Integrated strategy for the assessment of kidney toxicity: the case of aristolochic acids

This PhD thesis aimed to provide additional evidence to demonstrate the potential of an integrated testing strategy using in vitro assays with physiologically based kinetic (PBK) modeling based-reverse dosimetry to predict in vivo toxicity without animal testing. Kidney toxicity was chosen as the toxicity endpoint and aristolochic acids (AAs) were selected as model chemicals. AAs are natural nephrotoxic, genotoxic and carcinogenic chemicals present in Aristolochia species. PBK models for rat, mouse and human were developed for aristolochic acid I (AAI) based on kinetic parameter values derived from in vitro incubations using relevant tissue fractions. Then, in vitro concentration-response curves for cytotoxicity of AAI were obtained in kidney cell lines and translated to in vivo dose-response curves for kidney toxicity using PBK modeling-based reverse dosimetry. The points of departure (PODs) obtained from these predicted in vivo dose-response curves generally fell within the range of PODs derived from in vivo literature data on kidney toxicity of AAI. The same PBK models were subsequently used to translate the in vitro concentration-response curves for AAI-DNA adduct formation to in vivo dose-response curves for kidney AAI-DNA adduct formation. The predicted in vivo AAI-DNA adduct formation in the rat, mouse and human kidney varied within an order of magnitude compared to the in vivo values reported in the literature. The PBK models were also used to predict the dose level that would be required in humans to obtain the level of DNA adducts in rats at the BMD10 (the benchmark dose causing a 10% extra risk above background level) value for AAI-induced tumor formation in the rat kidney. This analysis revealed that the dose level required to induce the level of DNA adduct formation that equals the DNA adduct level at the BMD10 were similar to AA doses estimated to be taken in Belgian patients that developed urinary tract cancer. Given that the exposure to AAI is often accompanied by the presence of AAII, in a next study the relative formation of DNA adducts by these two major AA congeners was investigated. The results revealed that the relative higher formation of AAI-DNA adducts as compared to AAII-DNA adducts observed in vitro was not reflected in vivo where the levels formed upon exposure to equal dose levels were relatively similar. PBK model based translation of the in vitro data to the in vivo situation revealed that PBK model based prediction of in vivo DNA adduct formation is feasible. However, predicted AAI-DNA adduct levels were higher than predicted AAII-DNA adduct levels, indicating that the difference between the in vitro and in vivo AAI-/AAII-DNA adduct ratios could only in part be explained by differences in in vivo kinetics of AAI compared to AAII. The discrepancy between the difference in DNA adduct formation of AAI and AAII in the in vitro and the in vivo situation is an issue that needs further investigation to also adequately predict the relative differences between the two AAs. In a final chapter this thesis aimed to investigate the possible risks associated with exposure to AAs based on AA levels measured in plant food supplements (PFS) and herbal products. This is of interest given the restrictions on the presence of AAs in food, installed in various countries including The Netherlands, after the incidences with induction of Aristolochic Acid Nephropathy upon use of herbal weight loss preparations that accidentally contained AAs. The risk assessment of PFS and herbal products containing AAs purchased via online markets revealed that consumers can still be exposed to AA-containing PFS and herbal products and that the corresponding levels of exposure raise concern especially for people who frequently use the products. Altogether, this thesis presented further support for the use of combined in vitro-PBK modeling based alternative tools for risk assessment and revealed the continued risks posed by AAs present in PFS and herbal products

Median codeword Shift (MCS) technique for PAPR reduction with low complexity in OFDM system

With the rapid development of today’s communication technology, the need for a system capable to improve spectral efficiency, high data rates and at the same time can reduce inter-symbol interference (ISI) is necessary. Orthogonal Frequency Division Multiplexing (OFDM) meet all the requirements needed. However, the high peak to average power ratio (PAPR) has become its major obstacle. This paper is focusing on the development of Median Codeword Shift (MCS), which a new PAPR reduction technique with the capability to reduce the computational complexity of the system. This can be achieved through codeword structure alterization and bit position manipulation by utilizing the circulant shift process. The simulation results revealed that the proposed technique overwhelm conventional OFDM and SCS with 24% improvement and 0.5 dB gap from SCS. In fact, the proposed technique possess a lower computational complexity by reducing 16.67% of the use of IFFT block in the system in contrast with SCS technique

A Stock Market Trading System Using Deep Neural Network

The stock market prediction is a lucrativefield of interest withpromising profit and covered with landmines for the unprecedented. The mar-kets are complex, non-linear and chaotic in nature which poses huge difficultiesto predict the prices accurately. In this paper, a stock trading system utilizingfeed-forward deep neural network (DNN) to forecast index price of Singaporestock market using the FTSE Straits Time Index (STI) in t days ahead is pro-posed and tested through market simulations on historical daily prices. There are40 input nodes of DNN which are the past 10 days’opening, closing, minimumand maximum prices and consist of 3 hidden layers with 10 neurons per layer.The training algorithm used is stochastic gradient descent with back-propagationand is accelerated with multi-core processing. A trading system is proposedwhich utilizes the DNN forecasting results with defined entry and exit rules toenter a trade. DNN performance is evaluated using RMSE and MAPE. Theoverall trading system shows promising results with a profit factor of 18.67,70.83% profitable trades and Sharpe ratio of 5.34 based on market simulation ontest data

PAPR reduction in OFDM system using combined MCS and DHMT precoding

Orthogonal Frequency Division Multiplexing (OFDM) has become a preferable scheme for most high data rate wireless communication standards. However, the non-linear power amplifier effect experienced in the OFDM system has increases the peak-to-average power ratio (PAPR). This paper proposed a Median Codeword Shift (MCS) as a new solution to alleviate the effect of high PAPR. MCS takes advantage of the codeword structure and bit position changes through the manipulation of the codeword structure and permutation process to achieve a low PAPR value. Additionally, the enhanced version of MCS is also being proposed by merging MCS with the Discrete Hartley matrix transform (DHMT) precoding method to boost the PAPR reduction. Simulation results show that MCS is capable of minimizing PAPR of conventional OFDM with 24% improvement and at the same time outperform Selective Codeword Shift (SCS) with a 0.5 dB gap. A remarkable result was also achieved by MCS-DHMT with a 15.1% improvement without facing any bit error rate (BER) degradation

Gelam (Melaleuca spp.) Honey-Based Hydrogel as Burn Wound Dressing

A novel cross-linked honey hydrogel dressing was developed by incorporating Malaysian honey into hydrogel dressing formulation, cross-linked and sterilized using electron beam irradiation (25 kGy). In this study, the physical properties of the prepared honey hydrogel and its wound healing efficacy on deep partial thickness burn wounds in rats were assessed. Skin samples were taken at 7, 14, 21, and 28 days after burn for histopathological and molecular evaluations. Application of honey hydrogel dressings significantly enhanced (P < 0.05) wound closure and accelerated the rate of re-epithelialization as compared to control hydrogel and OpSite film dressing. A significant decrease in inflammatory response was observed in honey hydrogel treated wounds as early as 7 days after burn (P < 0.05). Semiquantitative analysis using RT-PCR revealed that treatment with honey hydrogel significantly (P < 0.05) suppressed the expression of proinflammatory cytokines (IL-1α, IL-1β, and IL-6). The present study substantiates the potential efficacy of honey hydrogel dressings in accelerating burn wound healing

The effect of topical application of Malaysian honey on burn wound healing

The efficacy of topical application of Malaysian honey on burn wound healing in Sprague-Dawley rats was investigated using 45 Sprague Dawley male rats weighing 200-300 g. Deep partial skin thickness burns were inflicted on the dorsal part of each animal. Two types of local honey (durian and Gelam) were applied twice a day in a quantity of 0.5 ml for each application, while control animals received no treatment. The rats were serially euthanisised at 3, 7, 14, 21 and 28 days post treatment for histological study. Histologically, early attenuation of inflammatory reaction and early reparative activities were observed in the honey treated wounds compared to control groups. Differential cells count showed a significant decreased in the number of inflammatory cells and increased vascularity in the honey treated wounds as early as 3 days post injury. In addition, epithelial regeneration appeared to be significant in gelam honey treated wound. This study showed that there was a significant acceleration of dermal repair in wound healing treated with durian and Gelam honey

Recent updates on phthalate exposure and human health: a special focus on liver toxicity and stem cell regeneration

Phthalates have been blended in various compositions as plasticizers worldwide for a variety of purposes. Consequently, humans are exposed to a wide spectrum of phthalates that needs to be researched and understood correctly. The goal of this review is to focus on phthalate's internal exposure pathways and possible role of human digestion on liver toxicity. In addition, special focus was made on stem cell therapy in reverting liver toxicity. The known entry of higher molecular weight phthalates is through ingestion while inhalation and dermal pathways are for lower molecular weight phthalates. In human body, certain phthalates are digested through phase 1 (hydrolysis, oxidation) and phase 2 (conjugation) metabolic processes. The phthalates that are made bioavailable through digestion enter the blood stream and reach the liver for further detoxification, and these are excreted via urine and/or feces. Bis(2-ethylhexyl) phthalate (DEHP) is a compound well studied involving human metabolism. Liver plays a pivotal role in humans for detoxification of pollutants. Thus, continuous exposure to phthalates in humans may lead to inhibition of liver detoxifying enzymes and may result in liver dysfunction. The potential of stem cell therapy addressed herewith will revert liver dysfunction and lead to restoration of liver function properly

Healthcare professionals use Electronic Medical Records System (EMRs) in Jordan Hospitals

Many hospitals have implemented Electronic Medical Record (EMR) although its effectiveness to improve healthcare is still in quest.EMR is use for patient registering, error reduction, administrative cost savings, increased productivity, and improved patient satisfaction, yet widespread adoption has been slow However, many barriers to the successful implementation of EMR systems continue to limit the uptake, including the lack of organizations culture, lack of incentives to the users and lack of vender support.Currently exists in terms of where users are and where they need to be in order to implement an EMR system.The promise of electronic medical records is great, but much careful planning is needed before the benefits can be reaped.This paper addresses post-implementation usage behavior of Electronic Medic Records system among healthcare professional in healthcare organization by applying the Technology Acceptance Model (TAM).EMR- TAM instrument was developed for this research and assessed with principal component analysis.The hypotheses were developed and tested using hierarchical multiple regressions

Overcoming challenges to use electronic medical records system (EMRs) in Jordan hospitals

Electronic Medical Record (EMR) is the electronic middleman which allows users to access and retrieve patients’ data, to review patients’ medical history, and to facilitate the activation between patients and medical users.Considered as a developing country, Jordan still suffers from modernized management information systems that organize store, retrieve, and facilitate medical data.The objective of this paper is to investigate some of the factors that affect the use of electronic medical record systems in Jordan. Focusing on those affective barriers, it is expected that this paper will provide a deeper insight into the EMR implementation problems in Jordan, and consequently providing well-informed inferences for decision makers to take into considerations for yielding better EMR implementation.This paper discusses the factors which are recognized to be the challenges in the implementations of EMR in hospitals.The paper also describes advantages and history of EMR.. This paper will also describe the Method (the sample) to test of the Hypotheses and final results

Assessing the risk of estragole consumption from natural products in the Malaysian market by using the margin of exposure approach

Introduction: Estragole is a naturally-occurring phytochemical found in variety of herbs, and spices, commonly used as food ingredients and in various natural products too. Despite some studies suggesting that estragole has health benefits, animal studies have shown that estragole is a hepatotoxic and genotoxic carcinogen, mainly due to the formation of its metabolites, specifically 1-hydroxyestragole. Objective: This study aims to perform health risk assessment of estragole in natural products from Malaysia by using the margin of exposure (MOE) approach. Methods: 30 samples of natural product were obtained from Malaysian market using targeted sampling strategy. All of the samples were extracted using methanol extraction and analyzed using Ultra Performance Liquid Chromatography (UPLC). The estimated daily intake (EDI) was calculated by using the quantified estragole concentrations and the recommended daily intake as stated on the product label. To assess the risk associated with estragole, the MOE approach was employed. Results: 9 out of 30 samples were found to contain estragole with levels ranging from 55.03 to 418.02 ¼g/g. The EDI values of estragole in these samples ranged from 0.99 - 9.44 ¼g/kg bw/day. Using the MOE approach, all positive samples were found to have MOE values less than 10,000 for long-term consumption, indicating high priority for risk management. However, for shorter-than-lifetime scenarios, the MOE values were above 10,000, indicating low priority for risk management. Conclusion: The presence of estragole in Malaysian natural products may raise health concern, especially when it is consumed daily over extended period