Search results for: T cell-mediated diseases

Authors: Uraib Sharaha, Guy Beck, Joseph Kapelushnik, Adam H. Agbaria, Itshak Lapidot, Shaul Mordechai, Ahmad Salman, Mahmoud Huleihel

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Infectious diseases cause a significant burden on the public health and the economic stability of societies all over the world for several centuries. A reliable detection of the causative agent of infection is not possible based on clinical features, since some of these infections have similar symptoms, including fever, sneezing, inflammation, vomiting, diarrhea, and fatigue. Moreover, physicians usually encounter difficulties in distinguishing between viral and bacterial infections based on symptoms. Therefore, there is an ongoing need for sensitive, specific, and rapid methods for identification of the etiology of the infection. This intricate issue perplex doctors and researchers since it has serious repercussions. In this study, we evaluated the potential of the mid-infrared spectroscopic method for rapid and reliable identification of bacterial and viral infections based on simple peripheral blood samples. Fourier transform infrared (FTIR) spectroscopy is considered a successful diagnostic method in the biological and medical fields. Many studies confirmed the great potential of the combination of FTIR spectroscopy and machine learning as a powerful diagnostic tool in medicine since it is a very sensitive method, which can detect and monitor the molecular and biochemical changes in biological samples. We believed that this method would play a major role in improving the health situation, raising the level of health in the community, and reducing the economic burdens in the health sector resulting from the indiscriminate use of antibiotics. We collected peripheral blood samples from young 364 patients, of which 93 were controls, 126 had bacterial infections, and 145 had viral infections, with ages lower than18 years old, limited to those who were diagnosed with fever-producing illness. Our preliminary results showed that it is possible to determine the infectious agent with high success rates of 82% for sensitivity and 80% for specificity, based on the WBC data.

Keywords: infectious diseases, (FTIR) spectroscopy, viral infections, bacterial infections.

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Authors: Hongmei Wang, Ziyun Xiang, Ying liu, Li Yu, Dongsheng Yue

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Intro: The COVID-19 (Corona Virus Disease 2019) has greatly changed the global economic, political and financial ecology. The mutation of the coronavirus in the UK in December 2020 has brought new panic to the world. Deep learning was performed on Chest Computed tomography (CT) of COVID-19 and Influenza and describes their characteristics. The predominant features of COVID-19 pneumonia was ground-glass opacification, followed by consolidation. Lesion density: most lesions appear as ground-glass shadows, and some lesions coexist with solid lesions. Lesion distribution: the focus is mainly on the dorsal side of the periphery of the lung, with the lower lobe of the lungs as the focus, and it is often close to the pleura. Other features it has are grid-like shadows in ground glass lesions, thickening signs of diseased vessels, air bronchi signs and halo signs. The severe disease involves whole bilateral lungs, showing white lung signs, air bronchograms can be seen, and there can be a small amount of pleural effusion in the bilateral chest cavity. At the same time, this year's flu season could be near its peak after surging throughout the United States for months. Chest CT for Influenza infection is characterized by focal ground glass shadows in the lungs, with or without patchy consolidation, and bronchiole air bronchograms are visible in the concentration. There are patchy ground-glass shadows, consolidation, air bronchus signs, mosaic lung perfusion, etc. The lesions are mostly fused, which is prominent near the hilar and two lungs. Grid-like shadows and small patchy ground-glass shadows are visible. Deep neural networks have great potential in image analysis and diagnosis that traditional machine learning algorithms do not. Method: Aiming at the two major infectious diseases COVID-19 and influenza, which are currently circulating in the world, the chest CT of patients with two infectious diseases is classified and diagnosed using deep learning algorithms. The residual network is proposed to solve the problem of network degradation when there are too many hidden layers in a deep neural network (DNN). The proposed deep residual system (ResNet) is a milestone in the history of the Convolutional neural network (CNN) images, which solves the problem of difficult training of deep CNN models. Many visual tasks can get excellent results through fine-tuning ResNet. The pre-trained convolutional neural network ResNet is introduced as a feature extractor, eliminating the need to design complex models and time-consuming training. Fastai is based on Pytorch, packaging best practices for in-depth learning strategies, and finding the best way to handle diagnoses issues. Based on the one-cycle approach of the Fastai algorithm, the classification diagnosis of lung CT for two infectious diseases is realized, and a higher recognition rate is obtained. Results: A deep learning model was developed to efficiently identify the differences between COVID-19 and influenza using chest CT.

Keywords: COVID-19, Fastai, influenza, transfer network

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Authors: Zohreh Bayat, Dariush Minai-Tehrani

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Pseudomonas aeruginosa is a Gram-negative, rode shape and aerobic bacterium that has shown to be resistance to many antibiotics. This resistance makes the bacterium very harmful in some diseases. It can also generate diseases in any part of the gastrointestinal tract from oropharynx to rectum. P. aeruginosa has become an important cause of infection, especially in patients with compromised host defense mechanisms. One of the most important reasons that make P. aeruginosa an emerging opportunistic pathogen in patients is its ability to use various compounds as carbon sources. Lipase is an enzyme that catalyzes the hydrolysis of lipids. Most lipases act at a specific position on the glycerol backbone of lipid substrate. Some lipases are expressed and secreted by pathogenic organisms during the infection. Muscarinic antagonist used as an antispasmodic and in urinary incontinence. The drug has little effect on glandular secretion or the cardiovascular system. It does have some local anesthetic properties and is used in gastrointestinal, biliary, and urinary tract spasms. Aim: In this study the inhibitory effect of a muscarinic antagonist on lipase of P. aeruginosa was investigated. Methods: P. aeruginosa was cultured in minimal salt medium with 1% olive oil as carbon source. The cells were harvested and the supernatant, which contained lipase, was used for enzyme assay. Results: Our results showed that the drug can inhibit P. aeruginosa lipase by competitive manner. In the presence of different concentrations of the drug, the Vmax (2 mmol/min/mg protein) of enzyme did not change, while the Km raised by increasing the drug concentration. The Ki (inhibition constant) and IC50 (the half maximal inhibitory concentration) value of drug was estimated to be about 30 uM and 60 uM which determined that the drug binds to enzyme with high affinity. Maximum activity of the enzyme was observed at pH 8 in the absence and presence of muscarinic antagonist, respectively. The maximum activity of lipase was observed at 600C and the enzyme became inactive at 900C. Conclusion: The muscarinic antagonist drug could inhibit lipase of P. aeruginosa and changed the kinetic parameters of the enzyme. The drug binded to enzyme with high affinity and did not chang the optimum pH of the enzyme. Temperature did not affect the binding of drug to musmuscarinic antagonist.

Keywords: Pseudomonas aeruginosa, drug, enzyme, inhibition

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Authors: Sonja Djilas, Gordana Ćetković, Jasna Čanadanović-Brunet, Vesna Tumbas Šaponjac, Slađana Stajčić, Jelena Vulić, Milica Vinčić

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In recent years, interest in food rich in bioactive compounds, such as polyphenols, increased the advantages of the functional food products. Bioactive components help to maintain health and prevention of diseases such as cancer, cardiovascular and many other degenerative diseases. Recent research has shown that the fruit pomace, a byproduct generated from the production of juice, can be a potential source of valuable bioactive compounds. The use of fruit industrial waste in the processing of functional foods represents an important new step for the food industry. Sour cherries have considerable nutritional, medicinal, dietetic and technological value. According to the production volume of cherries, Serbia ranks seventh in the world, with a share of 7% of the total production. The use of sour cherry pomace has so far been limited to animal feed, even though it can be potentially a good source of polyphenols. For this study, local variety of sour cherry cv. ‘Feketićka’ was chosen for its more intensive taste and deeper red color, indicating high anthocyanin content. The contents of total polyphenols, flavonoids and anthocyanins, as well as radical scavenging activity on DPPH radicals and reducing power of sour cherry juice and pomace were compared using spectrophotometrical assays. According to the results obtained, 66.91% of total polyphenols, 46.77% of flavonoids, 46.77% of total anthocyanins and 47.88% of anthocyanin monomers from sour cherry fruits have been transferred to juice. On the other hand, 29.85% of total polyphenols, 33.09% of flavonoids, 53.23% of total anthocyanins and 52.12% of anthocyanin monomers remained in pomace. Regarding radical scavenging activity, 65.51% of Trolox equivalents from sour cherries were exported to juice, while 34.49% was left in pomace. However, reducing power of sour cherry juice was much stronger than pomace (91.28% and 8.72% of Trolox equivalents from sour cherry fruits, respectively). Based on our results it can be concluded that sour cherry pomace is still a rich source of natural antioxidants, especially anthocyanins with coloring capacity, therefore it can be used for dietary supplements development and food fortification.

Keywords: antioxidants, polyphenols, pomace, sour cherry

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Authors: Gulmira Umarova

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The data on the assessment of the influence of environmental risk to the health of the population of Uralsk in the West region of Kazakhstan were presented. Calculation of non-carcinogenic risks was performed for such air pollutants as sulfur dioxide, nitrogen oxides, hydrogen sulfide, carbon monoxide. Here with the critical organs and systems, which are affected by the above-mentioned substances were taken into account. As well as indicators of primary and general morbidity by classes of diseases among the population were considered. The quantitative risk of the influence of substances on organs and systems is established by results of the calculation.

Keywords: environment, health, morbidity, non-carcinogenic risk

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Authors: Dar-Bin Shieh, Gwo-Bin Lee, Chen-Ming Chang, Chen Sheng Yeh, Chih-Chia Huang, Tsung-Ju Li

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Mitochondrial defects have a significant impact in many human diseases and aging associated phenotypes. The pathogenic mitochondrial DNA (mtDNA) mutations are diverse and usually present as heteroplasmic. mtDNA 4977bps deletion is one of the common mtDNA defects, and the ratio of mutated versus normal copy is significantly associated with clinical symptoms thus their quantitative detection has become an important unmet needs for advanced disease diagnosis and therapeutic guidelines. This study revealed a Micro-electro-mechanical-system (MEMS) enabled automatic microfluidic chip that only required minimal sample. The system integrated multiple laboratory operation steps into a Lab-on-a-Chip for high-sensitive and prompt measurement. The entire process including magnetic nanoparticle based mtDNA extraction in chip, mutation selective photonic DNA cleavage, and nanoparticle accelerated photonic quantitative polymerase chain reaction (qPCR). All subsystems were packed inside a miniature three-dimensional micro structured system and operated in an automatic manner. Integration of magnetic beads with microfluidic transportation could promptly extract and enrich the specific mtDNA. The near infrared responsive magnetic nanoparticles enabled micro-PCR to be operated by pulse-width-modulation controlled laser pulsing to amplify the desired mtDNA while quantified by fluorescence intensity captured by a complementary metal oxide system array detector. The proportions of pathogenic mtDNA in total DNA were thus obtained. Micro capillary electrophoresis module was used to analyze the amplicone products. In conclusion, this study demonstrated a new magnetophotonic based qPCR MEMS system that successfully detects and quantify specific disease related DNA mutations thus provides a promising future for rapid diagnosis of mitochondria diseases.

Keywords: mitochondrial DNA, micro-electro-mechanical-system, magnetophotonics, PCR

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Authors: Firouz Amani, Adalat Hoseinian, Sajjad Hakimian

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Background: The mortality due to Myocardial Infarction (MI) is often occur during the first hours after onset of symptom. So, for taking the necessary treatment and decreasing the mortality rate, timely visited of the hospital could be effective in this regard. The aim of this study was to investigate the impact of effective factors in mortality of MI patients by using Linear Logistic Regression. Materials and Methods: In this case-control study, all patients with Acute MI who referred to the Ardabil city hospital were studied. All of died patients were considered as the case group (n=27) and we select 27 matched patients without Acute MI as a control group. Data collected for all patients in two groups by a same checklist and then analyzed by SPSS version 24 software using statistical methods. We used the linear logistic regression model to determine the effective factors on mortality of MI patients. Results: The mean age of patients in case group was significantly higher than control group (75.1±11.7 vs. 63.1±11.6, p=0.001).The history of non-cardinal diseases in case group with 44.4% significantly higher than control group with 7.4% (p=0.002).The number of performed PCIs in case group with 40.7% significantly lower than control group with 74.1% (P=0.013). The time distance between hospital admission and performed PCI in case group with 110.9 min was significantly upper than control group with 56 min (P=0.001). The mean of delay time from Onset of symptom to hospital admission (patient delay) and the mean of delay time from hospital admissions to receive treatment (system delay) was similar between two groups. By using logistic regression model we revealed that history of non-cardinal diseases (OR=283) and the number of performed PCIs (OR=24.5) had significant impact on mortality of MI patients in compare to other factors. Conclusion: Results of this study showed that of all studied factors, the number of performed PCIs, history of non-cardinal illness and the interval between onset of symptoms and performed PCI have significant relation with morality of MI patients and other factors were not meaningful. So, doing more studies with a large sample and investigated other involved factors such as smoking, weather and etc. is recommended in future.

Keywords: acute MI, mortality, heart failure, arrhythmia

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Authors: Arsalan Ghaderi

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Introduction: Inactivity is one of the most important risk factors for cardiovascular disease. According to the study prevalence of inactivity in Iran, about 67.5% and in the staff, and especially nurses, are similar. The inflammatory index (HS-CRP) is highly predictive of the progression of these diseases. Physical activity education is very important in preventing these diseases. One of the modern educational methods is web-based theory-based education. Methods: This is a semi-experimental interventional study which was conducted in Isfahan and Kurdistan universities of medical sciences in two stages. A cross-sectional study was done to determine the status of physical activity and its predictive factors. Then, intervention was performed, and six months later the data were retrieved. The data was collected using a demographic questionnaire, an integrative model of behavior prediction constructs, a standard physical activity questionnaire and (HS-CRP) test. Data were analyzed by SPSS software. Results: Physical activity was low in 66.6% of nurses, 25.4% were moderate and 8% severe. According to Pearson correlation matrix, the highest correlation was found between behavioral intention and skill structures (0.553**), subjective norms (0.222**) and self-efficacy (0.198**). The relationship between age and physical activity in the first study was reverse and significant. After intervention, there was a significant change in attitudes, self-efficacy, skill and behavioral intention in the intervention group. This change was significant in attitudes, self-efficacy and environmental conditions of the control group. HS-CRP index decreased significantly after intervention in both groups, but there was not a significant relationship between inflammatory index and physical activity score. The change in physical activity level was significant only in the control group. Conclusion: Despite the effect of educational intervention on attitude, self-efficacy, skill, and behavioral intention, the results showed that if factors such as environmental factors are not corrected, training and changing structures cannot lead to physical activity behavior. On the other hand, no correlation between physical activity and HS-CRP showed that this index can be influenced by other factors, and this should be considered in any intervention to reduce the HS-CRP index.

Keywords: HS-CRP, integrative model of behavior prediction, physical activity, nurses, web-based education

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Authors: Jae Ni Jang, Young Uk Kim

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Background: Chat Generative Pre-training Transformer-3 (ChatGPT; San Francisco, California, Open Artificial Intelligence) is an artificial intelligence chatbot based on a large language model designed to generate human-like text. As the usage of ChatGPT is increasing among less knowledgeable patients, medical students, and anesthesia and pain medicine residents or trainees, we aimed to evaluate the accuracy of ChatGPT-3 responses to questions about the American Society of Anesthesiologists (ASA) classification based on patients’ underlying diseases and assess the quality of the generated responses. Methods: A total of 47 questions were submitted to ChatGPT using textual prompts. The questions were designed for ChatGPT-3 to provide answers regarding ASA classification in response to common underlying diseases frequently observed in adult patients. In addition, we created 18 questions regarding the ASA classification for pediatric patients and pregnant women. The accuracy of ChatGPT’s responses was evaluated by cross-referencing with Miller’s Anesthesia, Morgan & Mikhail’s Clinical Anesthesiology, and the American Society of Anesthesiologists’ ASA Physical Status Classification System (2020). Results: Out of the 47 questions pertaining to adults, ChatGPT -3 provided correct answers for only 23, resulting in an accuracy rate of 48.9%. Furthermore, the responses provided by ChatGPT-3 regarding children and pregnant women were mostly inaccurate, as indicated by a 28% accuracy rate (5 out of 18). Conclusions: ChatGPT provided correct responses to questions relevant to the daily clinical routine of anesthesiologists in approximately half of the cases, while the remaining responses contained errors. Therefore, caution is advised when using ChatGPT to retrieve anesthesia-related information. Although ChatGPT may not yet be suitable for clinical settings, we anticipate significant improvements in ChatGPT and other large language models in the near future. Regular assessments of ChatGPT's ASA classification accuracy are essential due to the evolving nature of ChatGPT as an artificial intelligence entity. This is especially important because ChatGPT has a clinically unacceptable rate of error and hallucination, particularly in pediatric patients and pregnant women. The methodology established in this study may be used to continue evaluating ChatGPT.

Keywords: American Society of Anesthesiologists, artificial intelligence, Chat Generative Pre-training Transformer-3, ChatGPT

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Authors: Hüseyin Biçer

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There are more than a thousand endemic plants growing in Turkey. On the other hand, apart from these plantsAnatolia is home to more plant diversitythan the neighboring countries due to its transitional zone. These plants become a part of traditional medicine in the hope of curing the people with whom they have lived for thousands of years. No matter how important the climate is for the plant, the diseases of the region have an important place in the plant's life. While the plants used for tea are in the foreground in regions with heavy winters, the use of raw plants and fruits is common in some gastrointestinal problems. The aim of this study is explaining using the area of endemic plants in Anatolia.

Keywords: anatolian traditional medicine, traditional medicine, anatolian medicine, herbs

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Authors: Sh. Khoshemehry, M. J. Pourvaghar, M. E. Bahram

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In modern life, daily physical activity is relatively reduced, which is why the incidence of some diseases associated with overweight and obesity, such as hypertension, diabetes and other chronic illnesses, even in young people are observed. Obesity and overweight is one of the most common metabolic disorders in industrialized countries and in developing countries. One consequence of pathological obesity is cardiovascular disease and metabolic syndrome. In the past, it was believed that adipose tissue was ineffective and served only for storing triglycerides. In this review article, it was tried to refer to the esteemed scientific sources about physical activity and responses of leptin.

Keywords: disease, leptin, obesity, physical activity

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Authors: Janneth Gonzalez, Andres Pinzon Velasco, Maria Angarita, Nicolas Mendoza

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Astrocytes play an important role in various processes in the brain, including pathological conditions such as neurodegenerative diseases. Recent studies have shown that the increase in saturated fatty acids such as palmitic acid (PA) triggers pro-inflammatory pathways in the brain. The use of synthetic neurosteroids such as tibolone has demonstrated neuro-protective mechanisms. However, there are few studies on the neuro-protective mechanisms of tibolone, especially at the systemic (omic) level. In this study, we performed the integration of multi-omic data (transcriptome and proteome) into a human astrocyte genomic scale metabolic model to study the astrocytic response during palmitate treatment. We evaluated metabolic fluxes in three scenarios (healthy, induced inflammation by PA, and tibolone treatment under PA inflammation). We also use control theory to identify those reactions that control the astrocytic system. Our results suggest that PA generates a modulation of central and secondary metabolism, showing a change in energy source use through inhibition of folate cycle and fatty acid β-oxidation and upregulation of ketone bodies formation.We found 25 metabolic switches under PA-mediated cellular regulation, 9 of which were critical only in the inflammatory scenario but not in the protective tibolone one. Within these reactions, inhibitory, total, and directional coupling profiles were key findings, playing a fundamental role in the (de)regulation in metabolic pathways that increase neurotoxicity and represent potential treatment targets. Finally, this study framework facilitates the understanding of metabolic regulation strategies, andit can be used for in silico exploring the mechanisms of astrocytic cell regulation, directing a more complex future experimental work in neurodegenerative diseases.

Keywords: astrocytes, data integration, palmitic acid, computational model, multi-omics, control theory

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Authors: Masoud Swalehe, Semra Günay

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Developed countries are losing many lives to non-communicable diseases as compared to their developing counterparts. The effects of these diseases are mostly sudden and manifest at a very short time prior to death or a dangerous attack and this has consolidated the significance of emergency medical system (EMS) as one of the vital areas of healthcare service delivery. The primary objective of this research is to reduce ambulance response times (RT) of Eskişehir province EMS since a number of studies have established a relationship between ambulance response times and survival chances of patients especially out of hospital cardiac arrest (OHCA) victims. It has been found out that patients who receive out of hospital medical attention in few (4) minutes after cardiac arrest because of low ambulance response times stand higher chances of survival than their counterparts who take longer times (more than 12 minutes) to receive out of hospital medical care because of higher ambulance response times. The study will make use of geographic information systems (GIS) technology to dynamically reallocate ambulance resources according to demand and time so as to reduce ambulance response times. Geospatial-time distribution of ambulance calls (demand) will be used as a basis for optimal ambulance deployment using system status management (SSM) strategy to achieve much demand coverage with the same number of ambulance resources to cause response time reduction. Drive-time polygons will be used to come up with time specific facility coverage areas and suggesting additional facility candidate sites where ambulance resources can be moved to serve higher demands making use of network analysis techniques. Emergency Ambulance calls’ data from 1st January 2014 to 31st December 2014 obtained from Eskişehir province health directorate will be used in this study. This study will focus on the reduction of ambulance response times which is a key Emergency Medical Services performance indicator.

Keywords: emergency medical services, system status management, ambulance response times, geographic information system, geospatial-time distribution, out of hospital cardiac arrest

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Authors: Esam Mohammed Al-shaebi

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One of the most crucial approaches for treating human diseases, particularly parasite infections, is nanomedicine. One of the most significant protozoan diseases that impact farm and domestic animals is coccidiosis. While, amprolium is one of the traditional anticoccidial medication, the advent of drug-resistant strains of Eimeria necessitates the development of novel treatments. The goal of the current investigation was to determine whether biosynthesized selenium nanoparticles (Bio-SeNPs) using Azadirachta indica leaves extract might treat mice with Eimeria papillata infection in the jejunal tissue. Five groups of seven mice each were used, as follows: Group 1: Non-infected-non-treated (negative control). Group 2: Non-infected treated group with Bio-SeNPs (0.5 mg/kg of body weight). Groups 3-5 were orally inoculated with 1×103 sporulated oocysts of E. papillata. Group 3: Infected-non-treated (positive control). Group 4: Infected and treated group with Bio-SeNPs (0.5 mg/kg). Group 5: Infected and treated group with the Amprolium. Groups 4 and 5 daily received oral administration (for 5 days) of Bio-SeNPs and anticoccidial medication, respectively, after infection. Bio-SeNPs caused a considerable reduction in oocyst output in mice feces (97.21%). This was also accompanied by a significant reduction in the number of developmental parasitic stages in the jejunal tissues. Glutathione reduced (GSH), glutathione peroxidase (GPx), and superoxide dismutase (SOD) levels were dramatically reduced by the Eimeria parasite, whereas, nitric oxide (NO) and malonaldehyde (MDA) levels were markedly elevated. The amount of goblet cells and MUC2 gene expression were used as apoptotic indicators, and both were considerably downregulated by infection. However, infection markedly increased the expression of inflammatory cytokines (IL-6 and TNF-α) and the apoptotic genes (Caspase-3 and BCL2). Bio-SeNPs were administrated to mice to drastically lower body weight, oxidative stress, and inflammatory and apoptotic indicators in the jejunal tissue. Our research thus showed the involvement of Bio-SeNPs in protecting mice with E. papillata infections against jejunal damage.

Keywords: coccidiosis, nanoparticles, azadirachta indica, oxidative stress

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Authors: Pei-Chih Wu, Hsin-Chih Lai, Yung-Lung Lee, Yun-Yao Chi, Ching-Yi Horng, Hsien-Chang Wang

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The impact of climate change to health has always been well documented. Amongst them, water-borne infectious diseases, chronic adverse effects or cancer risks due to chemical contamination in flooding or drought events are especially important in river basin. This study therefore utilizes GIS and different models to integrate demographic, land use, disaster prevention, social-economic factors, and human health assessment in the Erren River basin. Therefore, through the collecting of climatic, demographic, health surveillance, water quality and other water monitoring data, potential risks associated with the Erren River Basin are established and to understand human exposure and vulnerability in response to climate extremes. This study assesses the temporal and spatial patterns of melioidosis (2000-2015) and various cancer incidents in Tainan and Kaohsiung cities. The next step is to analyze the spatial association between diseases incidences, climatic factors, land uses, and other demographic factors by using ArcMap and GeoDa. The study results show that amongst all melioidosis cases in Taiwan, 24% cases (115) residence occurred in the Erren River basin. The relationship between the cases and in Tainan and Kaohsiung cities are associated with population density, aging indicator, and residence in Erren River basin. Risks from flooding due to heavy rainfall and fish farms in spatial lag regression are also related. Through liver cancer, the preliminary analysis in temporal and spatial pattern shows an increases pattern in annual incidence without clusters in Erren River basin. Further analysis of potential cancers connected to heavy metal contamination from water pollution in Erren River is established. The final step is to develop an assessment tool for human exposure from water contamination and vulnerability in response to climate extremes for the second year.

Keywords: climate change, health impact, health adaptation, Erren River Basin

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Authors: Franca De Sarno, Alfonso Maria Ponsiglione, Enza Torino

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Recent advances in diagnostic imaging technology have significantly contributed to a better understanding of specific changes associated with diseases progression. Among different imaging modalities, Magnetic Resonance Imaging (MRI) represents a noninvasive medical diagnostic technique, which shows low sensitivity and long acquisition time and it can discriminate between healthy and diseased tissues by providing 3D data. In order to improve the enhancement of MRI signals, some imaging exams require intravenous administration of contrast agents (CAs). Recently, emerging research reports a progressive deposition of these drugs, in particular, gadolinium-based contrast agents (GBCAs), in the body many years after multiple MRI scans. These discoveries confirm the need to have a biocompatible system able to boost a clinical relevant Gd-chelate. To this aim, several approaches based on engineered nanostructures have been proposed to overcome the common limitations of conventional CAs, such as the insufficient signal-to-noise ratios due to relaxivity and poor safety profile. In particular, nanocarriers, labeling or loading with CAs, capable of carrying high payloads of CAs have been developed. Currently, there’s no a comprehensive understanding of the thermodynamic contributions enable of boosting the efficacy of conventional CAs by using biopolymers matrix. Thus, considering the importance of MRI in diagnosing diseases, here it is reported a successful example of the next generation of these drugs where the commercial gadolinium chelate is incorporate into a biopolymer nanostructure, formed by cross-linked hyaluronic acid (HA), with improved relaxation properties. In addition, they are highlighted the basic principles ruling biopolymer-CA interactions in the perspective of their influence on the relaxometric properties of the CA by adopting a multidisciplinary experimental approach. On the basis of these discoveries, it is clear that the main point consists in increasing the rigidification of readily-available Gd-CAs within the biopolymer matrix by controlling the water dynamics, the physicochemical interactions, and the polymer conformations. In the end, the acquired knowledge about polymer-CA systems has been applied to develop of Gd-based HA nanoparticles with enhanced relaxometric properties.

Keywords: biopolymers, MRI, nanoparticles, contrast agent

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Authors: E. Grochowska-Niedworok, K. Brukało, M. Kardas

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The aim of this study was to analyze and evaluate the consumption of functional food by consumers by: age, sex, formal education level, place of residence and diagnosed diseases. The study employed an ad hoc questionnaire in a group of 300 inhabitants of Upper Silesia voivodship. Knowledge of functional food among the group covered in the study was far from satisfactory. The choice of functional food was of intuitive character. In addition, the group covered was more likely to choose pharmacotherapy instead of diet-related prevention then, which can be associated with presumption of too distant effects and a long period of treatment.

Keywords: consumer choice, functional food, healthy lifestyle, consumer knowledge

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Authors: Cangir Uyarlar, Ismail Bayram, Ibrahim Sadi Cetingul, Mustafa Kabu, Eyup Eren Gultepe

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This study was conducted to determine the effects of organic chromium and organic chromium+propylene glycol on milk yield and some blood parameters related with liver fatty acid metabolism in early lactation dairy cows. Thirty multiparous Holstein dairy cows were used as study material. Cows assigned to three groups as control (C), chromium (Cr) and chromium+propylene glycol (CP). Live weight, parity and body condition score were used as covariates for statistical analyses. The study began at calving and finished at 3 weeks after calving. All cows were consumed same diet. Organic chromium and organic chromium+propylene glycol were orally administrated to cows in treatment groups shortly after the morning milking. Blood samples were collected from all cows on 0 (calving), 3rd, 6th, 9th, 12th, 15th, 18th, 21th days after calving. Then, samples were analyzed for BHBA (Betahydroxybutiric acids), NEFA (Non Esterified Fatty Acids), urea, total protein (TP) and glucose concentrations. Weekly milk yields were calculated from daily milk data on farm. Organic chromium treatment had no significant differences on serum biochemical parameters and milk yields. However, administration of organic chromium and propylene glycol combination decreased serum urea and total protein concentration, helped to protection from subclinical metabolic diseases via decreasing serum NEFA and BHBA concentrations. Also, this combination decreased serum glucose levels of cows. Neither only chromium nor chromium and propylene glycol combination did not affect milk yield throughout the study. These findings were suggested that orally administrations of chromium and propylene glycol combination improved liver glucose and fatty acid metabolism, decreased serum parameters which are representing subclinical diseases in early lactation dairy cows.

Keywords: chromium, early lactation dairy cows, propylene glycol, milk yield

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Authors: Diego Luján Villarreal

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Visual prostheses are designed to repair some eyesight in patients blinded by photoreceptor diseases, such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD). Electrode-to-cell proximity has drawn attention due to its implications on secure single-localized stimulation. Yet, few techniques are available for understanding the relationship between the number of cells activated and the current injection. We propose an answering technique by solving the governing equation for time-dependent electrical currents using finite element discretization to obtain the volume of stimulation.

Keywords: visual prosthetic devices, volume for stimulation, FEM discretization, 3D simulation

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Authors: Mohd Shazad, Kamal Kumar Gupta

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Aedes aegypti (Diptera: Culicidae), commonly known as tiger mosquito is the vector of dengue fever, yellow fever, chikungunya and zika virus. In the absence of any effective vaccine against these diseases, control the mosquito population is the only promising mean to prevent the diseases. Currently used chemical insecticides cause environmental contamination, high mammalian toxicity and hazards to non-target organisms, insecticide resistance and vector resurgence. Present research work aimed to explore the potentials of phytochemicals present in the Ocimum sanctum in management of mosquito population. The leaves of Ocimum were extracted with ethanol by ‘cold extraction method’. 0-24h old fourth instar larvae of Aedes aegypti were treated with the extract of concentrations 50ppm, 100ppm, 200ppm and 400ppm for 24h. Survival, growth and development of the treated larvae were evaluated. The adults emerged from the treated larvae were used for the reproductive fitness studies. Our results indicate 77.2% mortality in the larvae exposed to 400 ppm. At lower doses, although there was no significant reduction in the survival after 24h however, it decreased during subsequent days of observations. In control experiments, no mortality was observed. It was also observed that the larvae survived after treatment showed severe growth and developmental abnormalities. There was significant increase in larval duration. In control, fourth instar moulted into pupa after 3 days while larvae treated with 400 ppm extract were moulted after 4.6 days. Larva-pupa intermediates and the pupa-adult intermediates were observed in many cases. The adults emerged from the treated larvae showed impaired mating and oviposition behaviour. The females exhibited longer preoviposition period, reduced oviposition rate and decreased egg output. GCMS analysis of the ethanol extract revealed presence of JH mimics and intermediates of JH biosynthetic pathway. Potentials of Ocimum sanctum in integrated vector management programme of Aedes aegypti were discussed.

Keywords: Aedes aegypti, Ocimum sanctum, oviposition, survival

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Authors: Satoshi Nishimura

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Although much information has been garnered from the genomes of humans and mice, it remains difficult to extend that information to explain physiological and pathological phenomena. This is because the processes underlying life are by nature stochastic and fluctuate with time. Thus, we developed novel "in vivo molecular imaging" method based on single and two-photon microscopy. We visualized and analyzed many life phenomena, including common adult diseases. We integrated the knowledge obtained, and established new models that will serve as the basis for new minimally invasive therapeutic approaches.

Keywords: two photon microscope, intravital visualization, thrombus, artery

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Authors: Meiling Yu, Nadia Rouatbi, Khuloud T. Al-Jamal

Abstract:

Background: Treatment of neurological disorders with modern medical and surgical approaches remains difficult. Gene therapy, allowing the delivery of genetic materials that encodes potential therapeutic molecules, represents an attractive option. The treatment of brain diseases with gene therapy requires the gene-editing tool to be delivered efficiently to the central nervous system. In this study, we explored the efficiency of different delivery routes, namely intravenous (i.v.), intra-cranial (i.c.), and intra-nasal (i.n.), to deliver stable nucleic acid-lipid particles (SNALPs) containing gene-editing tools namely Cas9 mRNA and sgRNA encoding for GFP as a reporter protein. We hypothesise that SNALPs can reach the brain and perform gene-editing to different extents depending on the administration route. Intranasal administration (i.n.) offers an attractive and non-invasive way to access the brain circumventing the blood–brain barrier. Successful delivery of gene-editing tools to the brain offers a great opportunity for therapeutic target validation and nucleic acids therapeutics delivery to improve treatment options for a range of neurodegenerative diseases. In this study, we utilised Rosa26-Cas9 knock-in mice, expressing GFP, to study brain distribution and gene-editing efficiency of SNALPs after i.v.; i.c. and i.n. routes of administration. Methods: Single guide RNA (sgRNA) against GFP has been designed and validated by in vitro nuclease assay. SNALPs were formulated and characterised using dynamic light scattering. The encapsulation efficiency of nucleic acids (NA) was measured by RiboGreen™ assay. SNALPs were incubated in serum to assess their ability to protect NA from degradation. Rosa26-Cas9 knock-in mice were i.v., i.n., or i.c. administered with SNALPs to test in vivo gene-editing (GFP knockout) efficiency. SNALPs were given as three doses of 0.64 mg/kg sgGFP following i.v. and i.n. or a single dose of 0.25 mg/kg sgGFP following i.c.. knockout efficiency was assessed after seven days using Sanger Sequencing and Inference of CRISPR Edits (ICE) analysis. In vivo, the biodistribution of DiR labelled SNALPs (SNALPs-DiR) was assessed at 24h post-administration using IVIS Lumina Series III. Results: Serum-stable SNALPs produced were 130-140 nm in diameter with ~90% nucleic acid loading efficiency. SNALPs could reach and stay in the brain for up to 24h following i.v.; i.n. and i.c. administration. Decreasing GFP expression (around 50% after i.v. and i.c. and 20% following i.n.) was confirmed by optical imaging. Despite the small number of mice used, ICE analysis confirmed GFP knockout in mice brains. Additional studies are currently taking place to increase mice numbers. Conclusion: Results confirmed efficient gene knockout achieved by SNALPs in Rosa26-Cas9 knock-in mice expressing GFP following different routes of administrations in the following order i.v.= i.c.> i.n. Each of the administration routes has its pros and cons. The next stages of the project involve assessing gene-editing efficiency in wild-type mice and replacing GFP as a model target with therapeutic target genes implicated in Motor Neuron Disease pathology.

Keywords: CRISPR, nanoparticles, brain diseases, administration routes

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Authors: Hamdy Khamis Korayem, Manal Yehia Tayel, Abeer Shawky El Hadedy, Emmanuel Kamal Aziz Saba, Shimaa Badr Abdelnaby Badr

Abstract:

The aim of the current study was to demonstrate whether serum Interleukin-18 (IL-18) is increased in rheumatoid arthritis (RA) and its correlation with disease activity, functional disability and quality of life in RA patients. The study included 30 RA patients and 20 healthy normal control subjects. The RA patients were diagnosed according to the 2010 ACR/EULAR classification criteria for RA with the exclusion of those who had diabetes mellitus, endocrine disorders, associated rheumatologic diseases, viral hepatitis B or C and other diseases with increased serum IL-18 level. All patients were subjected to clinical evaluation of the musculoskeletal system. Disease activity was assessed by disease activity score 28 with 4 variables (DAS 28). Functional disability was assessed by health assessment questionnaire disability index (HAQ-DI). The quality of life was assessed by Short form-36 (SF-36) questionnaire. Radiological assessment of both hands and feet by Sharp/van der Heijde (SvH) scoring method. Laboratory parameters including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA) were assessed in patients and serum level of IL-18 in both patients and control subjects. There was no statistically significant difference between patient and control group as regards age and sex. Among patients, 29 % were females and the age range was between 25 to 55 years. Extra-articular manifestations were presented in 56.7% of the patients. The mean of DAS 28 score was 5.73±1.46 and that of HAQ-DI was 1.22±0.72 while that of SF-36 was 40.03±13.96. The level of serum IL-18 was significantly higher in patients than in the control subjects (P= 0.030). Serum IL-18 was correlated with ACPA among the patient group. There were no statistically significant correlations between serum IL-18 and DAS28, HAQ-DI, SF-36, total SvH score and the other laboratory results. In conclusion, IL-18 is significantly higher in RA patient than in healthy control subjects and positively correlated with ACPA level. IL-18 is associated with extra-articular manifestations. However, it is not correlated with other laboratory parameters, disease activity, functional disability, quality of life nor radiological severity.

Keywords: disease activity score, Interleukin-18, quality of life assessment, rheumatoid arthritis

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Authors: Rihab Gamaoun, Cynthia El Hage, Laura Ruiz, Erin Prosk, Antonio Vigano

Abstract:

Introduction: Santé Cannabis (SC), a Canadian medical cannabis-specialized group of clinics based in Montreal and in the province of Québec, has served more than 5000 patients seeking cannabis-based treatment prescription for medical indications over the past five years. Within a research frame, data on the use of medical cannabis products from all the above patients were prospectively collected, leading to a large real-world database on the use of medical cannabis. The aim of this study was to gather information on the profiles of both patients and prescribed medical cannabis products at SC clinics and to assess the safety of medical cannabis among Canadian patients. Methods: Using a retrospective analysis of the database, records of 2585 patients who were prescribed medical cannabis products for therapeutic purposes between 01-November 2017 and 04-September 2019 were included. Patients’ demographics, primary diagnosis, route of administration, and chemovars recorded at the initial visits were investigated. Results: At baseline: 9% of SC patients were female, with a mean age of 57 (SD= 15.8, range= [18-96]); Cannabis products were prescribed mainly for patients with a diagnosis of chronic pain (65.9% of patients), cancer (9.4%), neurological disorders (6.5%), mood disorders (5.8 %) and inflammatory diseases (4.1%). Route of administration and chemovars of prescribed cannabis products were the following: 96% of patients received cannabis oil (51% CBD rich, 42.5% CBD:THC); 32.1% dried cannabis (21.3% CBD:THC, 7.4% THC rich, 3.4 CBD rich), and 2.1% oral spray cannabis (1.1% CBD:THC, 0.8% CBD rich, 0.2% THC rich). Most patients were prescribed simultaneously, a combination of products with different administration routes and chemovars. Safety analysis is undergoing. Conclusion: Our results provided initial information on the profile of medical cannabis products prescribed in a Canadian population and the experienced adverse events over the past three years. The Santé Cannabis database represents a unique opportunity for comparing clinical practices in prescribing and titrating cannabis-based medications across different centers. Ultimately real-world data, including information about safety and effectiveness, will help to create standardized and validated guidelines for choosing dose, route of administration, and chemovars types for the cannabis-based medication in different diseases and indications.

Keywords: medical cannabis, real-world data, safety, pharmacovigilance

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Authors: Obinna Afamefuna Echi

Abstract:

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

Keywords: ageing, resistance training, BDNF, cognitive function

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Authors: Sylwia Baluta, Joanna Cabaj, Karol Malecha

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The evolution of biosensors was driven by the need for faster and more versatile analytical methods for application in important areas including clinical, diagnostics, food analysis or environmental monitoring, with minimum sample pretreatment. Rapid and sensitive neurotransmitters detection is extremely important in modern medicine. These compounds mainly occur in the brain and central nervous system of mammals. Any changes in the neurotransmitters concentration may lead to many diseases, such as Parkinson’s or schizophrenia. Classical techniques of chemical analysis, despite many advantages, do not permit to obtain immediate results or automatization of measurements.

Keywords: adrenaline, biosensor, dopamine, laccase, tyrosinase

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Authors: Zhen Ye, Maryam Zaroudi, Elizabeth Aisenbrey, Nicolynn E. Davis, Peng Gao

Abstract:

Nanoparticles have been used as drug delivery systems in the treatment of life-threatening diseases for decades, but traditional formulation development methods are time consuming and labor intensive. Millipore Sigma has developed a platform¬¬– NanoFabTxTM¬¬– for rapid and reproducible formulation development and screening to ensure consistentnanoparticle characteristics. Reproducible and precise control of the development process for a range of nanoparticle formulations accelerates the introduction of novel formulations to the clinic.

Keywords: Bio platform, Formulation development, NanoFabTxTM, Drug delivery

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Authors: E. Carraro, Sa. Bonetta, Si. Bonetta, E. Ceretti, G. C. V. Viola, C. Pignata, S. Levorato, T. Salvatori, S. Vannini, V. Romanazzi, A. Carducci, G. Donzelli, T. Schilirò, A. De Donno, T. Grassi, S. Bonizzoni, A. Bonetti, G. Gilli, U. Gelatti

Abstract:

In 2013, air pollution and particulate matter were classified as carcinogenic to human by the IARC. At present, PM is Europe's most problematic pollutant in terms of harm to health, as reported by European Environmental Agency (EEA) in the EEA Technical Report on Air quality in Europe, 2015. A percentage between 17-30 of the EU urban population lives in areas where the EU air quality 24-hour limit value for PM10 is exceeded. Many studies have found a consistent association between exposure to PM and the incidence and mortality for some chronic diseases (i.e. lung cancer, cardiovascular diseases). Among the mechanisms responsible for these adverse effects, genotoxic damage is of particular concern. Children are a high-risk group in terms of the health effects of air pollution and early exposure during childhood can increase the risk of developing chronic diseases in adulthood. The MAPEC_LIFE (Monitoring Air Pollution Effects on Children for supporting public health policy) is a project founded by EU Life+ Programme (LIFE12 ENV/IT/000614) which intends to evaluate the associations between air pollution and early biological effects in children and to propose a model for estimating the global risk of early biological effects due to air pollutants and other factors in children. This work is focused on the micronuclei frequency in child buccal cells in association with airborne PM levels taking into account the influence of other factors associated with the lifestyle of children. The micronucleus test was performed in exfoliated buccal cells of 6–8 years old children from 5 Italian towns with different air pollution levels. Data on air quality during the study period were obtained from the Regional Agency for Environmental Protection. A questionnaire administered to children’s parents was used to obtain details on family socio-economic status, children health condition, exposures to other indoor and outdoor pollutants (i.e. passive smoke) and life-style, with particular reference to eating habits. During the first sampling campaign (winter 2014-15) 1315 children were recruited and sampled for Micronuclei test in buccal cells. In the sampling period the levels of the main pollutants and PM10 were, as expected, higher in the North of Italy (PM10 mean values 62 μg/m3 in Torino and 40 μg/m3 in Brescia) than in the other towns (Pisa, Perugia, Lecce). A higher Micronucleus frequency in buccal cells of children was found in Brescia (0.6/1000 cells) than in the other towns (range 0.3-0.5/1000 cells). The statistical analysis underlines a relation of the micronuclei frequency with PM concentrations, traffic level near child residence, and level of education of parents. The results suggest that, in addition to air pollution exposure, some other factors, related to lifestyle or further exposures, may influence micronucleus frequency and cellular response to air pollutants.

Keywords: air pollution, buccal cells, children, micronucleus cytome assay

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Authors: Mohamed Ahmed Madkour, Haitham Magdy Hamad

Abstract:

This research aims to study of the surgery science and imaging in ancient Egypt, and how to diagnose the surgical cases, whether due to injuries or disease that requires surgical intervention, Medical diagnosis and how to treat it. The ancient Egyptian physician tried to change over from magic and theological thinking to become a stand-alone experimental science, they were able to distinguish between diseases and they divide them into internal and external diseases even this division exists to date in modern medicine. There is no evidence to recognize the amount of human knowledge in the prehistoric knowledge of medicine and surgery except skeleton. It is not far from the human being in those times familiar with some means of treatment, Surgery in the Stone age was rudimentary, Flint stone was used after trimming in a certain way as a lancet to slit and open the skin. Wooden tree branches were used to make splints to treat bone fractures. Surgery developed further when copper was discovered, it led to the advancement of Egyptian civilization, then modern and advanced tools appeared in the operating theater like a knife or a scalpel. The climate and environmental conditions have preserved medical papyri and human remains that have confirmed their knowledge of surgical methods including sedation. The ancient Egyptians reached a great importance in surgery, evidenced by the scenes that depict the pathological image and the surgical process, but the image alone is not sufficient to prove the pathology, its presence in ancient Egypt and its treatment method. As there are a number of medical papyri, especially Edwin Smith and Ebris, which prove the ancient Egyptian surgeon's knowledge of the pathological condition that It requires a surgical intervention, otherwise its diagnosis and the method of treatment will not be described with such accuracy through these texts. Some surgeries are described in the department of surgery at Ebris papyrus. The level of surgery in ancient Egypt was high, and they performed surgery such as hernias and Aneurysm, however we have not received a lengthy explanation of the various surgeries and the surgeon has usually only said “treated surgically”. It is evident in the Ebris papyrus that they used sharp surgical tools and cautery in operations where bleeding is expected, such as hernias, arterial sacs and tumors.

Keywords: ancient Egypt, archaeology, Egyptian history, ancient asurgical imaging, Egyptian civilization, civilization

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Authors: Olusola Omolola Olafuyi, Michael Coleman, Raj Kumar Singh Badhan

Abstract:

Introduction: Malaria in pregnancy has morbidity and mortality implication on both mother and unborn child. Piperaquine (PQ) based antimalarial treatment is emerging as a choice antimalarial for pregnant women in the face of resistance to current antimalarial treatment recommendation in pregnancy. Physiological and biochemical changes in pregnant women may affect the pharmacokinetics of the antimalarial drug in these. In malaria endemic regions other infectious diseases like HIV/AIDs are prevalent. Pregnant women who are co-infected with malaria and HIV/AID are at even more greater risk of death not only due to complications of the diseases but also due to drug-drug interactions (DDIs) between antimalarials (AMT) and antiretroviral (ARVs). In this study, physiologically based pharmacokinetic (PBPK) modelling was used to investigate the effect of physiological and biochemical changes on the impact of ARV mediated DDIs in pregnant women in three countries. Method: A PBPK model for PQ was developed on SimCYP® using published physicochemical and pharmacokinetic data of PQ from literature, this was validated in three customized population groups from Thailand, Sudan and Papua New Guinea with clinical data. Validation of PQ model was also done in presence of interaction with efavirenz (pre-validated on SimCYP®). Different albumin levels and pregnancy stages was simulated in the presence of interaction with standard doses of efavirenz and ritonavir. PQ day 7 concentration of 30ng/ml was used as the efficacy endpoint for PQ treatment.. Results: The median day 7 concentration of PQ remained virtually consistent throughout pregnancy and were satisfactory across the three population groups ranging from 26-34.1ng/ml; this implied the efficacy of PQ throughout pregnancy. DDI interaction with ritonavir and efavirenz resulted in modest effect on the day 7 concentrations of PQ with AUCratio ranging from 0.56-0.8 and 1.64-1.79 for efavirenz and ritonavir respectively over 10-40 gestational weeks, however, a reduction in human serum albumin level reflective of severe malaria resulted in significantly reduced the number of subjects attaining the PQ day 7 concentration in the presence of both DDIs. The model demonstrated that the DDI between PQ and ARV in pregnant women with different malaria severities can alter the pharmacokinetic of PQ.

Keywords: antiretroviral, malaria, piperaquine, pregnancy, physiologically-based pharmacokinetics

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