of excess sludge. An alternative technology is the membrane bioreactor (MBR), which replaces two stages of the conventional ASP—clarification and settlement—with a single, integrated biotreatment and clarification step. The advantages offered by the MBR over conventional treatment include reduced footprint and sludge production through maintaining a high biomass concentration in the bioreactor. Notwithstanding these advantages, the widespread application of the MBR process is constrained by membrane fouling. Fouling leads to permeate flux decline, making more frequent membrane cleaning and replacement necessary and resulting to increased operating costs. In general, membrane fouling results from the interaction between the membrane material and the components in the activated sludge liquor. The latter includes substrate components, cells, cell debris and microbial metabolites, such as Extracellular Polymeric Substances (EPS) and Sludge Microbial Products (SMPs). The challenge for effective MBR operation is to minimize the rate of Transmembrane Pressure (TMP) increase. This can be achieved by several ways, one of which is the addition of specific additives, that enhance the coagulation and flocculation of compounds, which are responsible for fouling, hence reducing biofilm formation on the membrane surface and limiting the fouling rate. In this project the effectiveness of a non-commercial composite coagulant was studied as an agent for fouling control in a lab scale MBR system consisting in two aerated tanks. A flat sheet membrane module with 0.40 um pore size was submerged into the second tank. The system was fed by50 L/d of municipal wastewater collected from the effluent of the primary sedimentation basin. The TMP increase rate, which is directly related to fouling growth, was monitored by a PLC system. EPS, MLSS and MLVSS measurements were performed in samples of mixed liquor; in addition, influent and effluent samples were collected for the determination of physicochemical characteristics (COD, BOD5, NO3-N, NH4-N, Total N and PO4-P). The coagulant was added in concentrations 2, 5 and 10mg/L during a period of 2 weeks and the results were compared with the control system (without coagulant addition). EPS fractions were extracted by a three stages physical-thermal treatment allowing the identification of Soluble EPS (SEPS) or SMP, Loosely Bound EPS (LBEPS) and Tightly Bound EPS (TBEPS). Proteins and carbohydrates concentrations were measured in EPS fractions by the modified Lowry method and Dubois method, respectively. Addition of 2 mg/L coagulant concentration did not affect SEPS proteins in comparison with control process and their values varied between 32 to 38mg/g VSS. However a coagulant dosage of 5mg/L resulted in a slight increase of SEPS proteins at 35-40 mg/g VSS while 10mg/L coagulant further increased SEPS to 44-48mg/g VSS. Similar results were obtained for SEPS carbohydrates. Carbohydrates values without coagulant addition were similar to the corresponding values measured for 2mg/L coagulant; the addition of mg/L coagulant resulted to a slight increase of carbohydrates SEPS to 6-7mg/g VSS while a dose of 10 mg/L further increased carbohydrates content to 9-10mg/g VSS. Total LBEPS and TBEPS, consisted of proteins and carbohydrates of LBEPS and TBEPS respectively, presented similar variations by the addition of the coagulant. Total LBEPS at 2mg/L dose were almost equal to 17mg/g VSS, and their values increased to 22 and 29 mg/g VSS during the addition of 5 mg/L and 10 mg/L of coagulant respectively. Total TBEPS were almost 37 mg/g VSS at a coagulant dose of 2 mg/L and increased to 42 and 51 mg/g VSS at 5 mg/L and 10 mg/L doses, respectively. Therefore, it can be concluded that coagulant addition could potentially affect microorganisms activities, excreting EPS in greater amounts. Nevertheless, EPS increase, mainly SEPS increase, resulted to a higher membrane fouling rate, as justified by the corresponding TMP increase rate. However, the addition of the coagulant, although affected the EPS content in the reactor mixed liquor, did not change the filtration process: an effluent of high quality was produced, with COD values as low as 20-30 mg/L.

Keywords: extracellular polymeric substances, MBR, membrane fouling, EPS

Procedia PDF Downloads 266

Authors: Ghidey Ghebreyohanes, Eltahir Awad Gasim Khalil, Zemenfes Tsighe, Faiza Ali

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Background: reproductive health (RH) is a state of physical, mental and social well-being in all matters relating to the reproductive system at all stages of life. In East Africa including Eritrea, adolescents comprise more than a quarter of the population. The region holds the highest rates of sexually transmitted diseases, HIV, unwanted pregnancy and unsafe abortion with its complications. Young girls carry the highest burden of reproductive health problems due to their risk taking behavior, lack of knowledge, peer pressure, physiologic immaturity and low socioeconomic status. Design: this was a Community-based, randomized, case-controlled and pre-test-post-test intervention study. Setting: Zoba Debub was randomly selected out of the six zobas in Eritrea. The four high schools out of the 26 in Zoba Debub were randomly selected as study target schools. Over three quarter of the people live on farming. The target population was female students attending grade nine with majority of these girls live in the distant villages and walk to school. The study participants were randomly selected (n=165) from each school. Furthermore, the 1 intervention and 3 controls for the study arms were assigned randomly. Objectives: this study aimed to assess the effectiveness of peer reproductive health education in improving knowledge, attitude, and health service use of high school adolescent girls in Eritrea Methods: the protocol was reviewed and approved by the Scientific and Ethics Committees of Faculty of Nursing Sciences, University of Khartoum. Data was collected using pre-designed and pretested questionnaire emphasizing on reproductive health knowledge, attitude and practice. Sample size was calculated using proportion formula (α 0.01; power of 95%). Measures used were scores and proportions. Descriptive and inferential statistics, t-test and chi square at (α .01), 99% confidence interval were used to compare changes of pre and post-intervention scores using SPSS soft ware. Seventeen students were selected for peer educators by the school principals and other teachers based on inclusion criteria that include: good academic performance and acceptable behavior. One peer educator educated one group composed of 8-10 students for two months. One faculty member was selected to supervise peer educators. The principal investigator conducted the training of trainers and provided supervision and discussion to peer educators every two weeks until the end of intervention. Results: following informed consent, 627 students [164 in intervention and 463 in the control group] with a ratio of 1 to 3, were enrolled in the study. The mean age for the total study population was 15.4±1.0 years. The intervention group mean age was 15.3±1.0 year; while the control group had a mean age of 15.4±1.0. The mean ages for the study arms were similar (p= 0.4). The majority (96 %) of the study participants are from Tigrigna ethnic group. Reproductive knowledge scores which was calculated out of a total 61 grade points: intervention group (pretest 6.7 %, post-test 33.6 %; p= 0.0001); control group (pretest 7.3 %, posttest 7.3 %, p= 0.92). Proportion difference in attitude calculated out of 100%: intervention group (pretest 42.3 % post test 54.7% p= 0.001); controls group (pretest 45%, post test 44.8 p= 0.7). Proportion difference in Practice calculated out of 100 %: intervention group (pretest 15.4%, post test 80.4 % p= 0.0001); control group (pretest 16.8%, posttest 16.9 % p= 0.8). Mothers were quoted as major (> 90 %) source of reproductive health information. All focus group discussants and most of survey participants agreed on the urgent need of reproductive health information and services for adolescent girls. Conclusion: reproductive health knowledge and use of facilities is poor among adolescent girls in sub-urban Eretria. School-based peer reproductive health education is effective and is the best strategy to improve reproductive health knowledge and attitudes.

Keywords: reproductive health, adolescent girls, eretria, health education

Procedia PDF Downloads 362

Authors: Xu Fei (Philip) WU

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As waste recycling concept been accepted more and more in modern societies, the organic portion of the municipal waste become a sires issue in today’s life. Depend on location and season, the organic waste can bee anywhere between 40-65% of total municipal solid waste. Also composting and anaerobic digestion technologies been applied in this field for years, however both process have difficulties been selected by economical and environmental factors. Beside environmental pollution and risk of virus spread, the compost is not a product been welcomed by people even the waste management has to give up them at no cost. The anaerobic digester has to have 70% of water and keep at 35 degree C or above; base on above conditions, the retention time only can be up to two weeks and remain solid has to be dewater and composting again. The enhancive waste water treatment has to be added after. Because these reasons, the voice of suggesting cancelling recycling program and turning all waste to mass burn incinerations have been raised-A process has already been proved has least energy efficiency and most air pollution problem associated process. A newly developed WXF Bio-energy process employs recently developed and patented pre-designed separation, multi-layer and multi-cavity successive bioreactor landfill technology. It features an improved leachate recycling technology, technologies to maximize the biogas generation rate and a reduced overall turnaround period on the land. A single properly designed and operated site can be used indefinitely. In this process, all collected biogas will be processed to eliminate H2S and other hazardous gases. The methane, carbon dioxide and hydrogen will be utilized in a proprietary process to manufacture methanol which can be sold to mitigate operating costs of the landfill. This integration of new processes offers a more advanced alternative to current sanitary landfill, incineration and compost technology. Xu Fei (Philip) Wu Xu Fei Wu is founder and Chief Scientist of W&Y Environmental International Inc. (W & Y), a Canadian environmental and sustainable energy technology company with patented landfill processes and proprietary waste to energy technologies. He has worked in environmental and sustainable energy fields over the last 25 years. Before W&Y, he worked for Conestoga-Rovers & Associates Limited, Microbe Environmental Science and Technology Inc. of Canada and The Ministry of Nuclear Industry and Ministry of Space Flight Industry of China. Xu Fei Wu holds a Master of Engineering Science degree from The University of Western Ontario. I wish present this paper as an oral presentation only Selected Conference Presentations: • “Removal of Phenolic Compounds with Algae” Presented at 25th Canadian Symposium on Water Pollution Research (CAWPRC Conference), Burlington, Ontario Canada. February, 1990 • “Removal of Phenolic Compounds with Algae” Presented at Annual Conference of Pollution Control Association of Ontario, London, Ontario, Canada. April, 1990 • “Removal of Organochlorine Compounds in a Flocculated Algae Photo-Bioreactor” Presented at International Symposium on Low Cost and Energy Saving Wastewater Treatment Technologies (IAWPRC Conference), Kiyoto, Japan, August, 1990 • “Maximizing Production and Utilization of Landfill Gas” 2009 Wuhan International Conference on Environment(CAWPRC Conference, sponsored by US EPA) Wuhan, China. October, 2009. • “WXF Bio-Energy-A Green, Sustainable Waste to Energy Process” Presented at 9Th International Conference Cooperation for Waste Issues, Kharkiv, Ukraine March, 2012 • “A Lannfill Site Can Be Recycled Indefinitely” Presented at 28th International Conference on solid Waste Technology and Management, Philadelphia, Pennsylvania, USA. March, 2013. Hosted by The Journal of Solid Waste Technology and Management.

Keywords: green fuel, waste management, bio-energy, sustainable development, methanol

Procedia PDF Downloads 276

Authors: Katie M. Clark, Adriana A. Tienda, Krista C. Paffenroth, Lindsey N. Brigante, Daniel C. Colvin, Jose Maldonado, Erin S. Calipari, Fiona E. Harrison

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Manganese (Mn) is an essential trace element required for human health and is important in antioxidant defenses, as well as in the development and function of dopaminergic neurons. However, chronic low-level Mn exposure, such as through contaminated drinking water, poses risks that may contribute to neurodevelopmental and neurodegenerative conditions, including attention deficit hyperactivity disorder (ADHD). Pharmacological inhibition of the dopamine transporter (DAT) blocks reuptake, elevates synaptic dopamine, and alleviates ADHD symptoms. This study aimed to determine whether Mn exposure in juvenile mice modifies their response to DAT blockers, amphetamine, and methylphenidate and utilize neuroimaging methods to visualize and quantify Mn distribution across dopaminergic brain regions. Male and female heterozygous DATᵀ³⁵⁶ᴹ and wild-type littermates were randomly assigned to receive control (2.5% Stevia) or high Manganese (2.5 mg/ml Mn + 2.5% Stevia) via water ad libitum from weaning (21-28 days) for 4-5 weeks. Mice underwent repeated testing in locomotor activity chambers for three consecutive days (60 mins.) to ensure that they were fully habituated to the environments. On the fourth day, a 3-hour activity session was conducted following treatment with amphetamine (3 mg/kg) or methylphenidate (5 mg/kg). The second drug was administered in a second 3-hour activity session following a 1-week washout period. Following the washout, the mice were given one last injection of amphetamine and euthanized one hour later. Using the ex-vivo brains, magnetic resonance relaxometry (MRR) was performed on a 7Telsa imaging system to map T1- and T2-weighted (T1W, T2W) relaxation times. Mn inherent paramagnetic properties shorten both T1W and T2W times, which enhances the signal intensity and contrast, enabling effective visualization of Mn accumulation in the entire brain. A subset of mice was treated with amphetamine 1 hour before euthanasia. SmartSPIM light sheet microscopy with cleared whole brains and cFos and tyrosine hydroxylase (TH) labeling enabled an unbiased automated counting and densitometric analysis of TH and cFos positive cells. Immunohistochemistry was conducted to measure synaptic protein markers and quantify changes in neurotransmitter regulation. Mn exposure elevated Mn brain levels and potentiated stimulant effects in males. The globus pallidus, substantia nigra, thalamus, and striatum exhibited more pronounced T1W shortening, indicating regional susceptibility to Mn accumulation (p<0.0001, 2-Way ANOVA). In the cleared whole brains, initial analyses suggest that TH and c-Fos co-staining mirrors behavioral data with decreased co-staining in DATT356M+/- mice. Ongoing studies will identify the molecular basis of the effect of Mn, including changes to DAergic metabolism and transport and post-translational modification to the DAT. These findings demonstrate that alterations in T1W relaxation times, as measured by MRR, may serve as an early biomarker for Mn neurotoxicity. This neuroimaging approach exhibits remarkable accuracy in identifying Mn-susceptible brain regions, with a spatial resolution and sensitivity that surpasses current conventional dissection and mass spectrometry approaches. The capability to label and map TH and cFos expression across the entire brain provides insights into whole-brain neuronal activation and its connections to functional neural circuits and behavior following amphetamine and methylphenidate administration.

Keywords: manganese, environmental toxicology, dopamine dysfunction, biomarkers, drinking water, light sheet microscopy, magnetic resonance relaxometry (MRR)

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Authors: Claire Harrison, Raajit K. Rampal, Vikas Gupta, Srdan Verstovsek, Moshe Talpaz, Jean-Jacques Kiladjian, Ruben Mesa, Andrew Kuykendall, Alessandro Vannucchi, Francesca Palandri, Sebastian Grosicki, Timothy Devos, Eric Jourdan, Marielle J. Wondergem, Haifa Kathrin Al-Ali, Veronika Buxhofer-Ausch, Alberto Alvarez-Larrán, Sanjay Akhani, Rafael Muñoz-Carerras, Yury Sheykin, Gozde Colak, Morgan Harris, John Mascarenhas

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Myelofibrosis (MF) is characterized by bone marrow fibrosis, anemia, splenomegaly and constitutional symptoms. Progressive bone marrow fibrosis results from aberrant megakaryopoeisis and expression of proinflammatory cytokines, both of which are heavily influenced by bromodomain and extraterminal domain (BET)-mediated gene regulation and lead to myeloproliferation and cytopenias. Pelabresib (CPI-0610) is an oral small-molecule investigational inhibitor of BET protein bromodomains currently being developed for the treatment of patients with MF. It is designed to downregulate BET target genes and modify nuclear factor kappa B (NF-κB) signaling. MANIFEST-2 was initiated based on data from Arm 3 of the ongoing Phase 2 MANIFEST study (NCT02158858), which is evaluating the combination of pelabresib and ruxolitinib in Janus kinase inhibitor (JAKi) treatment-naïve patients with MF. Primary endpoint analyses showed splenic and symptom responses in 68% and 56% of 84 enrolled patients, respectively. MANIFEST-2 (NCT04603495) is a global, Phase 3, randomized, double-blind, active-control study of pelabresib and ruxolitinib versus placebo and ruxolitinib in JAKi treatment-naïve patients with primary MF, post-polycythemia vera MF or post-essential thrombocythemia MF. The aim of this study is to evaluate the efficacy and safety of pelabresib in combination with ruxolitinib. Here we report updates from a recent protocol amendment. The MANIFEST-2 study schema is shown in Figure 1. Key eligibility criteria include a Dynamic International Prognostic Scoring System (DIPSS) score of Intermediate-1 or higher, platelet count ≥100 × 10^9/L, spleen volume ≥450 cc by computerized tomography or magnetic resonance imaging, ≥2 symptoms with an average score ≥3 or a Total Symptom Score (TSS) of ≥10 using the Myelofibrosis Symptom Assessment Form v4.0, peripheral blast count <5% and Eastern Cooperative Oncology Group performance status ≤2. Patient randomization will be stratified by DIPSS risk category (Intermediate-1 vs Intermediate-2 vs High), platelet count (>200 × 10^9/L vs 100–200 × 10^9/L) and spleen volume (≥1800 cm^3 vs <1800 cm^3). Double-blind treatment (pelabresib or matching placebo) will be administered once daily for 14 consecutive days, followed by a 7 day break, which is considered one cycle of treatment. Ruxolitinib will be administered twice daily for all 21 days of the cycle. The primary endpoint is SVR35 response (≥35% reduction in spleen volume from baseline) at Week 24, and the key secondary endpoint is TSS50 response (≥50% reduction in TSS from baseline) at Week 24. Other secondary endpoints include safety, pharmacokinetics, changes in bone marrow fibrosis, duration of SVR35 response, duration of TSS50 response, progression-free survival, overall survival, conversion from transfusion dependence to independence and rate of red blood cell transfusion for the first 24 weeks. Study recruitment is ongoing; 400 patients (200 per arm) from North America, Europe, Asia and Australia will be enrolled. The study opened for enrollment in November 2020. MANIFEST-2 was initiated based on data from the ongoing Phase 2 MANIFEST study with the aim of assessing the efficacy and safety of pelabresib and ruxolitinib in JAKi treatment-naïve patients with MF. MANIFEST-2 is currently open for enrollment.

Keywords: CPI-0610, JAKi treatment-naïve, MANIFEST-2, myelofibrosis, pelabresib

Procedia PDF Downloads 200