Search results for: chronic kidney disease

Authors: Vaiyapuri Subbarayn Periasamy, Jegan Athinarayanan, Ali A. Alshatwi

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The widespread use of Titanium oxide nanoparticles (TiO2-NPs), now are found with different physic-chemical properties (size, shape, chemical properties, agglomeration, etc.) in many processed foods, agricultural chemicals, biomedical products, food packaging and food contact materials, personal care products, and other consumer products used in daily life. Growing evidences have been highlighted that there are risks of physico-chemical properties dependent toxicity with special attention to “TiO2-NPs and human immune system”. Unfortunately, agglomeration and aggregation have frequently been ignored in immuno-toxicological studies, even though agglomeration and aggregation would be expected to affect nanotoxicity since it changes the size, shape, surface area, and other properties of the TiO2-NPs. In this present investigation, we assessed the immune toxic effect of TiO2-NPs on human immune cells Total WBC including Lymphocytes (T cells (CD3+), T helper cells (CD3+, CD4+), Suppressor/cytotoxic T cells (CD3+/CD8+) and NK cells (CD3-/CD16+ and CD56+), Monocytes (CD14+, CD3-) and B lymphocytes (CD19+, CD3-) in order to find the immunological response (IL1A, IL1B, IL2 IL-4, IL5 IL-6, IL-10, IL-12, IL-13, IFN-γ, TGF-β, and TNF-a) and redox gene regulation (TNF, p53, BCl-2, CAT, GSTA4, TNF, CYP1A, POR, SOD1, GSTM3, GPX1, and GSR1)-linking physicochemical properties with special reference to agglomeration of TiO2-NPs. Our findings suggest that TiO2-NPs altered cytokine production, enhanced phagocytic indexing, metabolic stress through specific immune regulatory- genes expression in different WBC subsets and may contribute to pro-inflammatory response. Although TiO2-NPs have great advantages in the personal care products, biomedical, food and agricultural products, its chronic and acute immune-toxicity still need to be assessed carefully with special reference to food and environmental safety.

Keywords: TiO2 nanoparticles, oxidative stress, cytokine, human immune cells

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Authors: Rohita Gupta, G. S. Brah, R. Verma, C. S. Mukhopadhayay

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Although chicken strains show differences in susceptibility to a number of diseases, the underlying immunological basis is yet to be elucidated. In the present study, heterophils were subjected to LPS stimulation and total RNA extraction, further differential gene expression was studied in broiler, layer and indigenous Aseel strain by Real Time RT-PCR at different time periods before and after induction. The expression of the 14 AvBDs and chTLR 1, 2, 3, 4, 5, 7, 15 and 21 was detectable in heterophils. The expression level of most of the AvBDs significantly increased (P<0.05) 3 hours post in vitro lipopolysaccharide challenge. Higher expression level and stronger activation of most AvBDs, NFkB-1 and IRF-3 in heterophils was observed with the stimulation of LPS in layer compared to broiler, and in Aseel compared to both layer and broiler. This investigation will allow more refined interpretation of immuno-genetic basis of the variable disease resistance/susceptibility in divergent stock of chicken including indigenous breed. Moreover, this study will be helpful in formulation of strategy for isolation of antimicrobial peptides from heterophils.

Keywords: differential expression, heterophils, cytokines, defensin, TLR

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Authors: Liang Zhou, Xiaojing Zhu, Yin Lu

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Danshen can induce the angiogenesis in advanced ischemic heart disease while inhibiting the angiogenesis in cancer. Additionally, Danshen mainly contains two groups of ingredients: the hydrophilic phenolic acids (danshensu, caffeic acid and salvianolic acid B), and the lipophilic tanshinones (dihydrotanshinone I, tanshinone II A, and cryptotanshinone). The lipophilic tanshinones reduced the VEGF- and bFGF-induced proliferation of HUVECs in dose-dependent manner, but cannot perform in others. Conversely, caffeic acid and salvianolic acid B had the opposite effect. Danshensu inhibited the VEGF- and bFGF-induced migration of HUVECs, and others were not. Most of them interrupted the forming capillary-like structures of HUVECs, except the danshensu and caffeic acid. Oppositely, caffeic acid enhanced the ability of forming capillary-like structures of HUVECs. Ultimately, the lipophilic tanshinones, danshensu and salvianolic acid B inhibited the angiogenesis, whereas the caffeic acid induced the angiogenesis. These data provide useful information for the classification of ingredients of Danshen for angiogenesis.

Keywords: angiogenesis, Danshen, HUVECs, ingredients

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Authors: Mahdi Bazarganigilani

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Aortic enlargement, also known as an aortic aneurysm, can occur when the walls of the aorta become weak. This disease can become deadly if overlooked and undiagnosed. In this paper, a computer-aided diagnosis (CAD) system was introduced to accurately diagnose aortic enlargement from chest x-ray images. An enhanced convolutional neural network (CNN) was employed and then trained by transfer learning by using three different main areas from the original images. The areas included the left lung, heart, and right lung. The accuracy of the system was then evaluated on 1001 samples by using 4-fold cross-validation. A promising accuracy of 90% was achieved in terms of the F-measure indicator. The results showed using different areas from the original image in the training phase of CNN could increase the accuracy of predictions. This encouraged the author to evaluate this method on a larger dataset and even on different CAD systems for further enhancement of this methodology.

Keywords: computer-aided diagnosis systems, aortic enlargement, chest X-ray, image processing, convolutional neural networks

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Authors: G. I. Onwuka, A. Danbaba, S. U. Gulumbe

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This study investigated of Infant Mortality Rate as observed at a general hospital in Kaduna-South, Kaduna State, North West Nigeria. The causes of infant Mortality were examined. The data used for this analysis were collected at the statistics unit of the Hospital. The analysis was carried out on the data using Multiple Linear regression Technique and this showed that there is linear relationship between the dependent variable (death) and the independent variables (malaria, measles, anaemia, and coronary heart disease). The resultant model also revealed that a unit increment in each of these diseases would result to a unit increment in death recorded, 98.7% of the total variation in mortality is explained by the given model. The highest number of mortality was recorded in July, 2005 and the lowest mortality recorded in October, 2009.Recommendations were however made based on the results of the study.

Keywords: infant mortality rate, multiple linear regression, diseases, serial correlation

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Authors: Nayomi Ranathunga, Priyantha Perera, Sumal Nandasena, Nalini Sathiakumar, Anuradhini Kasthuriratne, Rajitha Wikremasinghe

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Solid fuel combustion is an important source of indoor air pollution (IAP) in developing countries that has adverse health impacts particularly in children. This study was conducted to determine the effect of IAP due to solid fuel combustion on physical growth of children under five in a Sri Lankan setting. A prospective study was conducted in a mixed population comprising urban and semi urban residents. The study included 240 children under 5 who were permanent residents of the area. Physical growth was assessed by measuring anthropometric indices based on the World Health Organization (WHO) guidelines and standards. Exposure levels were defined according to the main type of fuel used for cooking at home: children residing in households using biomass fuel or kerosene as the main type of fuel for cooking were classified as the “high exposure” group and children resident in households using liquefied petroleum gas (LPG) or electricity for cooking were classified as the “low exposure” group. Sixty percent of the children were classified as from the “high” exposure group and 40% of the children were classified as from the “low” exposure group; 54% of the children were male. At baseline, the prevalence of wasting was 17.1% and the prevalence of stunting was 10.4%; the mean z-score for weight for height was - 0.85, weight for age was - 0.46 and height for age was -0.38. At baseline, children from the “high” exposure group had a significantly lower mean weight for height z-score (p=0.02) and a mean height for age z-score (p=0.001) as compared to children from the “low” exposure group after adjusting for confounding factors such as father’s education, mother’s education and family income. Poor maternal education was significantly associated with lower height for age z-scores (p=0.04) after adjusting for exposure status. IAP due to combustion of biomass fuel leads to chronic malnutrition.

Keywords: children, growth, indoor air pollution, solid fuel

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Authors: Manohar Salla, Mark S. Butler, Ruby Pelingon, Geraldine Kaeslin, Daniel E. Croker, Janet C. Reid, Jong Min Baek, Paul V. Bernhardt, Elizabeth M. J. Gillam, Matthew A. Cooper, Avril A. B. Robertson

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MCC950 is a potent and selective inhibitor of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome that shows early promise for treatment of inflammatory diseases. The identification of major metabolites of lead molecule is an important step during drug development process. It provides an information about the metabolically labile sites in the molecule and thereby helping medicinal chemists to design metabolically stable molecules. To identify major metabolites of MCC950, the compound was incubated with human liver microsomes and subsequent analysis by (+)- and (−)-QTOF-ESI-MS/MS revealed a major metabolite formed due to hydroxylation on 1,2,3,5,6,7-hexahydro-s-indacene moiety of MCC950. This major metabolite can lose two water molecules and three possible regioisomers were synthesized. Co-elution of major metabolite with each of the synthesized compounds using HPLC-ESI-SRM-MS/MS revealed the structure of the metabolite (±) N-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide. Subsequent synthesis of individual enantiomers and coelution in HPLC-ESI-SRM-MS/MS using a chiral column revealed the metabolite was R-(+)- N-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide. To study the possible cytochrome P450 enzyme(s) responsible for the formation of major metabolite, MCC950 was incubated with a panel of cytochrome P450 enzymes. The result indicated that CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C18, CYP2C19, CYP2J2 and CYP3A4 are most likely responsible for the formation of the major metabolite. The biological activity of the major metabolite and the other synthesized regioisomers was also investigated by screening for for NLRP3 inflammasome inhibitory activity and cytotoxicity. The major metabolite had 170-fold less inhibitory activity (IC50-1238 nM) than MCC950 (IC50-7.5 nM). Interestingly, one regioisomer had shown nanomolar inhibitory activity (IC50-232 nM). However, no evidence of cytotoxicity was observed with any of these synthesized compounds when tested in human embryonic kidney 293 cells (HEK293) and human liver hepatocellular carcinoma G2 cells (HepG2). These key findings give an insight into the SAR of the hexahydroindacene moiety of MCC950 and reveal a metabolic soft spot which could be blocked by chemical modification.

Keywords: Cytochrome P450, inflammasome, MCC950, metabolite, microsome, NLRP3

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Authors: A. Biran, P. Sobhe Bidari, A. Almazroe, V. Lakshminarayanan, K. Raahemifar

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Diabetic Retinopathy (DR) is a severe retinal disease which is caused by diabetes mellitus. It leads to blindness when it progress to proliferative level. Early indications of DR are the appearance of microaneurysms, hemorrhages and hard exudates. In this paper, an automatic algorithm for detection of DR has been proposed. The algorithm is based on combination of several image processing techniques including Circular Hough Transform (CHT), Contrast Limited Adaptive Histogram Equalization (CLAHE), Gabor filter and thresholding. Also, Support Vector Machine (SVM) Classifier is used to classify retinal images to normal or abnormal cases including non-proliferative or proliferative DR. The proposed method has been tested on images selected from Structured Analysis of the Retinal (STARE) database using MATLAB code. The method is perfectly able to detect DR. The sensitivity specificity and accuracy of this approach are 90%, 87.5%, and 91.4% respectively.

Keywords: diabetic retinopathy, fundus images, STARE, Gabor filter, support vector machine

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Authors: Nsubuga Bright Titus

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The resource curse is an unavoidable phenomenon among oil producing states in Africa. There is no oil production currently in Uganda although exploration projections set 2020 as the year of initial production. But as the exploration proceeds and Production Sharing Agreements (PSA) are negotiated, so does the anticipation for oil revenues. The Indigenous people of Bunyoro are claiming the right to their indigenous lands through the African Commission on Human and People’s Rights (ACHPR) of the African Union. They urge the commission to investigate the government of Uganda on violations of their human rights. In this paper, oil as a resource curse is examined through the Dutch disease. Regional and global entanglements, as well as the contestation between the indigenous Bunyoro group and the oil industry in Uganda is explored. The paper also demonstrates that oil as a local possibility and national reality has propelled anxiety about oil revenues among various, local actors, State actors, regional and global actors.

Keywords: Entanglements, Extractive resources, Framing, web of relations

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Authors: Amani Waheed, Adel Mishriky, Rasha Farouk, Essam Abdallah, Sarah Hussein

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Background: Occupational stress plays a crucial role in professional drivers' health. They are exposed to high workloads, low physical activity, high demand and low decisions as well as poor lifestyle factors including poor diet, sedentary work, and smoking. Dyslipidemia is a well-established modifiable cardiovascular risk factor. Occupational stress and other forms of chronic stress have been associated with raised levels of atherogenic lipids. Although stress management has some evidence in improving lipid profile, the association between occupational stress and dyslipidemia is not clear. Objectives: To assess the relational between occupational stress and lipid profile among professional drivers. Methodology: A cross-sectional study conducted at a large company in Ismailia City, Egypt, where, 131 professional drivers divided into 44 car drivers, 43 bus drivers, and 44 truck drivers were eligible after applying exclusion criteria. Occupational stress index (OSI), non-occupational risk factors of dyslipidemia were assessed using interview structured questionnaire. Blood pressure, body mass index (BMI) and lipid profile were measured. Results: The mean of total OSI score was 79.98 ± 6.14. The total OSI score is highest among truck drivers (82.16 ± 4.62), then bus drivers (80.26 ± 6.02) and lowest among car drivers (77.55 ± 6.79) with statistically significant. Eighty percent had Dyslipidemia. The duration of driving hours per day, exposure to passive smoking and increased BMI were the risk factors. No statistical significance between Total OSI score and dyslipidemia. Using, logistic regression analysis, occupational stress, duration of driving hours per day, and BMI were positive significant predictors for dyslipidemia. Conclusion: Professional drivers are exposed to occupational stress. A high proportion of drivers have dyslipidemia. Total OSI score doesn't have statistically significant relation with dyslipidemia.

Keywords: body mass index, dyslipidaemia, occupational stress, professional drivers

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Authors: Md Shohidul Islam, Jongmyon Kim, Ui-pil Chong

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Medical image is an integral part of e-health care and e-diagnosis system. Medical image watermarking is widely used to protect patients’ information from malicious alteration and manipulation. The watermarked medical images are transmitted over the internet among patients, primary and referred physicians. The images are highly prone to corruption in the wireless transmission medium due to various noises, deflection, and refractions. Distortion in the received images leads to faulty watermark detection and inappropriate disease diagnosis. To address the issue, this paper utilizes error correction code (ECC) with (8, 4) Hamming code in an existing watermarking system. In addition, we implement the high complex ECC on a graphics processing units (GPU) to accelerate and support real-time requirement. Experimental results show that GPU achieves considerable speedup over the sequential CPU implementation, while maintaining 100% ECC efficiency.

Keywords: medical image watermarking, e-health system, error correction, Hamming code, GPU

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Authors: Noha Mohamed Abdelhafez Dahy, Azza Abd El-Aziz, Eman Ahmed, Marwa El-Sayed

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Osteoporosis is a metabolic bone disease characterized by low bone mass, deterioration of bone tissue, and disruption of bone microarchitecture, which leads to compromised bone strength and an increased risk of fracture, commonly it occurs in women 10-15 years after menopause, the mean age of menopause is 51 years. Menopause is natural physiological changes primary because of decline of ovaries function with age which leads to decrease of estrogen hormone production which is the main hormone for bone continuous remodeling for bone density maintenance. Exercise increase stimulation of bone growth to keep bone mass by the effect of the mechanical stimulation, antigravity loading and stress exerted on musculoskeletal muscles. Purpose: This study aimed to determine the effect of aerobic exercise on estrogen hormone and bone mineral density (BMD) in osteoporotic women and the correlation between the estrogen and BMD.

Keywords: Osteoporosis, Postmenopause, Aerobic exercise, DEXA, Serum Estrogen

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Authors: Leo Nnamdi Ozurumba-Dwight

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Messenger ribooxynucleic acid (mRNA) molecules are compositional, protein-based. These proteins, encoding mRNA molecules (which collectively connote the transcriptome), when analyzed by RNA sequencing (RNAseq), unveils the nature of gene expression in the RNA. The obtained gene expression provides clues of cellular traits and their dynamics in presentations. These can be studied in relation to function and responses. RNAseq is a practical concept in Genomics as it enables detection and quantitative analysis of mRNA molecules. Single cell and spatial transcriptomics both present varying avenues for expositions in genomic characteristics of single cells and pooled cells in disease conditions such as cancer, auto-immune diseases, hematopoietic based diseases, among others, from investigated biological tissue samples. Single cell transcriptomics helps conduct a direct assessment of each building unit of tissues (the cell) during diagnosis and molecular gene expressional studies. A typical technique to achieve this is through the use of a single-cell RNA sequencer (scRNAseq), which helps in conducting high throughput genomic expressional studies. However, this technique generates expressional gene data for several cells which lack presentations on the cells’ positional coordinates within the tissue. As science is developmental, the use of complimentary pre-established tissue reference maps using molecular and bioinformatics techniques has innovatively sprung-forth and is now used to resolve this set back to produce both levels of data in one shot of scRNAseq analysis. This is an emerging conceptual approach in methodology for integrative and progressively dependable transcriptomics analysis. This can support in-situ fashioned analysis for better understanding of tissue functional organization, unveil new biomarkers for early-stage detection of diseases, biomarkers for therapeutic targets in drug development, and exposit nature of cell-to-cell interactions. Also, these are vital genomic signatures and characterizations of clinical applications. Over the past decades, RNAseq has generated a wide array of information that is igniting bespoke breakthroughs and innovations in Biomedicine. On the other side, spatial transcriptomics is tissue level based and utilized to study biological specimens having heterogeneous features. It exposits the gross identity of investigated mammalian tissues, which can then be used to study cell differentiation, track cell line trajectory patterns and behavior, and regulatory homeostasis in disease states. Also, it requires referenced positional analysis to make up of genomic signatures that will be sassed from the single cells in the tissue sample. Given these two presented approaches to RNA transcriptomics study in varying quantities of cell lines, with avenues for appropriate resolutions, both approaches have made the study of gene expression from mRNA molecules interesting, progressive, developmental, and helping to tackle health challenges head-on.

Keywords: transcriptomics, RNA sequencing, single cell, spatial, gene expression.

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Authors: Jibril Mohammed, Usman Dadum Hamza, Muhammad Idris Misau, Baba Yahya Danjuma, Yusuf Bode Raji, Abdulsalam Surajudeen

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Volatile organic compounds (VOCs) have been reported to be responsible for many acute and chronic health effects and environmental degradations such as global warming. In this study, a renewable and low-cost coconut shell activated carbon (PHAC) was synthesized and treated with ammonia (PHAC-AM) to improve its hydrophobicity and affinity towards VOCs. Removal efficiencies and adsorption capacities of the ammonia treated activated carbon (PHAC-AM) for benzene and toluene were carried out through batch and fixed-bed studies respectively. Langmuir, Freundlich and Tempkin adsorption isotherms were tested for the adsorption process and the experimental data were best fitted by Langmuir model and least fitted by Tempkin model; the favourability and suitability of fitness were validated by equilibrium parameter (RL) and the root square mean deviation (RSMD). Judging by the deviation of the predicted values from the experimental values, pseudo-second-order kinetic model best described the adsorption kinetics than the pseudo-first-order kinetic model for the two VOCs on PHAC and PHAC-AM. In the fixed-bed study, the effect of initial VOC concentration, bed height and flow rate on benzene and toluene adsorption were studied. The highest bed capacities of 77.30 and 69.40 mg/g were recorded for benzene and toluene respectively; at 250 mg/l initial VOC concentration, 2.5 cm bed height and 4.5 ml/min flow rate. The results of this study revealed that ammonia treated activate carbon (PHAC-AM) is a sustainable adsorbent for treatment of VOCs in polluted waters.

Keywords: volatile organic compounds, equilibrium and kinetics studies, batch and fixed bed study, bio-based activated carbon

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Authors: Chongyang Ye, Rong Liu

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Elastic compression stockings (ECSs) have been widely applied in prophylaxis and treatment of chronic venous insufficiency of lower extremities. The medical function of ECS is to improve venous return and increase muscular pumping action to facilitate blood circulation, which is largely determined by the complex interaction between the ECS and lower limb tissues. Understanding the mechanical transmission of ECS along the skin surface, deeper tissues, and vascular system is essential to assess the effectiveness of the ECSs. In this study, a three-dimensional (3D) finite element (FE) model of the leg-ECS system integrated with a 3D fluid-solid interaction (FSI) model of the leg-vein system was constructed to analyze the biomechanical properties of veins and soft tissues under different ECS compression. The Magnetic Resonance Imaging (MRI) of the human leg was divided into three regions, including soft tissues, bones (tibia and fibula) and veins (peroneal vein, great saphenous vein, and small saphenous vein). The ECSs with pressure ranges from 15 to 26 mmHg (Classes I and II) were adopted in the developed FE-FSI model. The soft tissue was assumed as a Neo-Hookean hyperelastic model with the fixed bones, and the ECSs were regarded as an orthotropic elastic shell. The interfacial pressure and stress transmission were simulated by the FE model, and venous hemodynamics properties were simulated by the FSI model. The experimental validation indicated that the simulated interfacial pressure distributions were in accordance with the pressure measurement results. The developed model can be used to predict interfacial pressure, stress transmission, and venous hemodynamics exerted by ECSs and optimize the structure and materials properties of ECSs design, thus improving the efficiency of compression therapy.

Keywords: elastic compression stockings, fluid-solid interaction, tissue and vein properties, prediction

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Authors: Alexander Heckman, Rohan Goswami, Zachi Attia, Paul Friedman, Peter Noseworthy, Demilade Adedinsewo, Pablo Moreno-Franco, Rickey Carter, Tathagat Narula

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Background: Postoperative atrial fibrillation (POAF) is associated with adverse health consequences, higher costs, and longer hospital stays. Utilizing existing predictive models that rely on clinical variables and circulating biomarkers, multiple societies have published recommendations on the treatment and prevention of POAF. Although reasonably practical, there is room for improvement and automation to help individualize treatment strategies and reduce associated complications. Methods and Results: In this retrospective cohort study of solid organ transplant recipients, we evaluated the diagnostic utility of a previously developed AI-based ECG prediction for silent AF on the development of POAF within 30 days of transplant. A total of 2261 non-cardiac transplant patients without a preexisting diagnosis of AF were found to have a 5.8% (133/2261) incidence of POAF. While there were no apparent sex differences in POAF incidence (5.8% males vs. 6.0% females, p=.80), there were differences by race and ethnicity (p<0.001 and 0.035, respectively). The incidence in white transplanted patients was 7.2% (117/1628), whereas the incidence in black patients was 1.4% (6/430). Lung transplant recipients had the highest incidence of postoperative AF (17.4%, 37/213), followed by liver (5.6%, 56/1002) and kidney (3.6%, 32/895) recipients. The AUROC in the sample was 0.62 (95% CI: 0.58-0.67). The relatively low discrimination may result from undiagnosed AF in the sample. In particular, 1,177 patients had at least 1 AI-ECG screen for AF pre-transplant above .10, a value slightly higher than the published threshold of 0.08. The incidence of POAF in the 1104 patients without an elevated prediction pre-transplant was lower (3.7% vs. 8.0%; p<0.001). While this supported the hypothesis that potentially undiagnosed AF may have contributed to the diagnosis of POAF, the utility of the existing AI-ECG screening algorithm remained modest. When the prediction for POAF was made using the first postoperative ECG in the sample without an elevated screen pre-transplant (n=1084 on account of n=20 missing postoperative ECG), the AUROC was 0.66 (95% CI: 0.57-0.75). While this discrimination is relatively low, at a threshold of 0.08, the AI-ECG algorithm had a 98% (95% CI: 97 – 99%) negative predictive value at a sensitivity of 66% (95% CI: 49-80%). Conclusions: This study's principal finding is that the incidence of POAF is rare, and a considerable fraction of the POAF cases may be latent and undiagnosed. The high negative predictive value of AI-ECG screening suggests utility for prioritizing monitoring and evaluation on transplant patients with a positive AI-ECG screening. Further development and refinement of a post-transplant-specific algorithm may be warranted further to enhance the diagnostic yield of the ECG-based screening.

Keywords: artificial intelligence, atrial fibrillation, cardiology, transplant, medicine, ECG, machine learning

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Authors: B. Prashantha, S. Anish

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The aim of the present study is to computationally evaluate the hemodynamic factors which affect the formation of atherosclerosis and plaque rupture in the human artery. An increase of atherosclerosis disease in the artery causes geometry changes, which results in hemodynamic changes such as flow separation, reattachment, and adhesion of new cells (chemotactic) in the artery. Hence, geometry plays an important role in the determining the nature of hemodynamic patterns. Influence of stenosis in the non-bifurcating artery, under pulsatile flow condition, has been studied on an idealized geometry. Analysis of flow through symmetric and asymmetric stenosis in the artery revealed the significance of oscillating shear index (OSI), flow separation, low WSS zones and secondary flow patterns on plaque formation. The observed characteristic of flow in the post-stenotic region highlight the importance of plaque eccentricity on the formation of secondary stenosis on the arterial wall.

Keywords: atherosclerotic plaque, oscillatory shear index, stenosis nature, wall shear stress

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Authors: Sara Javanmardi, Sepehr Aziziz, Baharak Divband, Masoumeh Firouzamandi

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Post-operative adhesions are the most common cause of intestinal obstruction, female infertility and chronic abdominal pain. We developed a novel approach for preventing post-operative peritoneal adhesions using a biodegradable and thermosensitive curcumin hydrogel in rats. Thirteen male Sprague-Dawley rats were assigned randomly into five groups of six animals each: In SHAM group, the cecum was exteriorized, gently manipulated and sent back into the abdomen. In CONTROL group, the surgical abrasion was performed with no further treatment. In Hydrogel group, surgical abrasion was performed with local application of blank hydrogel (1 mL). In Curcumin group, surgical abrasion was performed with local application of curcumin (1 mL). In CUR/HGEL group, surgical abrasion was performed with local application of curcumin hydrogel (1 mL). On day 10, adhesions were assessed using a standardized scale (Evans model), and samples were collected for the Real-time PCR. Real-time PCR was performed to determine mRNA levels of VCAM-1, ICAM-1 and GAPDH. The macroscopic adhesion intensity showed statistically significant differences between the CUR/HGEL and other groups (P=0.0005). The findings of the present study revealed there were statistically significant differences between the groups regarding adhesion band length and numbers (P<0.0001). The protein and mRNA expression of VCAM-1 and ICAM-1 in secal tissues were significantly down regulated due to curcumin-hydrogel application in CUR/HGEL compared to other groups (p<0.05). The thermosensitive hydrogel could reduce the severity and even prevent formation of intra-abdominal adhesion. Curcumin hydrogel could serve as a potential barrier agent to prevent post-operative peritoneal adhesion in rats.

Keywords: peritoneal adhesion, hydrogel, curcumijn, ICAM-1, VCAM-1

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Authors: Aminu Mohammed, Shahidul Islam

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Aframomum melegueta K.Schum commonly known as Grains of Paradise has been a popularly used spice in most of the African food preparation. Available data have shown that ethyl acetate fraction from crude ethanolic extract exhibited α-amylase and α-glucosidase inhibitory actions, improved pancreatic β-cell damage and ameliorated insulin resistance in diabetic rats. Additionally, 6-gingerol, 6-shogaol, 6-paradol and oleanolic acid are shown to be the compounds responsible for the antidiabetic action of A. melegueta. However, detail antioxidant potential of this spice in a diabetic animal model has not yet been reported. Thus, the present study investigates the effect of oral consumption of A. melegueta fruit on the in vivo antioxidant status of type 2 diabetes (T2D) model of rats. T2D was induced in rats by feeding a 10% fructose solution ad libitum for two weeks followed by a single intraperitoneal injection of streptozotocin (40 mg/kg body weight (bw)). The animals were orally administered with 150 (DAML) or 300 mg/kg bw (DAMH) of the fraction once daily for four weeks. Data were analyzed by using a statistical software package (SPSS for Windows, version 22, IBM Corporation, NY, USA) using Tukey’s-HSD multiple range post-hoc test. Values were considered significantly different at p < 0.05. According to the data, after four weeks of intervention, diabetic untreated animals showed significantly (p < 0.05) elevation of blood glucose levels. The levels of thiobarbituric acid reactive substances (TBARS) were observed to increase with concomitant reduction of reduced glutathione (GSH) levels in the serum and organs (liver, kidney, heart and pancreas) of diabetic untreated animals. The activities of endogenous antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, and reductase) were greatly reduced in the serum and organs of diabetic untreated animals compared to the normal animals. These alterations were reverted to near-normal after the treatment of A. melegueta fruit in the treated groups (DAML & DAMH) within the study period, especially at the dose of 300 mg/kg bw. This potent antioxidant action may partly be attributed to the presence of the 6-Gingerol, 6-shogaol and 6-paradol are known to possess antioxidant action. The results of our study showed that A. melegueta intake improved the antioxidant status of T2D rats and therefore could be used to ameliorate the diabetes-induced oxidative damage.

Keywords: Aframomum melegueta, antioxidant, ethyl acetate extract, type 2 diabetes

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Authors: Antonis Elia, Theo Loizou, Gladys Onambele-Pearson, Matthew Barlow, Georgina Stebbings

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Hypoxic conditions have been reported to enhance red blood cell production in both acclimatised low-landers and altitude adapted populations. This process is mediated by the erythropoietin hormone, which is released predominantly by the hypoxic kidney. A higher haemoglobin concentration was previously reported in elite breath-hold divers when compared to elite-skiers and untrained individuals. Therefore, the present study aimed to investigate whether apnoea induced hypoxia could induce a significant increase in serum erythropoietin concentration in recreational breath-hold divers which would provide an explanation to the higher haemoglobin levels observed in elite breath-hold divers. Identifying whether apnoea induced hypoxia induces a significant increase in serum erythropoietin might suggest that apnoea can be used as an alternative acclimatisation method to high altitude exposure. Seven healthy, recreational male breath-hold divers performed two sets of five 180 second breath-holds with a ten-minute supine rest between each set and a two-minute seated rest between each apnoea. During each breath-hold, participant’s heart rate and peripheral oxygen saturation levels were recorded every subsequent 10 seconds until the end of the 180 second breath-hold. After each 180 second breath-hold a capillary blood sample was collected from the finger to identify circulating haemoglobin levels. Following completion of the apnoeic protocol, three blood samples were collected at 30, 90 and 180 minutes to measure circulating erythropoietin levels. A significant interaction between erythropoietin and time was observed (F(3,18)= 4.72, p < 0.001), with significant increases in erythropoietin evident at 30 (t(6)= -5.035, p < 0.0590 (t(6)= -6.162, p < 0.05) and 180 (t(6)= - 7.232, p < 0.001) minutes post the last apnoea when compared to baseline. Corresponding average increases when compared to baseline were 16% at 30, 23% at 90 and 40% at 180 minutes post the last apnoea. A significant interaction between haemoglobin and time was observed (F(78,84)= 20.814, p < 0.001), with significant increases in haemoglobin evident at the fifth (t(29)= -1.124, p < 0.001), ninth (t(29)= -1.357, p < 0.001) and tenth (t(29)= -1.211, p < 0.05) apnoeas when compared to baseline. A significant interaction between peripheral oxygen saturation and time was observed (F(10,60)= 408.23, p < 0.001). The present study demonstrates that a series of ten 180 second breath-holds is sufficient to induce a significant increase in the circulating erythropoietin concentration of recreational breath hold divers. These observations may suggest that apnoea induced hypoxia may be used as an alternative acclimatisation method to high altitude exposure.

Keywords: apnoea, breath-holding, diving reflex, erythropoietin, haemoglobin

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Authors: Mary Ghobrial, Sahar Wefky

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Marine macroalgae have proven to be rich source of bioactive compounds with biomedical potential, not only for human but also for veterinary medicine. Emergence of microbial disease in aquaculture industries implies serious loses. Usage of commercial antibiotics for fish disease treatment produces undesirable side effects. Marine organisms are a rich source of structurally novel biologically active metabolites. Competition for space and nutrients led to the evolution of antimicrobial defense strategies in the aquatic environment. The interest in marine organisms as a potential and promising source of pharmaceutical agents has increased in the last years. Many bioactive and pharmacologically active substances have been isolated from microalgae. Compounds with antibacterial, antifungal and antiviral activities have been also detected in green, brown and red algae. Selected species of marine benthic algae belonging to the Phaeophyta and Rhodophyta, collected from different coastal areas of Alexandria (Egypt), were investigated for their antibacterial and antifungal, activities. Macroalgae samples were collected during low tide from the Alexandria Mediterranean coast. Samples were air dried under shade at room temperature. The dry algae were ground, using electric mixer grinder. They were soaked in 10 ml of each of the solvents acetone, ethanol, methanol and hexane. Antimicrobial activity was evaluated using well-cut diffusion technique In vitro screening of organic solvent extracts from the marine macroalgae Laurencia pinnatifida, Pterocladia capillaceae, Stepopodium zonale, Halopteris scoparia and Sargassum hystrix, showed specific activity in inhibiting the growth of five virulent strains of bacteria pathogenic to fish Pseudomonas fluorescens, Aeromonas hydrophila, Vibrio anguillarum, V. tandara, Escherichia coli and two fungi Aspergillus flavus and A. niger. Results showed that, acetone and ethanol extracts of all test macroalgae exhibited antibacterial activity, while acetone extract of the brown Sargassum hystrix displayed the highest antifungal activity. The extracts of seaweeds inhibited bacteria more strongly than fungi and species of the Rhodophyta showed the greatest activity against the bacteria rather than fungi tested. The gas liquid chromatography coupled with mass spectrometry detection technique allows good qualitative and quantitative analysis of the fractionated extracts with high sensitivity to the smaller amounts of components. Results indicated that, the main common component in the acetone extracts of L. pinnatifida and P. capillacea is 4-hydroxy-4-methyl2-pentanone representing 64.38 and 58.60%. Thus, the extracts derived from the red macroalgae were more efficient than those obtained from the brown macroalgae in combating bacterial pathogens rather than pathogenic fungi. The most preferred species over all was the red Laurencia pinnatifida. In conclusion, the present study provides the potential of red and brown macroalgae extracts for development of anti-pathogenic agents for use in fish aquaculture.

Keywords: bacteria, fungi, extracts, solvents

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Authors: Ezra N. S. Lockhart

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The number of children diagnosed with autism spectrum disorder (ASD) has increased approximately 173% during the last decade making ASD the fastest growing developmental disability in the United States. This rise in prevalence rates indeed has an effect on schools. ASD is overwhelmingly the most reported primary special education eligibility category for students accessing special education, at a national average of 61.3%. ASD is regarded as an urgent public health concern at an estimated annual per capita cost of $3.2 million. Furthermore, considering that ASD is a lifelong disorder estimated lifetime per capita cost reach $35 billion. The resources available to special education programs are insufficient to meet the educational needs of the 6.4 million students receiving special educational services. This is especially true given that there has been and continues to be a chronic shortage of fully certified special education teachers for decades. Reports indicate that 81.1% of students with special needs spend 40% or more in general education classrooms. Regardless of whether support is implemented in the special education or general education classroom the resource demand is obvious. Schools are actively seeking to implement low-cost alternatives and budget saving measures in response to this demand. In public school settings, programs such as Applied Behavior Analysis are challenging to implement and fund at $40,000 per student per year. As an alternative, computer-based interventions are inexpensive, less time-consuming to implement, and require minimal teacher or paraprofessional training to administer. Affordability, pricing schemes, availability, and compatibility of computer-based interventions that support social and emotional skill development in individuals with ASD are discussed.

Keywords: affordability, autism spectrum disorder, computer-based intervention, emotional skills, social skills

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Authors: Syue-Wen Lin

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Objective:This article reviews the care experience of a 40-year-old male patient who underwent a thoracoscopic right lower lobectomy following a COVID-19 infection. His complex medical history included multiple metastases (lungs, liver, spleen, and left kidney) and lung damage from COVID-19, which complicated the weaning process from mechanical ventilation. The care involved managing cancer treatment, postoperative pain, wound care, and palliative care. Methods:Nursing care was provided from August 16 to August 17, 2024. Challenges included difficulty with sputum clearance, which exacerbated the patient's anxiety and fear of reintubation. Pain management strategies combined analgesic drugs, non-drug methods, essential oil massages with family members, and playing the patient’s favorite music to reduce pain and anxiety. Progressive rehabilitation began with stabilizing vital signs, followed by assistance with sitting on the edge of the bed and walking within the ward. Strict sterile procedures and advanced wound care technology were used for daily dressing changes, with meticulous documentation of wound conditions and appropriate dressing selection. Holistic cancer care and palliative measures were integrated to address the patient’s physical and psychological needs. Results:The interdisciplinary care team developed a comprehensive plan addressing both physical and psychological aspects. Respiratory therapy, lung expansion exercises, and a high-frequency chest wall oscillation vest facilitated sputum expulsion and assisted in weaning from mechanical ventilation. The integration of cancer care, pain management, wound care, and palliative care led to improved quality of life and recovery. The collaborative approach between nursing staff and family ensured that the patient received compassionate and effective care. Conclusion: The complex interplay of emergency surgery, COVID-19, and advanced cancer required a multifaceted care strategy. The care team’s approach, combining critical care with tailored cancer and palliative care, effectively improved the patient’s quality of life and facilitated recovery. The comprehensive care plan, developed with family collaboration, provided both high-quality medical care and compassionate support for the terminally ill patient.

Keywords: multiple metastases, testicular cancer, palliative care, nursing experience

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Authors: Mary Allagoa, Abir Al-Tabbaa

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The study explores the use of binders and additives, such as Portland cement, pulverized fuel ash, ground granulated blast furnace slag, and MgO, to decrease the concentration and leachability of pollutants in contaminated site soils. The research investigates their effectiveness and associated risks of using the binders, with a focus on Total Heavy metals (THM) and Total Petroleum Hydrocarbon (TPH). The goal of this research is to evaluate the performance and effectiveness of binders and additives in remediating soil pollutants. The study aims to assess the suitability of the mixtures for ground improvement purposes, determine the optimal dosage, and investigate the associated risks. The research utilizes physical (unconfined compressive strength) and chemical tests (batch leachability test) to assess the efficacy of the binders and additives. A completely randomized design one-way ANOVA is used to determine the significance within mix binders of THM. The study also employs incremental lifetime cancer risk assessments (ILCR) and other indexes to evaluate the associated risks. The study finds that Ground Granulated Blast Furnace Slag (GGBS): MgO is the most effective binder for remediation, particularly when using low dosages of MgO combined with higher dosages of GGBS binders on TPH. The results indicate that binders and additives can encapsulate and immobilize pollutants, thereby reducing their leachability and toxicity. The mean unconfined compressive strength of the soil ranges from 285.0- 320.5 kPa, while THM levels are less than 10 µg/l in GGBS: MgO and CEM: PFA but below 1 µg/l in CEM I based. The ILCR ranged from 6.77E-02 - 2.65E-01 and 5.444E-01 – 3.20 E+00, with the highest values observed under extreme conditions. The hazard index (HI), Risk allowable daily dose intake (ADI), and Risk chronic daily intake (CDI) were all less than 1 for the THM. The study identifies MgO as the best additive for use in soil remediation.

Keywords: risk ADI, risk CDI, ILCR, novel binders, additives binders, hazard index

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Authors: Vasishtha Avadhani Upadrasta, Mradul Kumar Daga, Smita Kaushik

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Background: Caffeine consumption has skyrocketed in the recent decades as we try to match pace with the machines. Studies have been conducted on animals and a few on humans, mainly on the acute effects of high-dose caffeine intake. Almost none have been conducted on the chronic effects of caffeine consumption. This study involved Medical professionals as case subjects, who consumed caffeine daily. Methods: This study, over a period of 3 months, involved 96 volunteers (chosen randomly w.r.t. gender and field in medical fraternity), including people who drank >500mg of caffeine a day to people who consumed none. People with any co-morbidities at all were excluded straight away. Two sets of blood samples were drawn and assessed. Three groups were created, Group 1 (>200mg caffeine/day) and Group 2 (15-200 mg caffeine/day) and Group 3 (<200mg Caffeine/day). Results: The result of the study found that exposure to caffeine at doses >200mg/day for more than 6 months leads to a significant difference in circulating free T3 [(-0.96 pmol/L ± 0.07) = (-18.5%), CI 95%, p = .000024] and Cortisol [(-123 nmol/L ± 9.8) = (-46.8%), CI 95%, p = .00029] hormones but shows an insignificant effect on circulating TSH [0.4 mIU/L, CI 95%, p=.37] and ACTH [(-3.2 pg/ml ± 0.3), CI 95%, p = .53) hormones, which stay within normal physiological ranges, irrespective of the daily dose of consumption. Results also highlight that women are more susceptible to decrement in fT3 than men (Relative Risk =1.58, ANOVA F-static = 7.15, p = 0.0105). Conclusions: Caffeine consumption in excess of 200mg/day, for more than or equal to 6 months, causes significant derangement in basal fT3 and Cortisol hormone levels, without affecting the TSH and ACTH (regulatory) hormone levels, indicating disturbance of action at the peripheral and/or cellular levels, possibly via the Paraventricular Nucleus –Leptin-CAR-Adenosine interactions. Women are more susceptible to decrement in fT3 levels than men (at same dose of caffeine).

Keywords: ACTH, adrenals, caffeine, cortisol, thyroid, thyroxin, TSH

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Authors: Boma Nellie S, Nambiar Ritu, K. Kanchanmala, T. Rashida, Israell Imelda, Moul Khusnud, Michael Marina

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Gestational diabetes (GDM) imparts an increased life long risk of developing Type 2 Diabetes Mellitus (T2DM) and cardiovascular disease in women. Once diagnosed with GDM women have up to 74% increased cumulative risk developing T2DM in 10-15 years. Identifying women at increased risk of developing T2DM and offering them pharmacological and lifestyle management interventions will delay or eliminate the development of diabetes in this population. While ADA recommends that all gestational diabetics be offered postnatal screening, worldwide the screening rates from 35-75% and Al Rahba Hospital with a robust universal antenatal screening program for GDM was at a dismal 9% in 2011. A multidisciplinary team was put together involving OB/Gyn Physicians, Midwives, Nurses (ward and OPD) Diabetic Educators, Dietitians, Medical Records, Laboratory & IT with the implementation of multiple strategies to increase the uptake of postpartum screening of the gestational diabetic.

Keywords: GDM, postnatal screening, preventing type 2 diabetes, lifestyle management

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Authors: Douglas Arthur, Oluwayemisi Ekor, Ernest Obese, Andrew Kissi Agyei, Elvis Ofori Ameyaw

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bjective: Pain negatively impacts every aspect of health, and patients with pain disorders create enormous demands on healthcare systems globally, costing economies up to $635 billion annually. The study was therefore conducted at the Cape Coast Teaching Hospital (CCTH), the only Tertiary Hospital in the Central Region of Ghana and was designed to assess pain disorders in patients between 18 and 90 years attending Urology Clinic. Methods: The study employed a descriptive cross-sectional design, and 149 subjects (16-24, 25-34, 35-44, 45-54, 55-64, 65-90 years) were conveniently selected. The McGill Pain Questionnaire (MPQ), a multidimensional instrument that assesses several aspects of pain by the use of words (descriptors) that the patient chooses to express his/her pain, was used as the primary instrument for data collection. A patient profile form (PPF) was also designed to document the demographics and history of patients. Results: The prevalence of pain disorders was higher among females compared to males. The univariate and multivariate analysis showed that females were more likely to experience pain while being married correlated with a lower likelihood of pain. Again, the 45-54 age group exhibited the highest prevalence of pain disorders. Results from the MPQ showed that half of the patients experienced pain on a daily basis, 15.91% had experienced pain for 3-6 months and 37% experienced pain for more than one year. Pain intensity was described by 25% of the subjects as excruciating for their worst pain experience, followed by 21% for the distressing experience. The most frequently reported area of pain was the abdominal region (22.72%). The co-administration of NSAIDs and opioid compounds was provided for 17.46% of the patients with chronic pain. Conclusion: The treatment interventions improved the pain and associated symptoms such as nausea, improved daily activities and ability to sleep. However, attention and resources should be devoted to 45-54 age group.

Keywords: pain, opioids, distressing, excruciating

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Authors: Cynthia Sau Chun Yip, Richard Fielding

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High meat and especially red meat intakes are significantly and positively associated with a multiple burden of diseases and also high greenhouse gas (GHG) emissions. This study investigated population meat intake patterns in Hong Kong. It quantified the burden of disease and GHG emission outcomes by modeling to adjust Hong Kong population meat intakes to recommended healthy levels. It compared age- and sex-specific population meat, fruit and vegetable intakes obtained from a population survey among adults aged 20 years and over in Hong Kong in 2005-2007, against intake recommendations suggested in the Modelling System to Inform the Revision of the Australian Guide to Healthy Eating (AGHE-2011-MS) technical document. This study found that meat and meat alternatives, especially red meat intakes among Hong Kong males aged 20+ years and over are significantly higher than recommended. Red meat intakes among females aged 50-69 years and other meat and alternatives intakes among aged 20-59 years are also higher than recommended. Taking the 2005-07 age- and sex-specific population meat intake as baselines, three counterfactual scenarios of adjusting Hong Kong adult population meat intakes to AGHE-2011-MS and Pre-2011 AGHE recommendations by the year 2030 were established. Consequent energy intake gaps were substituted with additional legume, fruit and vegetable intakes. To quantify the consequent GHG emission outcomes associated with Hong Kong meat intakes, Cradle-to-ready-to-eat lifecycle assessment emission outcome modelling was used. Comparative risk assessment of burden of disease model was used to quantify the health outcomes. This study found adjusting meat intakes to recommended levels could reduce Hong Kong GHG emission by 17%-44% when compared against baseline meat intake emissions, and prevent 2,519 to 7,012 premature deaths in males and 53 to 1,342 in females, as well as multiple burden of diseases when compared to the baseline meat intake scenario. Comparing lump sum meat intake reduction and outcome measures across the entire population, and using emission factors, and relative risks from individual studies in previous co-benefit studies, this study used age- and sex-specific input and output measures, emission factors and relative risks obtained from high quality meta-analysis and meta-review respectively, and has taken government dietary recommendations into account. Hence evaluations in this study are of better quality and more reflective of real life practices. Further to previous co-benefit studies, this study pinpointed age- and sex-specific population and meat-type-specific intervention points and leverages. When compared with similar studies in Australia, this study also showed that intervention points and leverages among populations in different geographic and cultural background could be different, and that globalization also globalizes meat consumption emission effects. More regional and cultural specific evaluations are recommended to promote more sustainable meat consumption and enhance global food security.

Keywords: burden of diseases, greenhouse gas emissions, Hong Kong diet, sustainable meat consumption

Procedia PDF Downloads 307

Authors: B. Dejanova, S. Petrovska, L. Todorovska, J. Pluncevic, S. Mancevska, V. Antevska, E. Sivevska, I. Karagjozova

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Introduction: Aging process is mainly related to endothelial function which may be impaired by oxidative stress (OS). Exercise is known to be beneficial to aging process, which may improve health and prevent appearance of chronic diseases in elderly. The aim of the study was to investigate the OS markers related to exercise. Methods: A number of 80 subjects (healthy volunteers) were examined (38 male and 32 female), divided in 3 age groups: group I ≤ 30 years (n=24); group II – 31-50 years (n=24); group III - ≥ 51 year (n=32). Each group was divided to subgroups of sedentary subjects (SS) and subjects who exercise (SE). Group I: SS (n=11), SE (n=13); group II: SS (n=13), SE (n=10); group III: SS (n=23) SE (n=9). Lipid peroxidation (LP) as a fluorimetric method with thiobarbituric acid was used to estimate OS. Antioxidative status was determined by cell antioxidants such as enzymes - superoxide dismutase (SOD), glutathione peroxidase (GPx) and glucose 6 phosphate (G-6-PD); and by extra cell antioxidants such as glutathione reductase (GR), nitric oxide (NO) and total antioxidant capacity (TAC). Results: Increased values of LP were noticed along the aging process: group I – 3.30±0.3 µmol/L; group II – 3.91±0.2 µmol/L; group III – 3.94±0.8 µmol/L (p<0.05), while no statistical significance was found between male and female subjects. Statistical significance for OS was not found between SS and SE in group I as it was found in group II (p<0.05) and in group III (p<0.01). No statistical significance was found for all cell antioxidants and GR within the groups, while NO and TAC showed lower values in SS compared to SE in II (p<0.05) and in group III (p<0.05). Discussion and conclusion: Aging process showed increased OS which may be either due to impaired function of scavengers of free radicals or due to their enormous production. Well balanced exercise might be one of the factors that keep the integrity of blood vessel endothelium which slows down the aging process. Possible mechanism of exercise beneficial influence is shear stress by upregulation of genes coding for nitric oxide bioavailability. Thus, due to obtained results we may conclude that OS is found to be diminished in the subject groups who perform exercise.

Keywords: oxidative stress, aging process, exercise, endothelial function

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Authors: Ibrahim M. Labouta, Gina N. Tageldin, Salwa M. Fahmy, Hayam M. Ashour, Mounir A. Khalil, Tamer M. Ibrahim, Nefertiti A. El-Nikhely

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Bruton’s tyrosine kinase (BTK) is a critical effector molecule in B cell antigen receptor (BCR) signaling transduction. It regulates B cell proliferation, development and survival. Since BTK is widely expressed in many B cell leukaemias and lymphomas, targeting BTK by small molecules inhibitors became an attractive idea as new treatment modalities for B cell mediated hematologic malignancies. Ibrutinib is the 1st generation BTK inhibitor, approved by FDA for treatment of relapsed mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). It binds irreversibly to the unique cysteine (Cys481) within the ATP-binding pocket of BTK. Besides ibrutinib, many irreversible covalent BTK inhibitors comprising pyrimidine nucleus such as spebrutinib (phase IIb) showed high selectivity and potency when compared to it. In this study, the designed compounds were based on 5-cyano-2-methylsulfanyl pyrimidine core and decorated with electrophilic warheads which are essential for the optimal activity for targeted covalent inhibition (TCI). However, modifications at pyrimidine C4 or C6 were made by introduction of substituted amines which are provided to behave differently. The synthesized derivatives were evaluated for their anticancer activity in leukemia cell lines (e.g. THP-1). Results showed that, some derivatives exhibited antiproliferative activity with IC50 ranged from 5-50 μM, The in vitro enzymatic inhibitory assay for these compounds against BTK is still under investigation. Nevertheless, we could conclude from the initial biological screening that, the synthesized 4 or 6-subsitituted aminopyrimidines represent promising and novel antileukemic agents. Meanwhile, further studies are still needed to attribute this activity through targeting BTK enzyme and inhibition of BCR signaling pathway.

Keywords: BTK inhibitors, hematologic malignancies, structure based drug design (SBDD), targeted covalent inhibitors (TCI)

Procedia PDF Downloads 144