Search results for: primary brain tumors

Authors: Hyeona Kim, Kichang Lee, Seunghee Lee, Jeongsu An, Kyungjun Min

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Contrast videofluoroscopy is the diagnostic imaging technique for evaluating cat with dysphagia. Generally, videofluoroscopic studies have been done with the cat restrained in lateral recumbency. It is different from the neutral position such as standing or sternal recumbency which is actual swallowing posture. We hypothesized that measurement of esophageal transit and peristalsis would be affected by body position. This experimental study analyzed the imaging findings of barium esophagram in 5 cats. Each cat underwent videofluoroscopy during swallowing of liquid barium and barium-soaked kibble in standing position and lateral recumbency. Esophageal transit time and the number of esophageal peristaltic waves were compared among body positions. Transit time in the cervical esophagus (0.57s), cranial thoracic esophagus (2.5s), and caudal thoracic esophagus(1.10s) was delayed when cats were in lateral recumbency for liquid barium. For kibble, transit time was more delayed than that of liquid through the entire esophagus in lateral recumbency. Liquid and kibble frequently started to delay at thoracic inlet region, transit time in the thoracic esophagus was significantly delayed than the cervical esophagus. In standing position, 60.2% of liquid swallows stimulated primary esophageal peristalsis. In lateral recumbency, 50.5% of liquid swallows stimulated primary esophageal peristalsis. Other variables were not significantly different. Lateral body positioning increases entire esophageal transit time and thoracic esophageal transit time is most significantly delayed. Thus, lateral recumbency decreases the number of primary esophageal peristalsis.

Keywords: barium esophagram, body positioning, cat, videofluoroscopy

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Authors: Yang Yang, Luciana Magalhães Rebelo Alencar, Martha Sahylí Ortega Pijeira, Beatriz da Silva Batista, Alefe Roger Silva França, Erick Rafael Dias Rates, Ruana Cardoso Lima, Sara Gemini-Piperni, Ralph Santos-Oliveira

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Radium-²²³ dichloride ([²²³Rₐ]RₐCl₂) is an alpha particle-emitting radiopharmaceutical currently approved for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases, and no known visceral metastatic disease. [²²³Rₐ]RₐCl₂ is bone-seeking calcium mimetic that bonds into the newly formed bone stroma, especially osteoblastic or sclerotic metastases, killing the tumor cells by inducing DNA breaks in a potent and localized manner. Nonetheless, the successful therapy of osteosarcoma as primary bone tumors is still a challenge. Nanomicelles are colloidal nanosystems widely used in drug development to improve blood circulation time, bioavailability, and specificity of therapeutic agents, among other applications. In addition, the enhanced permeability and retention effect of the nanosystems, and the renal excretion of the nanomicelles reported in most cases so far, are very attractive to achieve selective and increased accumulation in tumor site as well as to increase the safety of [²²³Rₐ]RₐCl₂ in the clinical routine. In the present work, [²²³Rₐ]RₐCl₂ nanomicelles were produced, characterized, in vitro evaluated, and compared with pure [²²³Rₐ]RₐCl2 solution using SAOS2 osteosarcoma cells. The [²²³Rₐ]RₐCl₂ nanomicelles were prepared using the amphiphilic copolymer Pluronic F127. The dynamic light scattering analysis of freshly produced [²²³Rₐ]RₐCl₂ nanomicelles demonstrated a mean size of 129.4 nm with a polydispersity index (PDI) of 0.303. After one week stored in the refrigerator, the mean size of the [²²³Rₐ]RₐCl₂ nanomicelles increased to 169.4 with a PDI of 0.381. Atomic force microscopy analysis of [223Rₐ]RₐCl₂ nanomicelles exhibited spherical structures whose heights reach 1 µm, suggesting the filling of 127-Pluronic nanomicelles with [²²³Rₐ]RₐCl₂. The viability assay with [²²³Rₐ]RₐCl₂ nanomicelles displayed a dose-dependent response as it was observed using pure [²²³Rₐ]RₐCl2. However, at the same dose, [²²³Rₐ]RₐCl₂ nanomicelles were 20% higher efficient in killing SAOS2 cells when compared with pure [²²³Rₐ]RₐCl₂. These findings demonstrated the effectiveness of the nanosystem validating the application of nanotechnology in targeted alpha therapy with [²²³Ra]RₐCl₂. In addition, the [²²³Rₐ]RaCl₂nanomicelles may be decorated and incorporated with a great variety of agents and compounds (e.g., monoclonal antibodies, aptamers, peptides) to overcome the limited use of [²²³Ra]RₐCl₂.

Keywords: nanomicelles, osteosarcoma, radium dichloride, targeted alpha therapy

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Authors: Christine F. Boos, Fernando M. Azevedo

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Electroencephalogram (EEG) is a record of the electrical activity of the brain that has many applications, such as monitoring alertness, coma and brain death; locating damaged areas of the brain after head injury, stroke and tumor; monitoring anesthesia depth; researching physiology and sleep disorders; researching epilepsy and localizing the seizure focus. Epilepsy is a chronic condition, or a group of diseases of high prevalence, still poorly explained by science and whose diagnosis is still predominantly clinical. The EEG recording is considered an important test for epilepsy investigation and its visual analysis is very often applied for clinical confirmation of epilepsy diagnosis. Moreover, this EEG analysis can also be used to help define the types of epileptic syndrome, determine epileptiform zone, assist in the planning of drug treatment and provide additional information about the feasibility of surgical intervention. In the context of diagnosis confirmation the analysis is made using long term EEG recordings with at least 24 hours long and acquired by a minimum of 24 electrodes in which the neurophysiologists perform a thorough visual evaluation of EEG screens in search of specific electrographic patterns called epileptiform discharges. Considering that the EEG screens usually display 10 seconds of the recording, the neurophysiologist has to evaluate 360 screens per hour of EEG or a minimum of 8,640 screens per long term EEG recording. Analyzing thousands of EEG screens in search patterns that have a maximum duration of 200 ms is a very time consuming, complex and exhaustive task. Because of this, over the years several studies have proposed automated methodologies that could facilitate the neurophysiologists’ task of identifying epileptiform discharges and a large number of methodologies used neural networks for the pattern classification. One of the differences between all of these methodologies is the type of input stimuli presented to the networks, i.e., how the EEG signal is introduced in the network. Five types of input stimuli have been commonly found in literature: raw EEG signal, morphological descriptors (i.e. parameters related to the signal’s morphology), Fast Fourier Transform (FFT) spectrum, Short-Time Fourier Transform (STFT) spectrograms and Wavelet Transform features. This study evaluates the application of these five types of input stimuli and compares the classification results of neural networks that were implemented using each of these inputs. The performance of using raw signal varied between 43 and 84% efficiency. The results of FFT spectrum and STFT spectrograms were quite similar with average efficiency being 73 and 77%, respectively. The efficiency of Wavelet Transform features varied between 57 and 81% while the descriptors presented efficiency values between 62 and 93%. After simulations we could observe that the best results were achieved when either morphological descriptors or Wavelet features were used as input stimuli.

Keywords: Artificial neural network, electroencephalogram signal, pattern recognition, signal processing

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Authors: Sanghoon Bae, Hanju Cha

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Failed fuel detector (FFD) in research reactor is a very crucial instrument to detect the anomaly from failed fuels in the early stage around primary cooling system (PCS) outlet prior to the decay tank. FFD is considered as a mandatory sensor to ensure the integrity of fuel assemblies and mitigate the consequence from a failed fuel accident. For the effective function of FFD, the location of them should be determined by contemplating the effect from coolant flow around two outlets. For this, the analysis on computational flow dynamics (CFD) should be first performed how the coolant outlet flow including radioactive materials from failed fuels are mixed and discharged through the outlet plenum within certain seconds. The analysis result shows that the outlet flow is well mixed regardless of the position of failed fuel and ultimately illustrates the effect of detector location.

Keywords: computational flow dynamics (CFD), failed fuel detector (FFD), fresh fuel assembly (FFA), spent fuel assembly (SFA)

Procedia PDF Downloads 244

Authors: Yun-Xuan Tang, Pei-Yuan Liu, Kun-Mu Lu, Min-Tsung Tseng, Liang-Kuang Chen, Yuh-Feng Tsai, Ching-Wen Lee, Jay Wu

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Breast cancer is predominant of malignant tumors in females. The increase in the glandular density increases the risk of breast cancer. BI-RADS is a frequently used density indicator in mammography; however, it significantly overestimates the glandularity. Therefore, it is very important to accurately and quantitatively assess the glandularity by mammography. In this study, 20%, 30% and 50% glandularity phantoms were exposed using a mammography machine at 28, 30 and 31 kVp, and 30, 55, 80 and 105 mAs, respectively. The regions of interest (ROIs) were drawn to assess the gray level. The relationship between the glandularity and gray level under various compression thicknesses, kVp, and mAs was established by the multivariable linear regression. A phantom verification was performed with automatic exposure control (AEC). The regression equation was obtained with an R-square value of 0.928. The average gray levels of the verification phantom were 8708, 8660 and 8434 for 0.952, 0.963 and 0.985 g/cm3, respectively. The percent differences of glandularity to the regression equation were 3.24%, 2.75% and 13.7%. We concluded that the proposed method could be clinically applied in mammography to improve the glandularity estimation and further increase the importance of breast cancer screening.

Keywords: mammography, glandularity, gray value, BI-RADS

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Authors: Hassan Al-Fugha

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The Pleistocene volcanism in northeastern Jordan is represented by basaltic scoria, cones and flows and covers approximately 12.000 km². Geochemical parameters such as Mg/Mg+Fe+2 and high Ti contents indicate that the corresponding magmas are of primary origin. Trace elements of primary magma show low variable abundances of compatible and incompatible elements, which reflect a homogenous source. They are under-saturated with respect to its silica content. These volcanic rocks belong to the alkaline to sub-alkaline rocks series. The rocks are mainly alkali basalts containing 46.1-50.0 wt.% SiO2 and 2.6-4.8 wt.% alkali oxides. Mantle xenoliths entrained in late Cenozoic volcanic rocks erupted throughout northeastern Jordan provide information about the evolution of the Lithospheric mantle, which could represent a potential source for Arabian intraplate volcanism. Xenoliths carried to the surface by magma in Northeast Jordan did not equilibrate with the melts, indicating that the transport from the mantle to the surface was rapid.

Keywords: petrogenesis, volcano-group, Harrat Al-Rufa'yat, NE-Jordan

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Authors: Xun Sun, Le Li, Ce Mo, Lei Mo, Ruiming Wang, Guosheng Ding

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Cognitive control plays a central role in information processing, which is comprised of various components including response suppression and inhibitory control. Response suppression is considered to inhibit the irrelevant response during the cognitive process; while inhibitory control to inhibit the irrelevant stimulus in the process of cognition. Both of them undertake distinct functions for the cognitive control, so as to enhance the performances in behavior. Among numerous factors on cognitive control, bilingual experience is a substantial and indispensible factor. It has been reported that bilingual experience can influence the neural activity of cognitive control as whole. However, it still remains unknown how the neural influences specifically present on the components of cognitive control imposed by bilingualism. In order to explore the further issue, the study applied fMRI, used anti-saccade paradigm and compared the cerebral activations between high and low proficient Chinese-English bilinguals. Meanwhile, the study provided experimental evidence for the brain plasticity of language, and offered necessary bases on the interplay between language and cognitive control. The results showed that response suppression recruited the middle frontal gyrus (MFG) in low proficient Chinese-English bilinguals, but the inferior patrietal lobe in high proficient Chinese-English bilinguals. Inhibitory control engaged the superior temporal gyrus (STG) and middle temporal gyrus (MTG) in low proficient Chinese-English bilinguals, yet the right insula cortex was more active in high proficient Chinese-English bilinguals during the process. These findings illustrate insights that bilingual experience has neural influences on different components of cognitive control. Compared with low proficient bilinguals, high proficient bilinguals turn to activate advanced neural areas for the processing of cognitive control. In addition, with the acquisition and accumulation of language, language experience takes effect on the brain plasticity and changes the neural basis of cognitive control.

Keywords: bilingual experience, cognitive control, inhibition control, response suppression

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Authors: Steven Hidalgo, Patricio Neumann

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The growth of societies has increased the consumption of raw materials and food obtained from nature. This has influenced the services offered by ecosystems to humans, mainly supply and regulation services. One of the indicators used to evaluate these services is Net Primary Productivity (NPP), which is understood as the energy stored in the form of biomass by primary organisms through the process of photosynthesis and respiration. The variation of NPP by defined area produces changes in the properties of terrestrial and aquatic ecosystems, which alter factors such as biodiversity, nutrient cycling, carbon storage and water quality. The analysis of NPP to evaluate variations in ecosystem services includes harvested NPP (understood as provisioning services), which is the raw material from agricultural systems used by humans as a source of energy and food, and the remaining NPP (expressed as a regulating service) or the amount of biomass that remains in ecosystems after the harvesting process, which is mainly related to factors such as biodiversity. Given that agriculture is a fundamental pillar of Chile's integral development, the purpose of this study is to evaluate provisioning and regulating ecosystem services in the agricultural sector, specifically in cereal production, in the communes of the central-southern regions of Chile through a conceptual framework based on the quantification of the fraction of Human Appropriation of Net Primary Productivity (HANPP) and the fraction remaining in the ecosystems (NPP remaining). A total of 161 communes were analyzed in the regions of O'Higgins, Maule, Ñuble, Bio-Bío, La Araucanía and Los Lagos, which are characterized by having the largest areas planted with cereals. It was observed that the region of La Araucanía produces the greatest amount of dry matter, understood as provisioning service, where Victoria is the commune with the highest cereal production in the country. In addition, the maximum value of HANPP was in the O'Higgins region, highlighting the communes of Coltauco, Quinta de Tilcoco, Placilla and Rengo. On the other hand, the communes of Futrono, Pinto, Lago Ranco and Pemuco, whose cereal production was important during the study, had the highest values of remaining NPP as a regulating service. Finally, an inverse correlation was observed between the provisioning and regulating ecosystem services, i.e., the higher the cereal or dry matter production in a defined area, the lower the net primary production remaining in the ecosystems. Based on this study, future research will focus on the evaluation of ecosystem services associated with other crops, such as forestry plantations, whose activity is an important part of the country's productive sector.

Keywords: provisioning services, regulating services, net primary productivity, agriculture

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Authors: Yan Li, Qi-Fan Jia, Jie Zhou

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In today’s China, primary and secondary teachers are living a hard life with high pressure but low payment, which results in a sense of unfair and less satisfaction of life. However, teachers’ life satisfaction is a significant factor of their mental health and plays an important role in the development and progress of the society. This study was aimed to explore the effect of teachers’ perception of social justice on life satisfaction. 450 primary and secondary teachers from China were measured with life satisfaction scales, social justice scales, income satisfaction scale, job satisfaction scale, pressure condition scale, and major life event scale. Results showed their pressure is significantly higher than average, while life satisfaction, job satisfaction, income satisfaction and perceived social justice are lower. Hierarchical regression analysis showed that demographic variables, i.e., gender, age, education level and matric status, and factors related to occupation, i.e., professional title, school type and working hours per day cannot predict teachers’ life satisfaction. Teachers who had worked for 11-20 years had a lower life satisfaction compared to those with 1-5 years working experience. However, social status, monthly household income, income satisfaction, as well as job satisfaction were positively related to life satisfaction, whereas pressure condition was negatively related to it. After controlling for demographic factors and individual attitudes, social justice still had a positive effect on life satisfaction, among which distributive justice played a more important role than procedural justice. The suggestions on teachers’ condition in China and the implications for education reform to improve teachers’ mental health are discussed.

Keywords: life satisfaction, mental health, primary and secondary teachers, social justice

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Authors: Mohammad Tahir Yousafzai, Rubina Qasim

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We assessed Hepatitis B vaccination and its determinants among health care workers (HCW) in Northwest Pakistan. HCWs from both public and private clinics were interviewed about hepatitis B vaccination, socio-demographic, hepatitis B virus transmission modes, disease threat and benefits of vaccination. Logistic regression was performed. Hepatitis B vaccination was 40% (Qualified Physicians: 86% and non-qualified Dispensers:16%). Being Qualified Physician (Adj. OR 26.6; 95%CI 9.3-73.2), Non-qualified Physician (Adj.OR 1.9; 95%CI 0.8-4.6), qualified Dispensers (Adj. OR 3.6; 95%CI 1.3-9.5) compared to non-qualified Dispensers, working in public clinics (Adj. OR 2.5; 95%CI 1.1-5.7) compared to private, perceived disease threat after exposure to blood and body fluids (Adj. OR 1.1; 95%CI 1.1-1.2) and perceived benefits of vaccination (Adj. OR 1.1; 95%CI 1.1-1.2) were significant predictors of hepatitis B vaccination. Improved perception of disease threat and benefits of vaccination and qualification of HCWs are associated with hepatitis B vaccination.

Keywords: Hepatitis B vaccine, immunization, healthcare workers, primary health

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Authors: Natalia C. E. S. Nascimento, Mercia L. Oliveira, Fernando R. A. Lima, Leonardo T. C. do Nascimento, Marina B. Silveira, Brigida G. A. Schirmer, Andrea V. Ferreira, Carlos Malamut, Juliana B. da Silva

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Tissue hypoxia is a common characteristic of solid tumors leading to decreased sensitivity to radiotherapy and chemotherapy. In the clinical context, tumor hypoxia assessment employing the positron emission tomography (PET) tracer ¹⁸F-fluoromisonidazole ([¹⁸F]FMISO) is helpful for physicians for planning and therapy adjusting. The aim of this work was to implement the synthesis of 18F-FMISO in a TRACERlab® MXFDG module and also to establish the quality control procedure. [¹⁸F]FMISO was synthesized at Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN/Brazil) using an automated synthesizer (TRACERlab® MXFDG, GE) adapted for the production of [¹⁸F]FMISO. The FMISO chemical standard was purchased from ABX. 18O- enriched water was acquired from Center of Molecular Research. Reagent kits containing eluent solution, acetonitrile, ethanol, 2.0 M HCl solution, buffer solution, water for injections and [¹⁸F]FMISO precursor (dissolved in 2 ml acetonitrile) were purchased from ABX. The [¹⁸F]FMISO samples were purified by Solid Phase Extraction method. The quality requirements of [¹⁸F]FMISO are established in the European Pharmacopeia. According to that reference, quality control of [¹⁸F]FMISO should include appearance, pH, radionuclidic identity and purity, radiochemical identity and purity, chemical purity, residual solvents, bacterial endotoxins, and sterility. The duration of the synthesis process was 53 min, with radiochemical yield of (37.00 ± 0.01) % and the specific activity was more than 70 GBq/µmol. The syntheses were reproducible and showed satisfactory results. In relation to the quality control analysis, the samples were clear and colorless at pH 6.0. The spectrum emission, measured by using a High-Purity Germanium Detector (HPGe), presented a single peak at 511 keV and the half-life, determined by the decay method in an activimeter, was (111.0 ± 0.5) min, indicating no presence of radioactive contaminants, besides the desirable radionuclide (¹⁸F). The samples showed concentration of tetrabutylammonium (TBA) < 50μg/mL, assessed by visual comparison to TBA standard applied in the same thin layer chromatographic plate. Radiochemical purity was determined by high performance liquid chromatography (HPLC) and the results were 100%. Regarding the residual solvents tested, ethanol and acetonitrile presented concentration lower than 10% and 0.04%, respectively. Healthy female mice were injected via lateral tail vein with [¹⁸F]FMISO, microPET imaging studies (15 min) were performed after 2 h post injection (p.i), and the biodistribution was analyzed in five-time points (30, 60, 90, 120 and 180 min) after injection. Subsequently, organs/tissues were assayed for radioactivity with a gamma counter. All parameters of quality control test were in agreement to quality criteria confirming that [¹⁸F]FMISO was suitable for use in non-clinical and clinical trials, following the legal requirements for the production of new radiopharmaceuticals in Brazil.

Keywords: automatic radiosynthesis, hypoxic tumors, pharmacopeia, positron emitters, quality requirements

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Authors: Bernardita Tornero

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Cognitive Acceleration in Mathematics Education (CAME) programmes have been used successfully for promoting the development of thinking skills in school students for the last 30 years. Given that the approach has had a tremendous impact on the thinking capabilities of participating students, this study explored the experience of using the programme with prospective primary teachers in Chile. Therefore, this study not only looked at the experience of prospective primary teachers during the CAME course as learners, but also examined how they perceived the approach from their perspective as future teachers, as well as how they could transfer the teaching strategies they observed to their future classrooms. Given the complexity of the phenomenon under study, this research used a mixed methods approach. For this reason, the impact that the CAME course had on prospective teachers’ thinking skills was not only approached by using a test that assessed the participants’ improvements in these skills, but their learning and teaching experiences were also recorded through qualitative research tools (learning journals, interviews and field notes). The main findings indicate that, at the end of the CAME course, prospective teachers not only demonstrated higher thinking levels, but also showed positive attitudinal changes towards teaching and learning in general, and towards mathematics in particular. The participants also had increased confidence in their ability to teach mathematics and to promote thinking skills in their students. In terms of the CAME methodology, prospective teachers not only found it novel and motivating, but also commented that dealing with the thinking skills topic during a university course was both unusual and very important for their professional development. This study also showed that, at the end of the CAME course, prospective teachers felt they had developed strategies that could be used in their classrooms in the future. In this context, the relevance of the study is not only that it described the impact and the positive results of the first experience of using a CAME approach with prospective teachers, but also that some of the conclusions have significant implications for the teaching of thinking skills and the training of primary school teachers.

Keywords: cognitive acceleration, formal reasoning, prospective teachers, initial teacher training

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Authors: Simran Ballani

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The purpose of this paper is to call education professionals to implement etiquette and public speaking skills for preschoolers, primary, middle and higher school students. In this paper the author aims to present importance of etiquette learning and public speaking curriculum for preschoolers, reflect on experiences from implementation of the curriculum and discuss the effect of the said implementation on higher education/global job market. Author’s aim to introduce this curriculum was to provide children with innovative learning and all around development. This training of soft skills at kindergarten level can have a long term effect on their social behaviors which in turn can contribute to professional success once they are ready for campus recruitment/global job markets. Additionally, if preschoolers learn polite, appropriate behavior at early age, it will enable them to become more socially attentive and display good manners as an adult. It is easier to nurture these skills in a child rather than changing bad manners at adulthood. Preschool/Kindergarten education can provide the platform for children to learn these crucial soft skills irrespective of the ethnicity, economic or social background they come from. These skills developed at such early years can go a long way to shape them into better and confident individuals. Unfortunately, accessibility of the etiquette learning and public speaking skill education is not standardized in pre-primary or primary level and most of the time embedding into the kindergarten curriculum is next to nil. All young children should be provided with equal opportunity to learn these soft skills which are essential for finding their place in job market.

Keywords: Early Childhood Learning, , public speaking, , confidence building, , innovative learning

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Authors: Adeleke Omolade

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The study investigated the impacts of capital goods' import and human capital on the economic growth of the Sub Sahahra Africa (SSA). 30 countries were used in the Panel- ARDL analysis where economic growth is the dependent variables and capital goods' import, human capital, primary export, investment exchange rate, among others were used as the independent variables. The result from the panel analysis indicates that capital goods' import will significantly and positively influence economic growth but human capital fails to have significant positive impact on economic growth of the SSA. Earlier the trend analysis and the correlation results have shown that there is a weak association between capital goods' import and human capital in the SSA. The results offer an expository analysis that reveals that the quality of the human capital is very germane to the effective utilization of capital goods' import for the purpose of growth in a primary goods' export dominated region like the SSA.

Keywords: capital goods import, economic growth, human capital, Sub-Sahara Africa

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Authors: Fred Mageto

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A great number of children in mainstream schools across Kenya are currently living with emotional, behavioural difficulties. This study aims to explore teachers’ perceptions of children’s emotional and behavioural difficulties (EBD) and their attributions of the causes of EBD. The relevance of this area of study to current educational practice is illustrated in the fact that primary school teachers in Kenya find classroom behaviour problems one of the major difficulties they face. The information presented in this study was gathered from 182 teachers that responded back to the survey, of whom 27 teachers were later interviewed. In general, teachers’ perceptions of EBD reflect personal experience, training, and attitudes. Teachers appear from this study to use words such as indifferent, frightened, withdrawn, aggressive, disobedient, hyperactive, less ambitious, lacking concentration, and academically weak to describe pupils with emotional and behavioural difficulties (EBD). The implications of this study are envisaged as being extremely important to support teachers addressing children’s EBD and shed light on the contributing factors to EBD for a successful teaching-learning process in Libyan primary schools.

Keywords: teachers, children, learning, emotional and behaviour difficulties

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Authors: Sakineh Nouri Saeidlou, Fatemeh Rezaiegoyjeloo, Parvin Ayremlou, Fariba Babaie

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Introduction: Childhood overweight and obesity is a major public health problem in both developed and developing countries. Overweight and obesity in children may have severe consequences later in adolescence and adulthood. The aim of current study was to determine the prevalence trend of overweight and obesity in school-aged children from 2009 to 2011. Methods: The present study was a population-based study and conducted in three consecutive years, from 2009 to 2011. The study population included all of primary, secondary and high school children in rural and urban regions of West Azarbijan province in West-North of Iran. Body mass index (BMI), the ratio of weight to height squared [weight (kg)]/ [height (m)]2, was calculated to the nearest decimal place. Overweight and obesity were classified using CDC recommendations for age and sex: a BMI 85th–95th percentile was classified as overweight and a BMI>95th percentile was classified as obese. All statistical analyses were performed using the Excel Software. Descriptive statistics were used to characterize the sample in different time periods. The prevalence was calculated as the ratio of number present cases to a given population number in a given subgroup at a given time. Results: Overall, 165740, 145146 and 146203 school children were assessed at 2009, 2010 and 2011, respectively. Prevalence of overweight in primary school children among girls were 52.83, 86.93 and 116.36 and for boys were 57.07, 53.4 and 93.55 per 1000 person in 2009, 2010 and 2011 years ,respectively. The prevalence of obesity in secondary school children for girls were 22.26, 27.75 and 28.43 and 26.52, 25.72 and 35.85 for boys per 1000 person in 2009, 2010 and 2011, respectively, The highest prevalence of overweight was 77.58, 142.4 and 126.46 per 1000 person among primary, secondary and high school children, respectively, in 2011. The lowest prevalence of obesity was 12.52, 24.1 and 21.61 per 1000 person among primary, secondary and high school children, respectively, in 2009. Conclusion: However, the rapid increase in both obesity and overweight should have a special attention. Research on prevalence trend of overweight and obesity in children is poorly reported in Iran. So that, future studies need to follow-up on the associations between overweight and obesity with health outcomes when children develop and reach adolescence and adulthood.

Keywords: overweight, obesity, school children, prevalence trend, Iran

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Authors: T. Jivita, M. S. Salmiah

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The aims of this study were to determine the prevalence of smoking, reasons for tried smoking, factors that influence smoking, and knowledge level on health risk among male Tamil primary school students. Seven urban Tamil primary schools in Kuala Lumpur were identified based on cluster sampling. A cross-sectional study was conducted in May 2014 and a total of 380 male children in standard 4 and 5 were selected. Survey included information on history of ever smoking even a puff, smoking a whole cigarette, smoking every day at least for 7 days, reasons for tried smoking, potential factors of smoking and knowledge related to smoking and health. Fifty seven had previously smoked, with a prevalence of 15.0% (95% CI = 11.4, 18.6) and 17 had smoked a whole cigarette (4.5%, 95% CI = 2.42, 6.58) while 8 had at least smoked 7 days continuously (2.1%, 95% CI = 0.66, 3.54). The reasons for tried smoking were because of curiosity (63.2%), it is not allowed (42.6%), it is relaxing (35.2%), it is cool (33.3%), to lose weight (20.4%), style (1.8%), by mistake (0.5%), for prayers purpose (0.3%), given by uncle (0.3%), and introduced by elder brother (0.3%). None of these reasons were associated with age factors (p > 0.05). Of those who had smoked a whole cigarette, 42.9% were significantly influenced by father (χ2 (1) = 6.42, p = 0.040) and 47.8% were significantly influenced by friends (χ2 (2) = 6.27, p = 0.043). Overall 91.5% had good level of knowledge about smoking, where the majority knew that smoking was dangerous to their health. However only 61.7% and 63.1% of them knew that smoking can cause high blood pressure and stroke, respectively. There is no significant different in mean rank between 10 years old and 11 years old students (p=0.987 < 0.05) for level of knowledge, tested by Mann-Whitney U Test. Odds of smoking increased 1.37 times having seen actors smoking (95% CI= 1.01, 1.86), 1.55 times having a father who smokes (95% CI= 1.26, 1.92), 1.64 times having siblings who smokes (95% CI= 1.32, 2.04), and 10.55 times having friends who offered cigarette (95% CI= 4.17, 26.68). As a conclusion, cessation of smoking in family members, who are role models, so as to reduce rates to taking up smoking among children.

Keywords: factors influence, knowledge on smoking, prevalence on smoking, reasons

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Authors: Tanveer Beg, Yasir H. Siddique, Gulshan Ara, Asfar S. Azmi, Mohammad Afzal

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Doxorubicin is a well-known DNA intercalating chemotherapy drug that is widely used for treatment of different cancers. Its clinical utility is limited due to the observed genotoxic side effects on healthy cells suggesting that newer combination and genoprotective regimens are urgently needed for the management of doxorubicin chemotherapy. Some dietary phytochemicals are well known for their protective mechanism of action and genistein from soy is recognized as an anti-oxidant with similar properties. Therefore, the present study investigates the effect of genistein against the genotoxic doses of doxorubicin by assessing chromosomal aberrations, sister chromatid exchanges, cell cycle kinetics, cell viability, apoptosis, and DNA damage markers in cultured human lymphocytes. Our results reveal that genistein treatment significantly suppresses genotoxic damage induced by doxorubicin. It is concluded that genistein has the potential to reduce the genotoxicity induced by anti-cancer drugs, thereby reducing the chances of developing secondary tumors during the therapy.

Keywords: apoptosis, DNA damage markers, doxorubicin, genistein, genotoxicity, human lymphocyte culture

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Authors: Abdelbasit Gadour

Abstract:

A great number of children in mainstream schools across Libya are currently living with emotional, behavioral difficulties. This study aims to explore teachers’ perceptions of children’s emotional and behavioral difficulties (EBD) and their attributions of the causes of EBD. The relevance of this area of study to current educational practice is illustrated in the fact that primary school teachers in Libya find classroom behavior problems one of the major difficulties they face. The information presented in this study was gathered from 182 teachers that responded back to the survey, of whom 27 teachers were later interviewed. In general, teachers’ perceptions of EBD reflect personal experience, training, and attitudes. Teachers appear from this study to use words such as indifferent, frightened, withdrawn, aggressive, disobedient, hyperactive, less ambitious, lacking concentration, and academically weak to describe pupils with emotional and behavioral difficulties (EBD). The implications of this study are envisaged as being extremely important to support teachers addressing children’s EBD and shed light on the contributing factors to EBD for a successful teaching-learning process in Libyan primary schools.

Keywords: children, emotional and behavior difficulties, learning, teachers'

Procedia PDF Downloads 147

Authors: S. Zolghadri, M. Mousavi-Daramoroudi, H. Yousefnia, F. Abbasi-Davani

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In this study, the absorbed dose of human organs after injection of ¹⁷⁷Lu-DOTATOC was studied based on the biodistribution of the complex in adenocarcinoma breast cancer bearing mice. For this purpose, the biodistribution of the radiolabelled complex was studied and compartmental modeling was applied to calculate the absorbed dose with high precision. As expected, ¹⁷⁷Lu-DOTATOC illustrated a notable specific uptake in tumor and pancreas, organs with high level of somatostatin receptor on their surface and the effectiveness of the radio-conjugate for targeting of the breast adenocarcinoma tumors was indicated. The elicited results of modeling were the exponential equations, and those are utilized for obtaining the cumulated activity data by taking their integral. The results also exemplified that non-target absorbed-doses such as the liver, spleen and pancreas were approximately 0.008, 0.004, and 0.039, respectively. While these values were so much lower than target (tumor) absorbed-dose, it seems due to this low toxicity, this complex is a good agent for therapy.

Keywords: ¹⁷⁷Lu, breast cancer, compartmental modeling, dosimetry

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Authors: Fleura Shkëmbi, Sevim Mustafa, Naim Fanaj

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Hypnosis, often known as cognitive therapy, is a sort of mind-body psychotherapy. A professional and certified hypnotist or hypnotherapist guides the patient into this extreme level of focus and relaxation during the session by utilizing verbal cues, repetition, and imagery. In recent years, hypnotherapy has gained popularity in the treatment of a variety of disorders, including anxiety and particular phobias. The term "phobia" is commonly used to define fear of a certain trigger. When faced with potentially hazardous situations, the brain naturally experiences dread. While a little dread here and there may keep us safe, phobias can drastically reduce our quality of life. In summary, persons who suffer from anxiety are considered to see particular environmental situations as dangerous, but those who do not suffer from anxiety do not. Hypnosis is essential in the treatment of anxiety disorders. Hypnosis can help patients minimize their anxiety symptoms. This broad concept has aided in the development of models and therapies for anxiety disorders such as generalized anxiety disorder, panic attacks, hypochondria, and obsessional disorders. Hypnosis techniques are supposed to be attentive and mental pictures, which is conceivable; this is why they're associated with improved working memory and visuospatial abilities. In this sense, the purpose of this study is to determine how effectively specific therapeutic methods perform in treating persons with anxiety and phobias. In addition to cognitive-behavioral therapy and other therapies, the approaches emphasized the use of therapeutic hypnosis. This study looks at the use of hypnosis and related psychotherapy procedures in the treatment of anxiety disorders. Following a discussion of the evolution of hypnosis as a therapeutic tool, neurobiological research is used to demonstrate the influence of hypnosis on the change of perception in the brain. The use of hypnosis in the treatment of phobias, stressful situations, and posttraumatic stress disorder is examined, as well as similarities between the hypnotic state and dissociative reactions to trauma. Through an extensive literature evaluation, this study will introduce hypnotherapy procedures that result in more successful anxiety and phobia treatment.

Keywords: anxiety, hypnosis, hypnotherapy, phobia, technique, state

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Authors: Ivonne N. Pérez-Sánchez. María L. Rascón- Gasca, Angélica Riveros-Rosas, Rebeca Robles García

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Introduction: Primary caregivers of cancer patients have health problems related to their lack of time, stress, and fiscal strain. Their health problems could affect their patients’ health and also increase the expenses in public health. Aim: To describe self-care and risk behaviors in a sample of Mexican primary caregiver and the relation of these behaviors with emotional distress (caregiver burden, anxiety and depression symptoms), coping and sociodemographic variables. Method: Participated in this study 173 caregivers of a third level reference medical facility (age: M=49.4, SD=13.5) females 78%, males 22%, 57.5% were caregivers of patients with terminal cancer (CPTC), and 40.5% were caregivers of patients on oncology treatment (CPOT). Results: The 75.7% of caregivers reported to have had health problem in last six months as well as several symptoms which were related to emotional distress, these symptoms were more frequently between CPTC and female caregivers. A half (47.3%) of sample reported have had difficulties in caring their health; these difficulties were related to emotional distress and lower coping, more affected caregivers were who attend male patients and CPTC. The 76.8% of caregivers had health problems in last six months, but 26.5% of them waited to search medical care until they were very sick, and 11% didn't do it. Also, more than a half of sample (56.1%) admitted to have risk behaviors as drink alcohol, smoke or overeating for feeling well, these caregivers showed high emotional distress and lower coping. About caregivers healthy behaviors, 80% of them had a hobby; 27.2% do exercise usually and between 12% to 60% did medical checkups (glucose tests, blood pressure and cholesterol tests, eye exams and watched their weight), these caregivers had lower emotional distress and high coping, some variables related health behaviors were: care only one patient or a female patient and be a CPOT, social support, high educational level and experience as a caregiver in past. The half of caregivers were worrying to develop cancer in the future; this idea was 2.5 times more frequent in caregiver with problems to care their health. Conclusions: The results showed a big proportion of caregivers with medical problems. High emotional distress and low coping were related to physical symptoms, risk behaviors, and low self-care; poor self-care was frequently even in caregiver who have chronic illness.

Keywords: cancer, primary caregiver, risk behaviors, self-care

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Authors: Sangkhao M., Butcher B. A.

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Diazepam (known as valium) is a medication for calming effect. Many reports on committed suicide cases shown that diazepam is frequently used for this purpose. This research aims to study effect of diazepam on the development of forensically important blowflies, Chrysomya megacephala (Diptera: Calliphoridae) using micro-computed tomography (micro CT). In this study, four rabbits were treated with three different lethal doses of diazepam and one control (LD₀, LD₅₀, LD₁₀₀ and LC). The rabbit’s livers were removed for rearing the blowflies. Pupae were sampled for two series (ages; S1: 24h and S2: 120h) of development. After preparing the specimens, all samples were performed Micro CT using Skyscan 1172. The results shown the effect of diazepam on internal organs and tissues such as brain, cavity of the body, gas bubble, meconium and especially fat body. In the control group, in series 1 (LCS1), fat body was equally dispersed in the head, thorax, and abdomen, development of internal organs were not completed, however, brain, thoracic muscle, wings, legs and rectum were able to observe at 24h after developing into the pupal stage. Development of each organ in the control group in the series two was completed. In the treatment groups, LD₀, LD₅₀, LD₁₀₀ (Series 1 and Series 2), tissues are different, such as gas bubble in LD₀S1, was observed due to rapidity morphological changes during the metamorphosis of blowfly’s pupa in this treatment. Meconium was observed in LD₅₀S2 group because excretion of metabolic waste was not completed. All of the samples in the treatment groups had differentiation of fat bodies because metabolic activities were not completed and these changes affected on functions of every internal system. Discovering of differentiated fat bodies are important results because fat bodies of insect functions as liver in human, therefore it is shown that toxin eliminates from blowfly’s body and homeostatic maintenance of the hemolymph proteins, lipid and carbohydrates in each treatment group are abnormal.

Keywords: forensic toxicology, forensic entomology, diptera, diazepam

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Authors: Natalia V. Minaeva, Natalia A. Zorina, Marina N. Khorobrikh, Philipp S. Sherstnev, Tatiana V. Krivokorytova, Alexander S. Luchinin, Maksim S. Minaev, Igor V. Paramonov

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Background. Over the last few decades, the Center for International Blood and Marrow Transplant Research (CIBMTR) and the World Marrow Donor Association (WMDA) have been actively working to ensure the safety of the hematopoietic stem cell (HSC) donation process. Registration of adverse events that may occur during the donation period and establishing a relationship between donation and side effects are included in the WMDA international standards. The level of blood serum N-terminal pro-brain natriuretic peptide (NT-proBNP) is an early marker of myocardial stress. Due to the high analytical sensitivity and specificity, laboratory assessment of NT-proBNP makes it possible to objectively diagnose myocardial dysfunction. It is well known that the main stimulus for proBNP synthesis and secretion from atrial and ventricular cardiac myocytes is myocyte stretch and increasement of myocardial extensibility and pressure in the heart chambers. Аim. The aim of the study was to assess the dynamic changes in the levels of blood serum N-terminal pro-brain natriuretic peptide of unrelated donors at various stages of hematopoietic stem cell mobilization. Materials. We have examined 133 unrelated donors, including 92 men and 41 women, that have been included into the study. The NT-proBNP levels were measured before the start of mobilization, then on the day of apheresis, and after the donation of allogeneic HSC. The relationship between NT-proBNP levels and body mass index (BMI), ferritin, hemoglobin, and white blood cells (WBC) levels was assessed on the day of apheresis. The median age of donors was 34 years. Mobilization of HSCs was managed with filgrastim administration at a dose of 10 μg/kg daily for 4-5 days. The first leukocytapheresis was performed on day 4 from the start of filgrastim administration. Quantitative values of the blood serum NT-proBNP level are presented as a median (Me), first and third quartiles (Q1-Q3). Comparative analysis was carried out using the t-test and correlation analysis as well by Spearman method. Results. The baseline blood serum NT-proBNP levels in all 133 donors were within the reference values (<125 pg/ml) and equaled 21,6 (10,0; 43,3) pg/ml. At the same time, the level of NT-proBNP in women was significantly higher than that of men. On the day of the HSC apheresis, a significant increase of blood serum NT-proBNP levels was detected and equald 131,2 (72,6; 165,3) pg/ml (p<0,001), with higher rates in female donors. A statistically significant weak inverse correleation was established between the level of NT-proBNP and the BMI of donors (-0.18, p = 0,03), as well as the level of hemoglobin (-0.33, p <0,001), and ferritin levels (-0.19, p = 0,03). No relationship has been established between the magnitude of WBC levels achieved as a result of the mobilization of HSC on the day of leukocytapheresis. A day after the apheresis, the blood serum NT-proBNP levels still exceeded the reference values, but there was a decreasing tendency. Conclusion. An increase of the blood serum NT-proBNP level in unrelated donors during the mobilization of HSC was established. Future studies should clarify the reason for this phenomenon, as well as its effects on donors' long-term health.

Keywords: unrelated donors, mobilization, hematopoietic stem cells, N-terminal pro-brain natriuretic peptide

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Authors: Maymona Al-Husari, Craig Murdoch, Steven Webb

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Some tumors are known to exhibit an extracellular pH that is more acidic than the intracellular, creating a 'reversed pH gradient' across the cell membrane and this has been shown to affect their invasive and metastatic potential. Tumour hypoxia also plays an important role in tumour development and has been directly linked to both tumour morphology and aggressiveness. In this paper, we present a hybrid mathematical model of intracellular pH regulation that examines the effect of oxygen and pH on tumour growth and morphology. In particular, we investigate the impact of pH regulatory mechanisms on the cellular pH gradient and tumour morphology. Analysis of the model shows that: low activity of the Na+/H+ exchanger or a high rate of anaerobic glycolysis can give rise to a 'fingering' tumour morphology; and a high activity of the lactate/H+ symporter can result in a reversed transmembrane pH gradient across a large portion of the tumour mass. Also, the reversed pH gradient is spatially heterogenous within the tumour, with a normal pH gradient observed within an intermediate growth layer, that is the layer between the proliferative inner and outermost layer of the tumour.

Keywords: acidic pH, cellular automaton, ebola, tumour growth

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Authors: Muhammad Ishaqa, Quanchao Zhanga, Qian Wangb

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The Indus Valley Civilization is predominantly found in the northeast of Afghanistan, Pakistan, and the northwest of India and is considered one of the four ancient civilizations of the Old World, as well as the first urban civilization in South Asia. In 1920, John Marshall and other archaeologists established the existence of this civilization. Over the course of a century, India and Pakistan have made significant advancements in their joint archaeological investigation and excavation, contributing to the study of the Indus Valley Civilization. Given the importance of early discovery and confirmation of this civilization, our research focuses on the academic history of its archaeology by gathering published research material. Our research begins by collecting research data associated with the Indus Valley Civilization and documenting the process of archaeological investigations and excavations from the 19th century until the present day. We also summarize the archaeological works conducted during different periods. Furthermore, we present the primary academic views on the Indus Civilization from the 19th century until the present, explaining their developmental process and highlighting recent research. This forms a foundation for further study. We discovered that the archaeological research of the Indus Civilization is significantly influenced by Western archaeology and has yet to establish an independent, local research system. We delve into the three primary sites of the Indus Valley Civilization - Harappa, Mohenjo-Daro, and Chanhudaro - discussing their history and archaeological excavation records. Our findings indicate that the Indus Civilization is solely dependent on archaeology, distinguishing it from the Sumerian Civilization and verifying that it originates from the Bronze Age of the Indus Valley. Lastly, we examine the primary academic issues associated with the Indus Civilization in greater depth. These issues include climate environment, political system, primitive religion, and academic contribution.

Keywords: Indus Valley civilization, archaeology, Harappa, Mohenjo-Daro

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Authors: Suyeon Bae, Abimbola Asojo, Denise Guerin, Caren Martin

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Post-occupancy evaluations (POEs) have been recognized for documenting occupant well-being and responses to indoor environmental quality (IEQ) factors such as thermal, lighting, and acoustic conditions. Sustainable Post-Occupancy evaluation survey (SPOES) developed by an interdisciplinary team at a Midwest University provides an evidence-based quantitative analysis of occupants’ satisfaction in office, classroom, and residential spaces to help direct attention to successful areas and areas that need improvement in buildings. SPOES is a self-administered and Internet-based questionnaire completed by building occupants. In this study, employees in three different office buildings rated their satisfaction on a Likert-type scale about 12 IEQ criteria including thermal condition, indoor air quality, acoustic quality, daylighting, electric lighting, privacy, view conditions, furnishings, appearance, cleaning and maintenance, vibration and movement, and technology. Employees rated their level of satisfaction on a Likert-type scale from 1 (very dissatisfied) to 7 (very satisfied). They also rate the influence of their physical environment on their perception of their work performance and the impact of their primary workspaces on their health on a scale from 1 (hinders) to 7 (enhances). Building A is a three-story building that includes private and group offices, classrooms, and conference rooms and amounted to 55,000 square-feet for primary workplace (N=75). Building B, a six-story building, consisted of private offices, shared enclosed office, workstations, and open desk areas for employees and amounted to 14,193 square-feet (N=75). Building C is a three-story 56,000 square-feet building that included classrooms, therapy rooms, an outdoor playground, gym, restrooms, and training rooms for clinicians (N=76). The results indicated that 10 IEQs for Building A except acoustic quality and privacy showed statistically significant correlations on the impact of the primary workspace on health. In Building B, 11 IEQs except technology showed statistically significant correlations on the impact of the primary workspace on health. Building C had statistically significant correlations between all 12 IEQ and the employees’ perception of the impact of their primary workspace on their health in two-tailed correlations (P ≤ 0.05). Out of 33 statistically significant correlations, 25 correlations (76%) showed at least moderate relationship (r ≥ 0.35). For the three buildings, daylighting, furnishings, and indoor air quality IEQs ranked highest on the impact on health. IEQs about vibration and movement, view condition, and electric lighting ranked second, followed by IEQs about cleaning and maintenance and appearance. These results imply that 12 IEQs developed in SPOES are highly related to employees’ perception of how their primary workplaces impact their health. The IEQs in this study offer an opportunity for improving occupants’ well-being and the built environment.

Keywords: post-occupancy evaluation, built environment, sustainability, well-being, indoor air quality

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Authors: L. Bernabeo, T. Loftus

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Many children often experience phases of picky eating, food aversions and/or avoidance. For families with children who have special needs, these experiences are often exacerbated, which can lead to feelings that negatively impact a caregiver’s relationship with their child. Within the scope of speech language pathology practice, knowledge of both emotional and feeding development is key. This paper will explore the significance of “messy play” within typical feeding development, and the challenges that may arise if a child does not have the opportunity to engage in this type of exploratory play. This paper will consider several contributing factors that can result in a “picky eater.” Further, research has shown that individuals with special needs, including autism, possess a neurological makeup that differs from that of a typical individual. Because autism is a disorder of relating and communicating due to differences in the limbic system, an individual with special needs may respond to a typical feeding experience as if it is a traumatic event. As a result, broadening one’s dietary repertoire may seem to be an insurmountable challenge. This paper suggests that introducing new foods through exploratory play can help broaden and strengthen diets, as well as improve the feeding experience, of individuals with autism. The DIRFloortimeⓇ methodology stresses the importance of following a child's lead. Within this developmental model, there is a special focus on a person’s individual differences, including the unique way they process the world around them, as well as the significance of therapy occurring within the context of a strong and motivating relationship. Using this child-centered approach, we can support our children in expanding their diets, while simultaneously building upon their cognitive and creative development through playful and respectful interactions that include exposure to foods that differ in color, texture, and smell. Further, this paper explores the importance of exploration, self-feeding and messy play on brain development, both in the context of typically developing individuals and those with disordered development.

Keywords: development, feeding, floortime, sensory

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Authors: Manee Hasap, Mongkolchai Hasap, Tasanee Nasae

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The purpose of this study was to evaluate the primary caregivers’ knowledge and capabilities for providing quality care to be hospitalized post-hip fracture surgery elderly patients. The theoretical framework of the study was derived from the concepts of dependent care agency in Orem’s Self-Care theory, and family care provision for the elderly and chronically ill patients. 59 subjects were purposively selected. The subjects were primary caregivers of post-operated hip fracture elderly patients who had been admitted to the Orthopaedic Ward of Songklanagarind Hospital. Demographic data of the caregivers and patients were collected by non-participant observation using the evaluation and recording forms. The reliability of caregivers’ knowledge measurement (0.86) was obtained by KR-20 and that of caregivers’ capabilities for post-operative care evaluation form (0.97) obtained from 2 observers by interrater reliability. The data were analyzed using descriptive statistic, which were frequency, percentage, mean, and standard deviation. The result of this study indicated that elderly patients with post-hip fracture surgery had many pre-discharge self care limitations. Approximately, 75% of the caregivers had knowledge to respond to patient’s essential needs at a high level, while the rest (25%) had this knowledge a moderate level. For observation, 57.63% of the subjects had capabilities in care practice at a moderate level; 28.81% had capabilities in care practice at a high level, while 13.56% had at a low level. The result of this study can be used as basic information for patients and caregivers capabilities developing plan especially, providing patients’ activities, accident surveillance and complications prevention for a good life quality of elderly patients after hip surgery both hospitalization and rehabilitation at home.

Keywords: care givers’ knowledge, care givers’ capabilities, elderly hip fracture patients, patients

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Authors: Milu T. Cherian, Sergio C. Chai, Morgan A. Casal, Taosheng Chen

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This study aims to use CINPA1, a recently discovered small-molecule inhibitor of the xenobiotic receptor CAR (constitutive androstane receptor) for understanding the binding modes of CAR and to guide CAR-mediated gene expression profiling studies in human primary hepatocytes. CAR and PXR are xenobiotic sensors that respond to drugs and endobiotics by modulating the expression of metabolic genes that enhance detoxification and elimination. Elevated levels of drug metabolizing enzymes and efflux transporters resulting from CAR activation promote the elimination of chemotherapeutic agents leading to reduced therapeutic effectiveness. Multidrug resistance in tumors after chemotherapy could be associated with errant CAR activity, as shown in the case of neuroblastoma. CAR inhibitors used in combination with existing chemotherapeutics could be utilized to attenuate multidrug resistance and resensitize chemo-resistant cancer cells. CAR and PXR have many overlapping modulating ligands as well as many overlapping target genes which confounded attempts to understand and regulate receptor-specific activity. Through a directed screening approach we previously identified a new CAR inhibitor, CINPA1, which is novel in its ability to inhibit CAR function without activating PXR. The cellular mechanisms by which CINPA1 inhibits CAR function were also extensively examined along with its pharmacokinetic properties. CINPA1 binding was shown to change CAR-coregulator interactions as well as modify CAR recruitment at DNA response elements of regulated genes. CINPA1 was shown to be broken down in the liver to form two, mostly inactive, metabolites. The structure-activity differences of CINPA1 and its metabolites were used to guide computational modeling using the CAR-LBD structure. To rationalize how ligand binding may lead to different CAR pharmacology, an analysis of the docked poses of human CAR bound to CITCO (a CAR activator) vs. CINPA1 or the metabolites was conducted. From our modeling, strong hydrogen bonding of CINPA1 with N165 and H203 in the CAR-LBD was predicted. These residues were validated to be important for CINPA1 binding using single amino-acid CAR mutants in a CAR-mediated functional reporter assay. Also predicted were residues making key hydrophobic interactions with CINPA1 but not the inactive metabolites. Some of these hydrophobic amino acids were also identified and additionally, the differential coregulator interactions of these mutants were determined in mammalian two-hybrid systems. CINPA1 represents an excellent starting point for future optimization into highly relevant probe molecules to study the function of the CAR receptor in normal- and pathophysiology, and possible development of therapeutics (for e.g. use for resensitizing chemoresistant neuroblastoma cells).

Keywords: antagonist, chemoresistance, constitutive androstane receptor (CAR), multi-drug resistance, structure activity relationship (SAR), xenobiotic resistance

Procedia PDF Downloads 290