Search results for: drug resistance
Commenced in January 2007
Frequency: Monthly
Edition: International
Paper Count: 4838

Search results for: drug resistance

368 Tip60 Histone Acetyltransferase Activators as Neuroepigenetic Therapeutic Modulators for Alzheimer’s Disease

Authors: Akanksha Bhatnagar, Sandhya Kortegare, Felice Elefant

Abstract:

Context: Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by progressive cognitive decline and memory loss. The cause of AD is not fully understood, but it is thought to be caused by a combination of genetic, environmental, and lifestyle factors. One of the hallmarks of AD is the loss of neurons in the hippocampus, a brain region that is important for memory and learning. This loss of neurons is thought to be caused by a decrease in histone acetylation, which is a process that regulates gene expression. Research Aim: The research aim of the study was to develop mall molecule compounds that can enhance the activity of Tip60, a histone acetyltransferase that is important for memory and learning. Methodology/Analysis: The researchers used in silico structural modeling and a pharmacophore-based virtual screening approach to design and synthesize small molecule compounds strongly predicted to target and enhance Tip60’s HAT activity. The compounds were then tested in vitro and in vivo to assess their ability to enhance Tip60 activity and rescue cognitive deficits in AD models. Findings: The researchers found that several of the compounds were able to enhance Tip60 activity and rescue cognitive deficits in AD models. The compounds were also developed to cross the blood-brain barrier, which is an important factor for the development of potential AD therapeutics. Theoretical Importance: The findings of this study suggest that Tip60 HAT activators have the potential to be developed as therapeutic agents for AD. The compounds are specific to Tip60, which suggests that they may have fewer side effects than other HDAC inhibitors. Additionally, the compounds are able to cross the blood-brain barrier, which is a major hurdle for the development of AD therapeutics. Data Collection: The study collected data from a variety of sources, including in vitro assays and animal models. The in vitro assays assessed the ability of compounds to enhance Tip60 activity using histone acetyltransferase (HAT) enzyme assays and chromatin immunoprecipitation assays. Animal models were used to assess the ability of the compounds to rescue cognitive deficits in AD models using a variety of behavioral tests, including locomotor ability, sensory learning, and recognition tasks. The human clinical trials will be used to assess the safety and efficacy of the compounds in humans. Questions: The question addressed by this study was whether Tip60 HAT activators could be developed as therapeutic agents for AD. Conclusions: The findings of this study suggest that Tip60 HAT activators have the potential to be developed as therapeutic agents for AD. The compounds are specific to Tip60, which suggests that they may have fewer side effects than other HDAC inhibitors. Additionally, the compounds are able to cross the blood-brain barrier, which is a major hurdle for the development of AD therapeutics. Further research is needed to confirm the safety and efficacy of these compounds in humans.

Keywords: Alzheimer's disease, cognition, neuroepigenetics, drug discovery

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367 Atypical Intoxication Due to Fluoxetine Abuse with Symptoms of Amnesia

Authors: Ayse Gul Bilen

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Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed antidepressants that are used clinically for the treatment of anxiety disorders, obsessive-compulsive disorder (OCD), panic disorders and eating disorders. The first SSRI, fluoxetine (sold under the brand names Prozac and Sarafem among others), had an adverse effect profile better than any other available antidepressant when it was introduced because of its selectivity for serotonin receptors. They have been considered almost free of side effects and have become widely prescribed, however questions about the safety and tolerability of SSRIs have emerged with their continued use. Most SSRI side effects are dose-related and can be attributed to serotonergic effects such as nausea. Continuous use might trigger adverse effects such as hyponatremia, tremor, nausea, weight gain, sleep disturbance and sexual dysfunction. Moderate toxicity can be safely observed in the hospital for 24 hours, and mild cases can be safely discharged (if asymptomatic) from the emergency department once cleared by Psychiatry in cases of intentional overdose and after 6 to 8 hours of observation. Although fluoxetine is relatively safe in terms of overdose, it might still be cardiotoxic and inhibit platelet secretion, aggregation, and plug formation. There have been reported clinical cases of seizures, cardiac conduction abnormalities, and even fatalities associated with fluoxetine ingestions. While the medical literature strongly suggests that most fluoxetine overdoses are benign, emergency physicians need to remain cognizant that intentional, high-dose fluoxetine ingestions may induce seizures and can even be fatal due to cardiac arrhythmia. Our case is a 35-year old female patient who was sent to ER with symptoms of confusion, amnesia and loss of orientation for time and location after being found wandering in the streets unconsciously by police forces that informed 112. Upon laboratory examination, no pathological symptom was found except sinus tachycardia in the EKG and high levels of aspartate transaminase (AST) and alanine transaminase (ALT). Diffusion MRI and computed tomography (CT) of the brain all looked normal. Upon physical and sexual examination, no signs of abuse or trauma were found. Test results for narcotics, stimulants and alcohol were negative as well. There was a presence of dysrhythmia which required admission to the intensive care unit (ICU). The patient gained back her conscience after 24 hours. It was discovered from her story afterward that she had been using fluoxetine due to post-traumatic stress disorder (PTSD) for 6 months and that she had attempted suicide after taking 3 boxes of fluoxetine due to the loss of a parent. She was then transferred to the psychiatric clinic. Our study aims to highlight the need to consider toxicologic drug use, in particular, the abuse of selective serotonin reuptake inhibitors (SSRIs), which have been widely prescribed due to presumed safety and tolerability, for diagnosis of patients applying to the emergency room (ER).

Keywords: abuse, amnesia, fluoxetine, intoxication, SSRI

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366 Chemical Composition of Volatiles Emitted from Ziziphus jujuba Miller Collected during Different Growth Stages

Authors: Rose Vanessa Bandeira Reidel, Bernardo Melai, Pier Luigi Cioni, Luisa Pistelli

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Ziziphus jujuba Miller is a common species of the Ziziphus genus (Rhamnaceae family) native to the tropics and subtropics known for its edible fruits, fresh consumed or used in healthy food, as flavoring and sweetener. Many phytochemicals and biological activities are described for this species. In this work, the aroma profiles emitted in vivo by whole fresh organs (leaf, bud flower, flower, green and red fruits) were analyzed separately by mean of solid phase micro-extraction (SPME) coupled with gas chromatography mass spectrometry (GC-MS). The emitted volatiles from different plant parts were analysed using Supelco SPME device coated with polydimethylsiloxane (PDMS, 100µm). Fresh plant material was introduced separately into a glass conical flask and allowed to equilibrate for 20 min. After the equilibration time, the fibre was exposed to the headspace for 15 min at room temperature, the fibre was re-inserted into the needle and transferred to the injector of the CG and CG-MS system, where the fibre was desorbed. All the data were submitted to multivariate statistical analysis, evidencing many differences amongst the selected plant parts and their developmental stages. A total of 144 compounds were identified corresponding to 94.6-99.4% of the whole aroma profile of jujube samples. Sesquiterpene hydrocarbons were the main chemical class of compounds in leaves also present in similar percentage in flowers and bud flowers where (E, E)-α-farnesene was the main constituent in all cited plant parts. This behavior can be due to a protection mechanism against pathogens and herbivores as well as resistance to abiotic factors. The aroma of green fruits was characterized by high amount of perillene while the red fruits release a volatile blend mainly constituted by different monoterpenes. The terpenoid emission of flesh fruits has important function in the interaction with animals including attraction of seed dispersers and it is related to a good quality of fruits. This study provides for the first time the chemical composition of the volatile emission from different Ziziphus jujuba organs. The SPME analyses of the collected samples showed different patterns of emission and can contribute to understand their ecological interactions and fruit production management.

Keywords: Rhamnaceae, aroma profile, jujube organs, HS-SPME, GC-MS

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365 Plasma Arc Burner for Pulverized Coal Combustion

Authors: Gela Gelashvili, David Gelenidze, Sulkhan Nanobashvili, Irakli Nanobashvili, George Tavkhelidze, Tsiuri Sitchinava

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Development of new highly efficient plasma arc combustion system of pulverized coal is presented. As it is well-known, coal is one of the main energy carriers by means of which electric and heat energy is produced in thermal power stations. The quality of the extracted coal decreases very rapidly. Therefore, the difficulties associated with its firing and complete combustion arise and thermo-chemical preparation of pulverized coal becomes necessary. Usually, other organic fuels (mazut-fuel oil or natural gas) are added to low-quality coal for this purpose. The fraction of additional organic fuels varies within 35-40% range. This decreases dramatically the economic efficiency of such systems. At the same time, emission of noxious substances in the environment increases. Because of all these, intense development of plasma combustion systems of pulverized coal takes place in whole world. These systems are equipped with Non-Transferred Plasma Arc Torches. They allow practically complete combustion of pulverized coal (without organic additives) in boilers, increase of energetic and financial efficiency. At the same time, emission of noxious substances in the environment decreases dramatically. But, the non-transferred plasma torches have numerous drawbacks, e.g. complicated construction, low service life (especially in the case of high power), instability of plasma arc and most important – up to 30% of energy loss due to anode cooling. Due to these reasons, intense development of new plasma technologies that are free from these shortcomings takes place. In our proposed system, pulverized coal-air mixture passes through plasma arc area that burns between to carbon electrodes directly in pulverized coal muffler burner. Consumption of the carbon electrodes is low and does not need a cooling system, but the main advantage of this method is that radiation of plasma arc directly impacts on coal-air mixture that accelerates the process of thermo-chemical preparation of coal to burn. To ensure the stability of the plasma arc in such difficult conditions, we have developed a power source that provides fixed current during fluctuations in the arc resistance automatically compensated by the voltage change as well as regulation of plasma arc length over a wide range. Our combustion system where plasma arc acts directly on pulverized coal-air mixture is simple. This should allow a significant improvement of pulverized coal combustion (especially low-quality coal) and its economic efficiency. Preliminary experiments demonstrated the successful functioning of the system.

Keywords: coal combustion, plasma arc, plasma torches, pulverized coal

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364 Feminising Football and Its Fandom: The Ideological Construction of Women's Super League

Authors: Donna Woodhouse, Beth Fielding-Lloyd, Ruth Sequerra

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This paper explores the structure and culture of the English Football Association (FA) the governing body of soccer in England, in relation to the development of the FA Women’s Super League (WSL). In doing so, it examines the organisation’s journey from banning the sport in 1921 to establishing the country’s first semi professional female soccer league in 2011. As the FA has a virtual monopoly on defining the structures of the elite game, we attempted to understand its behaviour in the context of broader issues of power, control and resistance by giving voice to the experiences of those affected by its decisions. Observations were carried out at 39 matches over three years. Semi structured interviews with 17 people involved in the women’s game, identified via snowball sampling, were also carried out. Transcripts accompanied detailed field notes and were inductively coded to identify themes. What emerged was the governing body’s desire to create a new product, jettisoning the long history of the women’s game in order to shape and control the sport in a way it is no longer able to, with the elite male club game. The League created was also shaped by traditional conceptualisations of gender, in terms of the portrayal of its style of play and target audience, setting increased participation and spectatorship targets as measures of ‘success’. The national governing body has demonstrated pseudo inclusion and a lack of enthusiasm for the implementation of equity reforms, driven by a belief that the organisation is already representative, fair and accessible. Despite a consistent external pressure, the Football Association is still dominated at its most senior levels by males. Via claiming to hold a monopoly on expertise around the sport, maintaining complex committee structures and procedures, and with membership rules rooted in the amateur game, it remains a deeply gendered organisation, resistant to structural and cultural change. In WSL, the FA's structure and culture have created a franchise over which it retains almost complete control, dictating the terms of conditions of entry and marginalising alternative voices. The organisation presents a feminised version of both play and spectatorship, portraying the sport as a distinct, and lesser, version of soccer.

Keywords: football association, organisational culture, soccer, women’s super league

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363 Budget Impact Analysis of a Stratified Treatment Cascade for Hepatitis C Direct Acting Antiviral Treatment in an Asian Middle-Income Country through the Use of Compulsory and Voluntary Licensing Options

Authors: Amirah Azzeri, Fatiha H. Shabaruddin, Scott A. McDonald, Rosmawati Mohamed, Maznah Dahlui

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Objective: A scaled-up treatment cascade with direct-acting antiviral (DAA) therapy is necessary to achieve global WHO targets for hepatitis C virus (HCV) elimination in Malaysia. Recently, limited access to Sofosbuvir/Daclatasvir (SOF/DAC) is available through compulsory licensing, with future access to Sofosbuvir/Velpatasvir (SOF/VEL) expected through voluntary licensing due to recent agreements. SOF/VEL has superior clinical outcomes, particularly for cirrhotic stages, but has higher drug acquisition costs compared to SOF/DAC. It has been proposed that a stratified treatment cascade might be the most cost-efficient approach for Malaysia whereby all HCV patients are treated with SOF/DAC except for patients with cirrhosis who are treated with SOF/VEL. This study aimed to conduct a five-year budget impact analysis from the provider perspective of the proposed stratified treatment cascade for HCV treatment in Malaysia. Method: A disease progression model that was developed based on model-predicted HCV epidemiology data in Malaysia was used for the analysis, where all HCV patients in scenario A were treated with SOF/DAC for all disease stages while in scenario B, SOF/DAC was used only for non-cirrhotic patients and SOF/VEL was used for the cirrhotic patients. The model projections estimated the annual numbers of patients in care and the numbers of patients to be initiated on DAA treatment nationally. Healthcare costs associated with DAA therapy and disease stage monitoring was included to estimate the downstream cost implications. For scenario B, the estimated treatment uptake of SOF/VEL for cirrhotic patients were 25%, 50%, 75%, 100% and 100% for 2018, 2019, 2020, 2021 and 2022 respectively. Healthcare costs were estimated based on standard clinical pathways for DAA treatment described in recent guidelines. All costs were reported in US dollars (conversion rate US$1=RM4.09, the price year 2018). Scenario analysis was conducted for 5% and 10% reduction of SOF/VEL acquisition cost anticipated from the competitive market pricing of generic DAA in Malaysia. Results: The stratified treatment cascade with SOF/VEL in Scenario B was found to be cost-saving compared to Scenario A. A substantial portion of the cost reduction was due to the costs associated with DAA therapy which resulted in USD 40 thousand (year 1) to USD 443 thousand (year 5) savings annually, with cumulative savings of USD 1.1 million after 5 years. Cost reductions for disease stage monitoring were seen in year three onwards which resulted in cumulative savings of USD 1.1 thousand. Scenario analysis estimated cumulative savings of USD 1.24 to USD 1.35 million when the acquisition cost of SOF/VEL was reduced. Conclusion: A stratified treatment cascade with SOF/VEL was expected to be cost-saving and can results in a budget impact reduction in overall healthcare expenditure in Malaysia compared to treatment with SOF/DAC. The better clinical efficacy with SOF/VEL is expected to halt patients’ HCV disease progression and may reduce downstream costs of treating advanced disease stages. The findings of this analysis may be useful to inform healthcare policies for HCV treatment in Malaysia.

Keywords: Malaysia, direct acting antiviral, compulsory licensing, voluntary licensing

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362 Anti-proliferative Activity and HER2 Receptor Expression Analysis of MCF-7 (Breast Cancer Cell) Cells by Plant Extract Coleus Barbatus (Andrew)

Authors: Anupalli Roja Rani, Pavithra Dasari

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Background: Among several, breast cancer has emerged as the most common female cancer in developing countries. It is the most common cause of cancer-related deaths worldwide among women. It is a molecularly and clinically heterogeneous disease. Moreover, it is a hormone–dependent tumor in which estrogens can regulate the growth of breast cells by binding with estrogen receptors (ERs). Moreover, the use of natural products in cancer therapeutics is due to their properties of biocompatibility and less toxicity. Plants are the vast reservoirs for various bioactive compounds. Coleus barbatus (Lamiaceae) contains anticancer properties against several cancer cell lines. Method: In the present study, an attempt is being made to enrich the knowledge of the anticancer activity of pure compounds extracted from Coleus barbatus (Andrew). On human breast cancer cell lines MCF-7. Here in, we are assessing the antiproliferative activity of Coleus barbatus (Andrew) plant extracts against MCF 7 and also evaluating their toxicity in normal human mammary cell lines such as Human Mammary Epithelial Cells (HMEC). The active fraction of plant extract was further purified with the help of Flash chromatography, Medium Pressure Liquid Chromatography (MPLC) and preparative High-Performance Liquid Chromatography (HPLC). The structure of pure compounds will be elucidated by using modern spectroscopic methods like Nuclear magnetic resonance (NMR), Electrospray Ionisation Mass Spectrometry (ESI-MS) methods. Later, the growth inhibition morphological assessment of cancer cells and cell cycle analysis of purified compounds were assessed using FACS. The growth and progression of signaling molecules HER2, GRP78 was studied by secretion assay using ELISA and expression analysis by flow cytometry. Result: Cytotoxic effect against MCF-7 with IC50 values were derived from dose response curves, using six concentrations of twofold serially diluted samples, by SOFTMax Pro software (Molecular device) and respectively Ellipticine and 0.5% DMSO were used as a positive and negative control. Conclusion: The present study shows the significance of various bioactive compounds extracted from Coleus barbatus (Andrew) root material. It acts as an anti-proliferative and shows cytotoxic effects on human breast cancer cell lines MCF7. The plant extracts play an important role pharmacologically. The whole plant has been used in traditional medicine for decades and the studies done have authenticated the practice. Earlier, as described, the plant has been used in the ayurveda and homeopathy medicine. However, more clinical and pathological studies must be conducted to investigate the unexploited potential of the plant. These studies will be very useful for drug designing in the future.

Keywords: coleus barbatus, HPLC, MPLC, NMR, MCF7, flash chromatograph, ESI-MS, FACS, ELISA.

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361 Commercial Winding for Superconducting Cables and Magnets

Authors: Glenn Auld Knierim

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Automated robotic winding of high-temperature superconductors (HTS) addresses precision, efficiency, and reliability critical to the commercialization of products. Today’s HTS materials are mature and commercially promising but require manufacturing attention. In particular to the exaggerated rectangular cross-section (very thin by very wide), winding precision is critical to address the stress that can crack the fragile ceramic superconductor (SC) layer and destroy the SC properties. Damage potential is highest during peak operations, where winding stress magnifies operational stress. Another challenge is operational parameters such as magnetic field alignment affecting design performance. Winding process performance, including precision, capability for geometric complexity, and efficient repeatability, are required for commercial production of current HTS. Due to winding limitations, current HTS magnets focus on simple pancake configurations. HTS motors, generators, MRI/NMR, fusion, and other projects are awaiting robotic wound solenoid, planar, and spherical magnet configurations. As with conventional power cables, full transposition winding is required for long length alternating current (AC) and pulsed power cables. Robotic production is required for transposition, periodic swapping of cable conductors, and placing into precise positions, which allows power utility required minimized reactance. A full transposition SC cable, in theory, has no transmission length limits for AC and variable transient operation due to no resistance (a problem with conventional cables), negligible reactance (a problem for helical wound HTS cables), and no long length manufacturing issues (a problem with both stamped and twisted stacked HTS cables). The Infinity Physics team is solving manufacturing problems by developing automated manufacturing to produce the first-ever reliable and utility-grade commercial SC cables and magnets. Robotic winding machines combine mechanical and process design, specialized sense and observer, and state-of-the-art optimization and control sequencing to carefully manipulate individual fragile SCs, especially HTS, to shape previously unattainable, complex geometries with electrical geometry equivalent to commercially available conventional conductor devices.

Keywords: automated winding manufacturing, high temperature superconductor, magnet, power cable

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360 Case Report of Left Atrial Myxoma Diagnosed by Bedside Echocardiography

Authors: Anthony S. Machi, Joseph Minardi

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We present a case report of left atrial myxoma diagnosed by bedside transesophageal (TEE) ultrasound. Left atrial myxoma is the most common benign cardiac tumor and can obstruct blood flow and cause valvular insufficiency. Common symptoms consist of dyspnea, pulmonary edema and other features of left heart failure in addition to thrombus release in the form of tumor fragments. The availability of bedside ultrasound equipment is essential for the quick diagnosis and treatment of various emergency conditions including cardiac neoplasms. A 48-year-old Caucasian female with a four-year history of an untreated renal mass and anemia presented to the ED with two months of sharp, intermittent, bilateral flank pain radiating into the abdomen. She also reported intermittent vomiting and constipation along with generalized body aches, night sweats, and 100-pound weight loss over last year. She had a CT in 2013 showing a 3 cm left renal mass and a second CT in April 2016 showing a 3.8 cm left renal mass along with a past medical history of diverticulosis, chronic bronchitis, dyspnea on exertion, uncontrolled hypertension, and hyperlipidemia. Her maternal family history is positive for breast cancer, hypertension, and Type II Diabetes. Her paternal family history is positive for stroke. She was a current everyday smoker with an 11 pack/year history. Alcohol and drug use were denied. Physical exam was notable for a Grade II/IV systolic murmur at the right upper sternal border, dyspnea on exertion without angina, and a tender left lower quadrant. Her vitals and labs were notable for a blood pressure of 144/96, heart rate of 96 beats per minute, pulse oximetry of 96%, hemoglobin of 7.6 g/dL, hypokalemia, hypochloremia, and multiple other abnormalities. Physicians ordered a CT to evaluate her flank pain which revealed a 7.2 x 8.9 x 10.5 cm mixed cystic/solid mass in the lower pole of the left kidney and a filling defect in the left atrium. Bedside TEE was ordered to follow up on the filling defect. TEE reported an ejection fraction of 60-65% and visualized a mobile 6 x 3 cm mass in the left atrium attached to the interatrial septum extending into the mitral valve. Cardiothoracic Surgery and Urology were consulted and confirmed a diagnosis of left atrial myxoma and clear cell renal cell carcinoma. The patient returned a week later due to worsening nausea and vomiting and underwent emergent nephrectomy, lymph node dissection, and colostomy due to a necrotic colon. Her condition declined over the next four months due to lung and brain metastases, infections, and other complications until she passed away.

Keywords: bedside ultrasound, echocardiography, emergency medicine, left atrial myxoma

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359 Women's Pathways to Prison in Thailand

Authors: Samantha Jeffries, Chontit Chuenurah

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Thailand incarcerates the largest number of women and has the highest female incarceration rate in South East Asia. Since the 1990s, there has been a substantial increase in the number, rate and proportion of women imprisoned. Thailand places a high priority on the gender specific contexts out of which offending arises and the different needs of women in the criminal justice system. This is manifested in work undertaken to guide the development of the United Nations Rules for the Treatment of Women Prisoners and Non-Custodial Measures for Women Offenders (the Bangkok Rules); adopted by the United Nations General Assembly in 2010. The Bangkok Rules make a strong statement about Thailand’s recognition of and commitment to the fair and equitable treatment of women throughout their contact with the criminal justice system including at sentencing and in prison. This makes the comparatively high use of imprisonment for women in Thailand particularly concerning and raises questions about the relationship between gender, crime and criminal justice. While there is an extensive body of research in Western jurisdictions exploring women’s pathways to prison, there is a relative dearth of methodologically robust research examining the possible gendered circumstances leading to imprisonment in Thailand. In this presentation, we will report preliminary findings from a qualitative study of women’s pathways to prison in Thailand. Our research aims were to ascertain: 1) the type, frequency, and context of criminal behavior that led to women’s incarceration, 2) women’s experiences of the criminal justice system, 3) the broader life experiences and circumstances that led women to prison in Thailand. In-depth life history interviews (n=77) were utilized to gain a comprehensive understanding of women’s journeys into prison. The interview schedule was open-ended consisting of prisoner responses to broad discussion topics. This approach provided women with the opportunity to describe significant experiences in their lives, to bring together distinct chronologies of events, and to analyze links between their varied life experiences, offending, and incarceration. Analyses showed that women’s journey’s to prison take one of eight pathways which tentatively labelled as follows, the: 1) harmed and harming pathway, 2) domestic/family violence victimization pathway, 3) drug connected pathway, 4) street woman pathway, 5) economically motivated pathway, 6) jealousy anger and/or revenge pathway, 7) naivety pathway, 8) unjust and/or corrupted criminal justice pathway. Each will be fully discussed during the presentation. This research is significant because it is the first in-depth methodologically robust exploration of women’s journeys to prison in Thailand and one of a few studies to explore gendered pathways outside of western contexts. Understanding women’s pathways into Thailand’s prisons is crucial to the development of effective planning, policy and program responses not only while women are in prison but also post-release. To best meet women’s needs in prison and effectively support their reintegration, we must have a comprehensive understanding of who these women are, what offenses they commit, the reasons that trigger their confrontations with the criminal justice system and the impact of the criminal justice system on them.

Keywords: pathways, prison, women, Thailand

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358 Use of Proton Pump Inhibitors Medications during the First Years of Life and Late Complications

Authors: Kamelia Hamza

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Background: Proton pump inhibitors (PPIs) are the most prescribed drug classes for pediatric gastroesophageal reflux disease (GERD).Many patients are treated with these drugs for atypical manifestations attributed to gastroesophageal reflux (GER), even in the absence of proved causal relationship. There is an impression of increase use of PPI's treatment for reflux in "clalit health services," the largest health organization in Israel. In the recent years, the medicine is given without restriction, it's not limited to pediatric gastroenterologists only, but pediatricians and family doctors. The objective of this study is to evaluate the hypothesis that exposure to PPIs during the first year of life is associated with an increased risk of developing late adverse diseases: pneumonia, asthma, AGE, IBD, celiac disease, allergic disorders, obesity, attention deficit hyperactivity disorders (ADHD), autism spectrum disorders (ASD). Methods: The study is a retrospective case-control cohort study based on a computerized database of Clalit Health Services (CHS). It includes 9844 children born between 2002-2018 and reported to complain of at least one of the symptoms (reflux/ spitting up, irritability, feeding difficulties, colics). The study population included the study group (n=4922) of children exposed to PPIs at any time prior to the first year of life and a control group (n=4922) child not exposed to PPIs who were matched to each case of the study group on age, race, socioeconomic status, and year of birth. The prevalence of late complications/diseases in the study group was compared with the prevalence of late complications/diseases diagnosis between 2002-2020 in the control group. Odds ratios and 95% confidence intervals were calculated by using logistic regression models. Results: We found that compared to the control group, children exposed to PPIs in the first year of life had an increased risk of developing several late complications/ disorders: pneumonia, asthma, various allergies (urticaria, allergic rhinitis, or allergic conjunctivitis) OR, inhalant allergies, and food allergies. In addition, they showed an increased risk of being diagnosed with ADHD or ASD, but children exposed to PPIs in the first year of life had decrease the risk of obesity by 17% (OR 0.825, 95%CI 0.697-0.976). Conclusions: We found significant associations between the use of PPIs during the first year of life and subsequent development of late complications/diseases such as respiratory diseases, allergy diseases, ADHD, and ASD. More studies are needed to prove causality and determine the mechanism behind the effect of PPIs and the development of late complications.

Keywords: acid suppressing medications, proton pump inhibitors, histamine 2 blocker, late complications, gastroesophageal reflux, gastroesophageal reflux disease, acute gastroenteritis, community acquired pneumonia, asthma, allergic diseases, obesity, inflammatory bowel diseases, ulcerative colitis, crohn disease, attention deficit hyperactivity disorders, autism spectrum disorders

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357 Microbiological Assessment of Soft Cheese (Wara), Raw Milk and Dairy Drinking Water from Selected Farms in Ido, Ibadan, Nigeria

Authors: Blessing C. Nwachukwu, Michael O. Taiwo, Wasiu A. Abibu, Isaac O. Ayodeji

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Milk is an important source of micro and macronutrients for humans. Soft Cheese (Wara) is an example of a by-product of milk. In addition, water is considered as one of the most vital resources in cattle farms. Due to the high consumption rate of milk and soft cheese and the traditional techniques involved in their production in Nigeria, there was a need for a microbiological assessment which will be of utmost public health importance. The study thus investigated microbial risk assessments associated with consumption of milk and soft cheese (Wara). It also investigated common pathogens present in dairy water in farms and antibiotic sensitivity profiling for implicated pathogens were conducted. Samples were collected from three different Fulani dairy herds in Ido local government, Ibadan, Oyo State, Nigeria and subjected to microbiological evaluation and antimicrobial susceptibility testing. Aspergillus flavus was the only isolated fungal isolate from Wara while Staphylococcus aureus, Vibro cholera, Hafnia alvei, Proteus mirabilis, Escherishia coli, Psuedomonas aeuroginosa, Citrobacter freundii, and Klebsiella pneumonia were the bacteria genera isolated from Wara, dairy milk and dairy drinking water. Bacterial counts from Wara from the three selected farms A, B and C were 3.5×105 CFU/ml, 4.0×105 CFU/ml and 5.3×105 CFU/ml respectively while the fungal count was 3CFU/100µl. The total bacteria count from dairy milk from the three selected farms A, B and C were Farms 2.0 ×105 CFU/ml, 3.5 × 105 CFU/ml and 6.5 × 105 CFU/ml respectively. 1.4×105 CFU/ml, 1.9×105 CFU/ml and 4.9×105 CFU/ml were the recorded bacterial counts from dairy water from farms A, B and C respectively. The highest antimicrobial resistance of 100% was recorded in Wara with Enrofloxacin, Gentamycin, Cefatriaxone and Colistin. The highest antimicrobial susceptibility of 100% was recorded in Raw milk with Enrofloxacin and Gentamicin. Highest antimicrobial intermediate response of 100% was recorded in Raw milk with Streptomycin. The study revealed that most of the cheeses sold at Ido local Government are contaminated with pathogens. Further research is needed on standardizing the production method to prevent pathogens from gaining access. The presence of bacteria in raw milk indicated contamination due to poor handling and unhygienic practices. Thus, drinking unpasteurized milk is hazardous as it increases the risk of zoonoses. Also, the Provision of quality drinking water is crucial for optimum productivity of dairy. Health education programs aiming at increasing awareness of the importance of clean water for animal health will be helpful.

Keywords: dairy, raw milk, soft cheese, Wara

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356 Development of a Stable RNAi-Based Biological Control for Sheep Blowfly Using Bentonite Polymer Technology

Authors: Yunjia Yang, Peng Li, Gordon Xu, Timothy Mahony, Bing Zhang, Neena Mitter, Karishma Mody

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Sheep flystrike is one of the most economically important diseases affecting the Australian sheep and wool industry (>356M/annually). Currently, control of Lucillia cuprina relies almost exclusively on chemicals controls and the parasite has developed resistance to nearly all control chemicals used in the past. It is therefore critical to develop an alternative solution for the sustainable control and management of flystrike. RNA interference (RNAi) technologies have been successfully explored in multiple animal industries for developing parasites controls. This research project aims to develop a RNAi based biological control for sheep blowfly. Double-stranded RNA (dsRNA) has already proven successful against viruses, fungi and insects. However, the environmental instability of dsRNA is a major bottleneck for successful RNAi. Bentonite polymer (BenPol) technology can overcome this problem, as it can be tuned for the controlled release of dsRNA in the gut challenging pH environment of the blowfly larvae, prolonging its exposure time to and uptake by target cells. To investigate the potential of BenPol technology for dsRNA delivery, four different BenPol carriers were tested for their dsRNA loading capabilities, and three of them were found to be capable of affording dsRNA stability under multiple temperatures (4°C, 22°C, 40°C, 55°C) in sheep serum. Based on stability results, dsRNA from potential targeted genes was loaded onto BenPol carriers and tested in larvae feeding assays, three genes resulting in knockdowns. Meanwhile, a primary blowfly embryo cell line (BFEC) derived from L. cuprina embryos was successfully established, aim for an effective insect cell model for testing RNAi efficacy for preliminary assessments and screening. The results of this study establish that the dsRNA is stable when loaded on BenPol particles, unlike naked dsRNA rapidly degraded in sheep serum. The stable nanoparticle delivery system offered by BenPol technology can protect and increase the inherent stability of dsRNA molecules at higher temperatures in a complex biological fluid like serum, providing promise for its future use in enhancing animal protection.

Keywords: flystrike, RNA interference, bentonite polymer technology, Lucillia cuprina

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355 Neuro-Epigenetic Changes on Diabetes Induced-Synaptic Fidelity in Brain

Authors: Valencia Fernandes, Dharmendra Kumar Khatri, Shashi Bala Singh

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Background and Aim: Epigenetics are the inaudible signatures of several pathological processes in the brain. This study understands the influence of DNA methylation, a major epigenetic modification, in the prefrontal cortex and hippocampus of the diabetic brain and its notable effect on the cellular chaperones and synaptic proteins. Method: Chronic high fat diet and STZ-induced diabetic mice were studied for cognitive dysfunction, and global DNA methylation, as well as DNA methyltransferase (DNMT) activity, were assessed. Further, the cellular chaperones and synaptic proteins were examined using DNMT inhibitor, 5-aza-2′-deoxycytidine (5-aza-dC)-via intracerebroventricular injection. Moreover, % methylation of these synaptic proteins were also studied so as to correlate its epigenetic involvement. Computationally, its interaction with the DNMT enzyme were also studied using bioinformatic tools. Histological studies for morphological alterations and neuronal degeneration were also studied. Neurogenesis, a characteristic marker for new learning and memory formation, was also assessed via the BrdU staining. Finally, the most important behavioral studies, including the Morris water maze, Y maze, passive avoidance, and Novel object recognition test, were performed to study its cognitive functions. Results: Altered global DNA methylation and increased levels of DNMTs within the nucleus were confirmed in the cortex and hippocampus of the diseased mice, suggesting hypermethylation at a genetic level. Treatment with AzadC, a global DNA demethylating agent, ameliorated the protein and gene expression of the cellular chaperones and synaptic fidelity. Furthermore, the methylation analysis profile showed hypermethylation of the hsf1 protein, a master regulator for chaperones and thus, confirmed the epigenetic involvement in the diseased brain. Morphological improvements and decreased neurodegeneration, along with enhanced neurogenesis in the treatment group, suggest that epigenetic modulations do participate in learning and memory. This is supported by the improved behavioral test battery seen in the treatment group. Conclusion: DNA methylation could possibly accord in dysregulating the memory-associated proteins at chronic stages in type 2 diabetes. This could suggest a substantial contribution to the underlying pathophysiology of several metabolic syndromes like insulin resistance, obesity and also participate in transitioning this damage centrally, such as cognitive dysfunction.

Keywords: epigenetics, cognition, chaperones, DNA methylation

Procedia PDF Downloads 172
354 Mathematical Modelling of Biogas Dehumidification by Using of Counterflow Heat Exchanger

Authors: Staņislavs Gendelis, Andris Jakovičs, Jānis Ratnieks, Aigars Laizāns, Dāvids Vardanjans

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Dehumidification of biogas at the biomass plants is very important to provide the energy efficient burning of biomethane at the outlet. A few methods are widely used to reduce the water content in biogas, e.g. chiller/heat exchanger based cooling, usage of different adsorbents like PSA, or the combination of such approaches. A quite different method of biogas dehumidification is offered and analyzed in this paper. The main idea is to direct the flow of biogas from the plant around it downwards; thus, creating additional insulation layer. As the temperature in gas shell layer around the plant will decrease from ~ 38°C to 20°C in the summer or even to 0°C in the winter, condensation of water vapor occurs. The water from the bottom of the gas shell can be collected and drain away. In addition, another upward shell layer is created after the condensate drainage place on the outer side to further reducing heat losses. Thus, counterflow biogas heat exchanger is created around the biogas plant. This research work deals with the numerical modelling of biogas flow, taking into account heat exchange and condensation on cold surfaces. Different kinds of boundary conditions (air and ground temperatures in summer/winter) and various physical properties of constructions (insulation between layers, wall thickness) are included in the model to make it more general and useful for different biogas flow conditions. The complexity of this problem is fact, that the temperatures in both channels are conjugated in case of low thermal resistance between layers. MATLAB programming language is used for multiphysical model development, numerical calculations and result visualization. Experimental installation of a biogas plant’s vertical wall with an additional 2 layers of polycarbonate sheets with the controlled gas flow was set up to verify the modelling results. Gas flow at inlet/outlet, temperatures between the layers and humidity were controlled and measured during a number of experiments. Good correlation with modelling results for vertical wall section allows using of developed numerical model for an estimation of parameters for the whole biogas dehumidification system. Numerical modelling of biogas counterflow heat exchanger system placed on the plant’s wall for various cases allows optimizing of thickness for gas layers and insulation layer to ensure necessary dehumidification of the gas under different climatic conditions. Modelling of system’s defined configuration with known conditions helps to predict the temperature and humidity content of the biogas at the outlet.

Keywords: biogas dehumidification, numerical modelling, condensation, biogas plant experimental model

Procedia PDF Downloads 514
353 Experimental Determination of Water Productivity of Improved Cassava Varieties Propagation under Rain-Fed Condition in Tropical Environment

Authors: Temitayo Abayomi Ewemoje, Isaac Olugbemiga Afolayan, Badmus Alao Tayo

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Researchers in developing countries have worked on improving cassava resistance to diseases and pests, high yielding and early maturity However, water management has received little or no attention as cassava cultivation in Sub-Saharan Africa depended on available precipitation (rain-fed condition). Therefore the need for water management in Agricultural crop production cannot be overemphasized. As other sectors compete with agricultural sector for fresh water (which is not readily available), there is need to increase water productivity in agricultural production. Experimentation was conducted to examine water use, growth and yield of improved cassava varieties under rain fed condition using Latin- square design with four replications. Four improved disease free stem cassava varieties TMS (30572, 980505, 920326 and 090581) were planted and growth parameters of the varieties were monitored for 90 and 120 days after planting (DAP). Effective rainfall useful for the plant growth was calculated using CROPWAT8 for Windows. Results indicated TMS090581 was having the highest tuber yield and plant height while TMS30572 had highest number of nodes. Tuber stem and leaf water productivities at 90 and 120 DAP of TMS (30572, 980505, 920326 and 090581) are (1.27 and 3.58, 1.44 and 2.35, 0.89 and 1.86, 1.64 and 3.77) kg/m3 (1.56 and 2.59, 1.95 and 2.02, 1.98 and 2.05, 1.95 and 2.18) kg/m3, and (1.34 and 2.32, 1.94 and 2.16, 1.57 and 1.40, 1.27 and 1.80) kg/m3 respectively. Based on tuber water productivity TMS090581 are recommended while TMS30572 are recommended based on leaf and stem productivity in water scarce regions.Experimentation was conducted to examine water use, growth and yield of improved cassava varieties under rain fed condition using Latin- square design with four replications. Four improved disease free stem cassava varieties TMS (30572, 980505, 920326 and 090581) were planted and growth parameters of the varieties were monitored for 90 and 120 days after planting (DAP). Effective rainfall useful for the plant growth was calculated using CROPWAT8 for Windows. Results indicated TMS090581 was having the highest tuber yield and plant height while TMS30572 had the highest number of nodes. Tuber, stem and leaf water productivities at 90 and 120 DAP of TMS (30572, 980505, 920326 and 090581) are (1.27 and 3.58, 1.44 and 2.35, 0.89 and 1.86, 1.64 and 3.77) kg/m3 (1.56 and 2.59, 1.95 and 2.02, 1.98 and 2.05, 1.95 and 2.18) kg/m3, and (1.34 and 2.32, 1.94 and 2.16, 1.57 and 1.40, 1.27 and 1.80) kg/m3 respectively. Based on tuber water productivity TMS090581 are recommended while TMS30572 are recommended based on leaf and stem productivity in water scarce regions

Keywords: improved TMS varieties, leaf productivity, rain-fed cassava production, stem productivity, tuber productivity

Procedia PDF Downloads 313
352 Impact of Twin Therapeutic Approaches on Certain Biophysiological Parameters among Breast Cancer Patients after Breast Surgery at Selected Hospital

Authors: Selvia Arokiya Mary

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Introduction: Worldwide, breast cancer comprises 10.4% of all cancer incidence among women. In 2004, breast cancer caused 519,000 deaths worldwide (7% of cancer deaths; almost 1% of all deaths). Many women who undergo breast surgery suffer from ill-defined pain syndromes. STATEMENT OF THE PROBLEM: A study to assess the effectiveness of twin therapeutic approaches on certain bio-physiological parameters in breast cancer patients after breast surgery at selected hospital, Chennai. Objectives: This study is to 1. assess the level of certain biophysiological parameters in women after mastectomy. 2. assess the effectiveness of twin therapeutic approaches on certain biophysiological parameters in women after mastectomy. 3. correlate the practice of twin therapeutic approaches with certain biophysiological parameters. 4. associate the selected demographic variables with certain biophysiological parameters in women after mastectomy Research Design and Method: Pre experimental research design was used. Fifty women were selected by using convenient sampling technique at government general hospital, Chennai. Results: The Level of pain shows, in the study group 49(98%) of them had moderate in the pre test and after the intervention all of them had mild pain in the post test. In relation to level of shoulder function before the intervention shows that in the study group 49(98%) of them had movement towards gravity and after intervention 24 (48%) of them had movement against gravity maximum resistance. There was a significant reduction in pain and shoulder stiffness level at a ‘P’ level of < 0.001. There was a negative correlation between the pranayama practice and the level of pain, there was a positive correlation between the arm exercise practice and the level of shoulder function. There was no significant association between demographic and clinical variables with the level of pain and shoulder function in the study. Hypothesis: There is a significant difference in level of pain and shoulder function among women following breast surgery who receive pranayama & arm exercise programme. The pranayama had effect in terms of reduction of pain, arm exercise programme had effect in prevention of arm stiffness among post operative women following breast surgery. Thus the stated hypothesis was accepted. Conclusion: On the basis of the findings of the present study there was Advancing age related to increasing risk of breast cancer, level of pain also the type of surgery was associated with level of pain and shoulder function, There fore it is to be concluded that the study participants may get benefited by practice of pranayama and arm exercise program.

Keywords: biophysiological parameters breast surgery, lumpectomy , mastectomy, radical mastectomy, twin therapeutic approach, pranayama, arm exercise

Procedia PDF Downloads 222
351 The Significance of Picture Mining in the Fashion and Design as a New Research Method

Authors: Katsue Edo, Yu Hiroi

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T Increasing attention has been paid to using pictures and photographs in research since the beginning of the 21th century in social sciences. Meanwhile we have been studying the usefulness of Picture mining, which is one of the new ways for a these picture using researches. Picture Mining is an explorative research analysis method that takes useful information from pictures, photographs and static or moving images. It is often compared with the methods of text mining. The Picture Mining concept includes observational research in the broad sense, because it also aims to analyze moving images (Ochihara and Edo 2013). In the recent literature, studies and reports using pictures are increasing due to the environmental changes. These are identified as technological and social changes (Edo et.al. 2013). Low price digital cameras and i-phones, high information transmission speed, low costs for information transferring and high performance and resolution of the cameras of mobile phones have changed the photographing behavior of people. Consequently, there is less resistance in taking and processing photographs for most of the people in the developing countries. In these studies, this method of collecting data from respondents is often called as ‘participant-generated photography’ or ‘respondent-generated visual imagery’, which focuses on the collection of data and its analysis (Pauwels 2011, Snyder 2012). But there are few systematical and conceptual studies that supports it significance of these methods. We have discussed in the recent years to conceptualize these picture using research methods and formalize theoretical findings (Edo et. al. 2014). We have identified the most efficient fields of Picture mining in the following areas inductively and in case studies; 1) Research in Consumer and Customer Lifestyles. 2) New Product Development. 3) Research in Fashion and Design. Though we have found that it will be useful in these fields and areas, we must verify these assumptions. In this study we will focus on the field of fashion and design, to determine whether picture mining methods are really reliable in this area. In order to do so we have conducted an empirical research of the respondents’ attitudes and behavior concerning pictures and photographs. We compared the attitudes and behavior of pictures toward fashion to meals, and found out that taking pictures of fashion is not as easy as taking meals and food. Respondents do not often take pictures of fashion and upload their pictures online, such as Facebook and Instagram, compared to meals and food because of the difficulty of taking them. We concluded that we should be more careful in analyzing pictures in the fashion area for there still might be some kind of bias existing even if the environment of pictures have drastically changed in these years.

Keywords: empirical research, fashion and design, Picture Mining, qualitative research

Procedia PDF Downloads 339
350 Bioleaching of Metals Contained in Spent Catalysts by Acidithiobacillus thiooxidans DSM 26636

Authors: Andrea M. Rivas-Castillo, Marlenne Gómez-Ramirez, Isela Rodríguez-Pozos, Norma G. Rojas-Avelizapa

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Spent catalysts are considered as hazardous residues of major concern, mainly due to the simultaneous presence of several metals in elevated concentrations. Although hydrometallurgical, pyrometallurgical and chelating agent methods are available to remove and recover some metals contained in spent catalysts; these procedures generate potentially hazardous wastes and the emission of harmful gases. Thus, biotechnological treatments are currently gaining importance to avoid the negative impacts of chemical technologies. To this end, diverse microorganisms have been used to assess the removal of metals from spent catalysts, comprising bacteria, archaea and fungi, whose resistance and metal uptake capabilities differ depending on the microorganism tested. Acidophilic sulfur oxidizing bacteria have been used to investigate the biotreatment and extraction of valuable metals from spent catalysts, namely Acidithiobacillus thiooxidans and Acidithiobacillus ferroxidans, as they present the ability to produce leaching agents such as sulfuric acid and sulfur oxidation intermediates. In the present work, the ability of A. thiooxidans DSM 26636 for the bioleaching of metals contained in five different spent catalysts was assessed by growing the culture in modified Starkey mineral medium (with elemental sulfur at 1%, w/v), and 1% (w/v) pulp density of each residue for up to 21 days at 30 °C and 150 rpm. Sulfur-oxidizing activity was periodically evaluated by determining sulfate concentration in the supernatants according to the NMX-k-436-1977 method. The production of sulfuric acid was assessed in the supernatants as well, by a titration procedure using NaOH 0.5 M with bromothymol blue as acid-base indicator, and by measuring pH using a digital potentiometer. On the other hand, Inductively Coupled Plasma - Optical Emission Spectrometry was used to analyze metal removal from the five different spent catalysts by A. thiooxidans DSM 26636. Results obtained show that, as could be expected, sulfuric acid production is directly related to the diminish of pH, and also to highest metal removal efficiencies. It was observed that Al and Fe are recurrently removed from refinery spent catalysts regardless of their origin and previous usage, although these removals may vary from 9.5 ± 2.2 to 439 ± 3.9 mg/kg for Al, and from 7.13 ± 0.31 to 368.4 ± 47.8 mg/kg for Fe, depending on the spent catalyst proven. Besides, bioleaching of metals like Mg, Ni, and Si was also obtained from automotive spent catalysts, which removals were of up to 66 ± 2.2, 6.2±0.07, and 100±2.4, respectively. Hence, the data presented here exhibit the potential of A. thiooxidans DSM 26636 for the simultaneous bioleaching of metals contained in spent catalysts from diverse provenance.

Keywords: bioleaching, metal removal, spent catalysts, Acidithiobacillus thiooxidans

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349 Approaches to Inducing Obsessional Stress in Obsessive-Compulsive Disorder (OCD): An Empirical Study with Patients Undergoing Transcranial Magnetic Stimulation (TMS) Therapy

Authors: Lucia Liu, Matthew Koziol

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Obsessive-compulsive disorder (OCD), a long-lasting anxiety disorder involving recurrent, intrusive thoughts, affects over 2 million adults in the United States. Transcranial magnetic stimulation (TMS) stands out as a noninvasive, cutting-edge therapy that has been shown to reduce symptoms in patients with treatment-resistant OCD. The Food and Drug Administration (FDA) approved protocol pairs TMS sessions with individualized symptom provocation, aiming to improve the susceptibility of brain circuits to stimulation. However, limited standardization or guidance exists on how to conduct symptom provocation and which methods are most effective. This study aims to compare the effect of internal versus external techniques to induce obsessional stress in a clinical setting during TMS therapy. Two symptom provocation methods, (i) Asking patients thought-provoking questions about their obsessions (internal) and (ii) Requesting patients to perform obsession-related tasks (external), were employed in a crossover design with repeated measurement. Thirty-six treatments of NeuroStar TMS were administered to each of two patients over 8 weeks in an outpatient clinic. Patient One received 18 sessions of internal provocation followed by 18 sessions of external provocation, while Patient Two received 18 sessions of external provocation followed by 18 sessions of internal provocation. The primary outcome was the level of self-reported obsessional stress on a visual analog scale from 1 to 10. The secondary outcome was self-reported OCD severity, collected biweekly in a four-level Likert-scale (1 to 4) of bad, fair, good and excellent. Outcomes were compared and tested between provocation arms through repeated measures ANOVA, accounting for intra-patient correlations. Ages were 42 for Patient One (male, White) and 57 for Patient Two (male, White). Both patients had similar moderate symptoms at baseline, as determined through the Yale-Brown Obsessive Compulsive Scale (YBOCS). When comparing obsessional stress induced across the two arms of internal and external provocation methods, the mean (SD) was 6.03 (1.18) for internal and 4.01 (1.28) for external strategies (P=0.0019); ranges were 3 to 8 for internal and 2 to 8 for external strategies. Internal provocation yielded 5 (31.25%) bad, 6 (33.33%) fair, 3 (18.75%) good, and 2 (12.5%) excellent responses for OCD status, while external provocation yielded 5 (31.25%) bad, 9 (56.25%) fair, 1 (6.25%) good, and 1 (6.25%) excellent responses (P=0.58). Internal symptom provocation tactics had a significantly stronger impact on inducing obsessional stress and led to better OCD status (non-significant). This could be attributed to the fact that answering questions may prompt patients to reflect more on their lived experiences and struggles with OCD. In the future, clinical trials with larger sample sizes are warranted to validate this finding. Results support the increased integration of internal methods into structured provocation protocols, potentially reducing the time required for provocation and achieving greater treatment response to TMS.

Keywords: obsessive-compulsive disorder, transcranial magnetic stimulation, mental health, symptom provocation

Procedia PDF Downloads 39
348 Protective Role of Autophagy Challenging the Stresses of Type 2 Diabetes and Dyslipidemia

Authors: Tanima Chatterjee, Maitree Bhattacharyya

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The global challenge of type 2 diabetes mellitus is a major health concern in this millennium, and researchers are continuously exploring new targets to develop a novel therapeutic strategy. Type 2 diabetes mellitus (T2DM) is often coupled with dyslipidemia increasing the risks for cardiovascular (CVD) complications. Enhanced oxidative and nitrosative stresses appear to be the major risk factors underlying insulin resistance, dyslipidemia, β-cell dysfunction, and T2DM pathogenesis. Autophagy emerges to be a promising defense mechanism against stress-mediated cell damage regulating tissue homeostasis, cellular quality control, and energy production, promoting cell survival. In this study, we have attempted to explore the pivotal role of autophagy in T2DM subjects with or without dyslipidemia in peripheral blood mononuclear cells and insulin-resistant HepG2 cells utilizing flow cytometric platform, confocal microscopy, and molecular biology techniques like western blotting, immunofluorescence, and real-time polymerase chain reaction. In the case of T2DM with dyslipidemia higher population of autophagy, positive cells were detected compared to patients with the only T2DM, which might have resulted due to higher stress. Autophagy was observed to be triggered both by oxidative and nitrosative stress revealing a novel finding of our research. LC3 puncta was observed in peripheral blood mononuclear cells and periphery of HepG2 cells in the case of the diabetic and diabetic-dyslipidemic conditions. Increased expression of ATG5, LC3B, and Beclin supports the autophagic pathway in both PBMC and insulin-resistant Hep G2 cells. Upon blocking autophagy by 3-methyl adenine (3MA), the apoptotic cell population increased significantly, as observed by caspase‐3 cleavage and reduced expression of Bcl2. Autophagy has also been evidenced to control oxidative stress-mediated up-regulation of inflammatory markers like IL-6 and TNF-α. To conclude, this study elucidates autophagy to play a protective role in the case of diabetes mellitus with dyslipidemia. In the present scenario, this study demands to have a significant impact on developing a new therapeutic strategy for diabetic dyslipidemic subjects by enhancing autophagic activity.

Keywords: autophagy, apoptosis, dyslipidemia, reactive oxygen species, reactive nitrogen species, Type 2 diabetes

Procedia PDF Downloads 101
347 The Impact of Climate Change on Sustainable Aquaculture Production

Authors: Peyman Mosberian-Tanha, Mona Rezaei

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Aquaculture sector is the fastest growing food sector with annual growth rate of about 10%. The sustainability of aquaculture production, however, has been debated mainly in relation to the feed ingredients used for farmed fish. The industry has been able to decrease its dependency on marine-based ingredients in line with policies for more sustainable production. As a result, plant-based ingredients have increasingly been incorporated in aquaculture feeds, especially in feeds for popular carnivorous species, salmonids. The effect of these ingredients on salmonids’ health and performance has been widely studied. In most cases, plant-based diets are associated with varying degrees of health and performance issues across salmonids, partly depending on inclusion levels of plant ingredients and the species in question. However, aquaculture sector is facing another challenge of concern. Environmental challenges in association with climate change is another issue the aquaculture sector must deal with. Data from trials in salmonids subjected to environmental challenges of various types show adverse physiological responses, partly in relation to stress. To date, there are only a limited number of studies reporting the interactive effects of adverse environmental conditions and dietary regimens on salmonids. These studies have shown that adverse environmental conditions exacerbate the detrimental effect of plant-based diets on digestive function and health in salmonids. This indicates an additional challenge for the aquaculture sector to grow in a sustainable manner. The adverse environmental conditions often studied in farmed fish is the change in certain water quality parameters such as oxygen and/or temperature that are typically altered in response to climate change and, more specifically, global warming. In a challenge study, we observed that the in the fish fed a plant-based diet, the fish’s ability to absorb dietary energy was further reduced when reared under low oxygen level. In addition, gut health in these fish was severely impaired. Some other studies also confirm the adverse effect of environmental challenge on fish’s gut health. These effects on the digestive function and gut health of salmonids may result in less resistance to diseases and weaker performance with significant economic and ethical implications. Overall, various findings indicate the multidimensional negative effects of climate change, as a major environmental issue, in different sectors, including aquaculture production. Therefore, a comprehensive evaluation of different ways to cope with climate change is essential for planning more sustainable strategies in aquaculture sector.

Keywords: aquaculture, climate change, sustainability, salmonids

Procedia PDF Downloads 157
346 A Low-Cost Memristor Based on Hybrid Structures of Metal-Oxide Quantum Dots and Thin Films

Authors: Amir Shariffar, Haider Salman, Tanveer Siddique, Omar Manasreh

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According to the recent studies on metal-oxide memristors, researchers tend to improve the stability, endurance, and uniformity of resistive switching (RS) behavior in memristors. Specifically, the main challenge is to prevent abrupt ruptures in the memristor’s filament during the RS process. To address this problem, we are proposing a low-cost hybrid structure of metal oxide quantum dots (QDs) and thin films to control the formation of filaments in memristors. We aim to use metal oxide quantum dots because of their unique electronic properties and quantum confinement, which may improve the resistive switching behavior. QDs have discrete energy spectra due to electron confinement in three-dimensional space. Because of Coulomb repulsion between electrons, only a few free electrons are contained in a quantum dot. This fact might guide the growth direction for the conducting filaments in the metal oxide memristor. As a result, it is expected that QDs can improve the endurance and uniformity of RS behavior in memristors. Moreover, we use a hybrid structure of intrinsic n-type quantum dots and p-type thin films to introduce a potential barrier at the junction that can smooth the transition between high and low resistance states. A bottom-up approach is used for fabricating the proposed memristor using different types of metal-oxide QDs and thin films. We synthesize QDs including, zinc oxide, molybdenum trioxide, and nickel oxide combined with spin-coated thin films of titanium dioxide, copper oxide, and hafnium dioxide. We employ fluorine-doped tin oxide (FTO) coated glass as the substrate for deposition and bottom electrode. Then, the active layer composed of one type of quantum dots, and the opposite type of thin films is spin-coated onto the FTO. Lastly, circular gold electrodes are deposited with a shadow mask by using electron-beam (e-beam) evaporation at room temperature. The fabricated devices are characterized using a probe station with a semiconductor parameter analyzer. The current-voltage (I-V) characterization is analyzed for each device to determine the conduction mechanism. We evaluate the memristor’s performance in terms of stability, endurance, and retention time to identify the optimal memristive structure. Finally, we assess the proposed hypothesis before we proceed to the optimization process for fabricating the memristor.

Keywords: memristor, quantum dot, resistive switching, thin film

Procedia PDF Downloads 99
345 Comparative Comparison (Cost-Benefit Analysis) of the Costs Caused by the Earthquake and Costs of Retrofitting Buildings in Iran

Authors: Iman Shabanzadeh

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Earthquake is known as one of the most frequent natural hazards in Iran. Therefore, policy making to improve the strengthening of structures is one of the requirements of the approach to prevent and reduce the risk of the destructive effects of earthquakes. In order to choose the optimal policy in the face of earthquakes, this article tries to examine the cost of financial damages caused by earthquakes in the building sector and compare it with the costs of retrofitting. In this study, the results of adopting the scenario of "action after the earthquake" and the policy scenario of "strengthening structures before the earthquake" have been collected, calculated and finally analyzed by putting them together. Methodologically, data received from governorates and building retrofitting engineering companies have been used. The scope of the study is earthquakes occurred in the geographical area of Iran, and among them, eight earthquakes have been specifically studied: Miane, Ahar and Haris, Qator, Momor, Khorasan, Damghan and Shahroud, Gohran, Hormozgan and Ezgole. The main basis of the calculations is the data obtained from retrofitting companies regarding the cost per square meter of building retrofitting and the data of the governorate regarding the power of earthquake destruction, the realized costs for the reconstruction and construction of residential units. The estimated costs have been converted to the value of 2021 using the time value of money method to enable comparison and aggregation. The cost-benefit comparison of the two policies of action after the earthquake and retrofitting before the earthquake in the eight earthquakes investigated shows that the country has suffered five thousand billion Tomans of losses due to the lack of retrofitting of buildings against earthquakes. Based on the data of the Budget Law's of Iran, this figure was approximately twice the budget of the Ministry of Roads and Urban Development and five times the budget of the Islamic Revolution Housing Foundation in 2021. The results show that the policy of retrofitting structures before an earthquake is significantly more optimal than the competing scenario. The comparison of the two policy scenarios examined in this study shows that the policy of retrofitting buildings before an earthquake, on the one hand, prevents huge losses, and on the other hand, by increasing the number of earthquake-resistant houses, it reduces the amount of earthquake destruction. In addition to other positive effects of retrofitting, such as the reduction of mortality due to earthquake resistance of buildings and the reduction of other economic and social effects caused by earthquakes. These are things that can prove the cost-effectiveness of the policy scenario of "strengthening structures before earthquakes" in Iran.

Keywords: disaster economy, earthquake economy, cost-benefit analysis, resilience

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344 The Use of Vasopressin in the Management of Severe Traumatic Brain Injury: A Narrative Review

Authors: Nicole Selvi Hill, Archchana Radhakrishnan

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Introduction: Traumatic brain injury (TBI) is a leading cause of mortality among trauma patients. In the management of TBI, the main principle is avoiding cerebral ischemia, as this is a strong determiner of neurological outcomes. The use of vasoactive drugs, such as vasopressin, has an important role in maintaining cerebral perfusion pressure to prevent secondary brain injury. Current guidelines do not suggest a preferred vasoactive drug to administer in the management of TBI, and there is a paucity of information on the therapeutic potential of vasopressin following TBI. Vasopressin is also an endogenous anti-diuretic hormone (AVP), and pathways mediated by AVP play a large role in the underlying pathological processes of TBI. This creates an overlap of discussion regarding the therapeutic potential of vasopressin following TBI. Currently, its popularity lies in vasodilatory and cardiogenic shock in the intensive care setting, with increasing support for its use in haemorrhagic and septic shock. Methodology: This is a review article based on a literature review. An electronic search was conducted via PubMed, Cochrane, EMBASE, and Google Scholar. The aim was to identify clinical studies looking at the therapeutic administration of vasopressin in severe traumatic brain injury. The primary aim was to look at the neurological outcome of patients. The secondary aim was to look at surrogate markers of cerebral perfusion measurements, such as cerebral perfusion pressure, cerebral oxygenation, and cerebral blood flow. Results: Eight papers were included in the final number. Three were animal studies; five were human studies, comprised of three case reports, one retrospective review of data, and one randomised control trial. All animal studies demonstrated the benefits of vasopressors in TBI management. One animal study showed the superiority of vasopressin in reducing intracranial pressure and increasing cerebral oxygenation over a catecholaminergic vasopressor, phenylephrine. All three human case reports were supportive of vasopressin as a rescue therapy in catecholaminergic-resistant hypotension. The retrospective review found vasopressin did not increase cerebral oedema in TBI patients compared to catecholaminergic vasopressors; and demonstrated a significant reduction in the requirements of hyperosmolar therapy in patients that received vasopressin. The randomised control trial results showed no significant differences in primary and secondary outcomes between TBI patients receiving vasopressin versus those receiving catecholaminergic vasopressors. Apart from the randomised control trial, the studies included are of low-level evidence. Conclusion: Studies favour vasopressin within certain parameters of cerebral function compared to control groups. However, the neurological outcomes of patient groups are not known, and animal study results are difficult to extrapolate to humans. It cannot be said with certainty whether vasopressin’s benefits stand above usage of other vasoactive drugs due to the weaknesses of the evidence. Further randomised control trials, which are larger, standardised, and rigorous, are required to improve knowledge in this field.

Keywords: catecholamines, cerebral perfusion pressure, traumatic brain injury, vasopressin, vasopressors

Procedia PDF Downloads 48
343 Localized and Time-Resolved Velocity Measurements of Pulsatile Flow in a Rectangular Channel

Authors: R. Blythman, N. Jeffers, T. Persoons, D. B. Murray

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The exploitation of flow pulsation in micro- and mini-channels is a potentially useful technique for enhancing cooling of high-end photonics and electronics systems. It is thought that pulsation alters the thickness of the hydrodynamic and thermal boundary layers, and hence affects the overall thermal resistance of the heat sink. Although the fluid mechanics and heat transfer are inextricably linked, it can be useful to decouple the parameters to better understand the mechanisms underlying any heat transfer enhancement. Using two-dimensional, two-component particle image velocimetry, the current work intends to characterize the heat transfer mechanisms in pulsating flow with a mean Reynolds number of 48 by experimentally quantifying the hydrodynamics of a generic liquid-cooled channel geometry. Flows circulated through the test section by a gear pump are modulated using a controller to achieve sinusoidal flow pulsations with Womersley numbers of 7.45 and 2.36 and an amplitude ratio of 0.75. It is found that the transient characteristics of the measured velocity profiles are dependent on the speed of oscillation, in accordance with the analytical solution for flow in a rectangular channel. A large velocity overshoot is observed close to the wall at high frequencies, resulting from the interaction of near-wall viscous stresses and inertial effects of the main fluid body. The steep velocity gradients at the wall are indicative of augmented heat transfer, although the local flow reversal may reduce the upstream temperature difference in heat transfer applications. While unsteady effects remain evident at the lower frequency, the annular effect subsides and retreats from the wall. The shear rate at the wall is increased during the accelerating half-cycle and decreased during deceleration compared to steady flow, suggesting that the flow may experience both enhanced and diminished heat transfer during a single period. Hence, the thickness of the hydrodynamic boundary layer is reduced for positively moving flow during one half of the pulsation cycle at the investigated frequencies. It is expected that the size of the thermal boundary layer is similarly reduced during the cycle, leading to intervals of heat transfer enhancement.

Keywords: Heat transfer enhancement, particle image velocimetry, localized and time-resolved velocity, photonics and electronics cooling, pulsating flow, Richardson’s annular effect

Procedia PDF Downloads 325
342 Cartilage Mimicking Coatings to Increase the Life-Span of Bearing Surfaces in Joint Prosthesis

Authors: L. Sánchez-Abella, I. Loinaz, H-J. Grande, D. Dupin

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Aseptic loosening remains as the principal cause of revision in total hip arthroplasty (THA). For long-term implantations, submicron particles are generated in vivo due to the inherent wear of the prosthesis. When this occurs, macrophages undergo phagocytosis and secretion of bone resorptive cytokines inducing osteolysis, hence loosening of the implanted prosthesis. Therefore, new technologies are required to reduce the wear of the bearing materials and hence increase the life-span of the prosthesis. Our strategy focuses on surface modification of the bearing materials with a hydrophilic coating based on cross-linked water-soluble (meth)acrylic monomers to improve their tribological behavior. These coatings are biocompatible, with high swelling capacity and antifouling properties, mimicking the properties of natural cartilage, i.e. wear resistance with a permanent hydrated layer that prevents prosthesis damage. Cartilage mimicking based coatings may be also used to protect medical device surfaces from damage and scratches that will compromise their integrity and hence their safety. However, there are only a few reports on the mechanical and tribological characteristics of this type of coatings. Clear beneficial advantages of this coating have been demonstrated in different conditions and different materials, such as Ultra-high molecular weight polyethylene (UHMWPE), Polyethylene (XLPE), Carbon-fiber-reinforced polyetheretherketone (CFR-PEEK), cobalt-chromium (CoCr), Stainless steel, Zirconia Toughened Alumina (ZTA) and Alumina. Using routine tribological experiments, the wear for UHMWPE substrate was decreased by 75% against alumina, ZTA and stainless steel. For PEEK-CFR substrate coated, the amount of material lost against ZTA and CrCo was at least 40% lower. Experiments on hip simulator allowed coated ZTA femoral heads and coated UHMWPE cups to be validated with a decrease of 80% of loss material. Further experiments on hip simulator adding abrasive particles (1 micron sized alumina particles) during 3 million cycles, on a total of 6 million, demonstrated a decreased of around 55% of wear compared to uncoated UHMWPE and uncoated XLPE. In conclusion, CIDETEC‘s hydrogel coating technology is versatile and can be adapted to protect a large range of surfaces, even in abrasive conditions.

Keywords: cartilage, hydrogel, hydrophilic coating, joint

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341 Extraction and Quantification of Peramine Present in Dalaca pallens, a Pest of Grassland in Southtern Chile

Authors: Leonardo Parra, Daniel Martínez, Jorge Pizarro, Fernando Ortega, Manuel Chacón-Fuentes, Andrés Quiroz

Abstract:

Control of Dalaca pallens or blackworms, one of the most important hypogeous pest in grassland in southern Chile, is based on the use of broad-spectrum insecticides such as organophosphates and pyrethroids. However, the rapid development of insecticide resistance in field populations of this insect and public concern over the environmental impact of these insecticides has resulted in the search for other control methods. Specifically, the use of endophyte fungi for controlling pest has emerged as an interesting and promising strategy. Endophytes from ryegrass (Lolium perenne), establish a biotrophic relationship with the host, defined as mutualistic symbiosis. The plant-fungi association produces alkaloids where peramine is the main toxic substance against Listronotus bonariensis, the most important epigean pest of ryegrass. Nevertheless, the effect of peramina on others pest insects, such as D. pallens, to our knowledge has not been studied, and also its possible metabolization in the body of the larvae. Therefore, we addressed the following research question: Do larvae of D. pallens store peramine after consumption of ryegrass endophyte infected (E+)? For this, specimens of blackworms were fed with ryegrass plant of seven experimental lines and one commercial cultivar endophyte free (E-) sown at the Instituto de Investigaciones Agropecuarias Carillanca (Vilcún, Chile). Once the feeding period was over, ten larvae of each treatment were examined. Individuals were dissected, and their gut was removed to exclude any influence of remaining material. The rest of the larva's body was dried at 60°C by 24-48 h and ground into a fine powder using a mortar. 25 mg of dry powder was transferred to a microcentrifuge tube and extracted in 1 mL of a mixture of methanol:water:formic acid. Then, the samples were centrifuged at 16,000 rpm for 3 min, and the supernatant was colected and injected in the liquid chromatography of high resolution (HPLC). The results confirmed the presence of peramine in the larva's body of D. pallens. The insects that fed the experimental lines LQE-2 and LQE-6 were those where peramine was present in high proportion (0.205 and 0.199 ppm, respectively); while LQE-7 and LQE-3 obtained the lowest concentrations of the alkaloid (0.047 and 0.053 ppm, respectively). Peramine was not detected in the insects when the control cultivar Jumbo (E-) was tested. These results evidenced the storage and metabolism of peramine during consumption of the larvae. However, the effect of this alkaloid present in 'future ryegrass cultivars' (LQE-2 and LQE-6) on the performance and survival of blackworms must be studied and confirmed experimentally.

Keywords: blackworms, HPLC, alkaloid, pest

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340 Effect of Wheat Germ Agglutinin- and Lactoferrin-Grafted Catanionic Solid Lipid Nanoparticles on Targeting Delivery of Etoposide to Glioblastoma Multiforme

Authors: Yung-Chih Kuo, I-Hsin Wang

Abstract:

Catanionic solid lipid nanoparticles (CASLNs) with surface wheat germ agglutinin (WGA) and lactoferrin (Lf) were formulated for entrapping and releasing etoposide (ETP), crossing the blood–brain barrier (BBB), and inhibiting the growth of glioblastoma multiforme (GBM). Microemulsified ETP-CASLNs were modified with WGA and Lf for permeating a cultured monolayer of human brain-microvascular endothelial cells (HBMECs) regulated by human astrocytes and for treating malignant U87MG cells. Experimental evidence revealed that an increase in the concentration of catanionic surfactant from 5 μM to 7.5 μM reduced the particle size. When the concentration of catanionic surfactant increased from 7.5 μM to 12.5 μM, the particle size increased, yielding a minimal diameter of WGA-Lf-ETP-CASLNs at 7.5 μM of catanionic surfactant. An increase in the weight percentage of BW from 25% to 75% enlarged WGA-Lf-ETP-CASLNs. In addition, an increase in the concentration of catanionic surfactant from 5 to 15 μM increased the absolute value of zeta potential of WGA-Lf-ETP-CASLNs. It was intriguing that the increment of the charge as a function of the concentration of catanionic surfactant was approximately linear. WGA-Lf-ETP-CASLNs revealed an integral structure with smooth particle contour, displayed a lighter exterior layer of catanionic surfactant, WGA, and Lf and showed a rigid interior region of solid lipids. A variation in the concentration of catanionic surfactant between 5 μM and 15 μM yielded a maximal encapsulation efficiency of ETP ata 7.5 μM of catanionic surfactant. An increase in the concentration of Lf/WGA decreased the grafting efficiency of Lf/WGA. Also, an increase in the weight percentage of ETP decreased its encapsulation efficiency. Moreover, the release rate of ETP from WGA-Lf-ETP-CASLNs reduced with increasing concentration of catanionic surfactant, and WGA-Lf-ETP-CASLNs at 12.5 μM of catanionic surfactant exhibited a feature of sustained release. The order in the viability of HBMECs was ETP-CASLNs ≅ Lf-ETP-CASLNs ≅ WGA-Lf-ETP-CASLNs > ETP. The variation in the transendothelial electrical resistance (TEER) and permeability of propidium iodide (PI) was negligible when the concentration of Lf increased. Furthermore, an increase in the concentration of WGA from 0.2 to 0.6 mg/mL insignificantly altered the TEER and permeability of PI. When the concentration of Lf increased from 2.5 to 7.5 μg/mL and the concentration of WGA increased from 2.5 to 5 μg/mL, the enhancement in the permeability of ETP was minor. However, 10 μg/mL of Lf promoted the permeability of ETP using Lf-ETP-CASLNs, and 5 and 10 μg/mL of WGA could considerably improve the permeability of ETP using WGA-Lf-ETP-CASLNs. The order in the efficacy of inhibiting U87MG cells was WGA-Lf-ETP-CASLNs > Lf-ETP-CASLNs > ETP-CASLNs > ETP. As a result, WGA-Lf-ETP-CASLNs reduced the TEER, enhanced the permeability of PI, induced a minor cytotoxicity to HBMECs, increased the permeability of ETP across the BBB, and improved the antiproliferative efficacy of U87MG cells. The grafting of WGA and Lf is crucial to control the medicinal property of ETP-CASLNs and WGA-Lf-ETP-CASLNs can be promising colloidal carriers in GBM management.

Keywords: catanionic solid lipid nanoparticle, etoposide, glioblastoma multiforme, lactoferrin, wheat germ agglutinin

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339 A Delphi Study of Factors Affecting the Forest Biorefinery Development in the Pulp and Paper Industry: The Case of Bio-Based Products

Authors: Natasha Gabriella, Josef-Peter Schöggl, Alfred Posch

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Being a mature industry, pulp and paper industry (PPI) possess strength points coming from its existing infrastructure, technology know-how, and abundant availability of biomass. However, the declining trend of the wood-based products sales sends a clear signal to the industry to transform its business model in order to increase its profitability. With the emerging global attention on bio-based economy and circular economy, coupled with the low price of fossil feedstock, the PPI starts to integrate biorefinery as a value-added business model to keep the industry’s competitiveness. Nonetheless, biorefinery as an innovation exposes the PPI with some barriers, of which the uncertainty of the promising product becomes one of the major hurdles. This study aims to assess factors that affect the diffusion and development of forest biorefinery in the PPI, including drivers, barriers, advantages, disadvantages, as well as the most promising bio-based products of forest biorefinery. The study examines the identified factors according to the layer of business environment, being the macro-environment, industry, and strategic group level. Besides, an overview of future state of the identified factors is elaborated as to map necessary improvements for implementing forest biorefinery. A two-phase Delphi method is used to collect the empirical data for the study, comprising of an online-based survey and interviews. Delphi method is an effective communication tools to elicit ideas from a group of experts to further reach a consensus of forecasting future trends. Collaborating a total of 50 experts in the panel, the study reveals that influential factors are found in every layers of business of the PPI. The politic dimension is apparent to have a significant influence for tackling the economy barrier while reinforcing the environmental and social benefits in the macro-environment. In the industry level, the biomass availability appears to be a strength point of the PPI while the knowledge gap on technology and market seem to be barriers. Consequently, cooperation with academia and the chemical industry has to be improved. Human resources issue is indicated as one important premise behind the preceding barrier, along with the indication of the PPI’s resistance towards biorefinery implementation as an innovation. Further, cellulose-based products are acknowledged for near-term product development whereas lignin-based products are emphasized to gain importance in the long-term future.

Keywords: forest biorefinery, pulp and paper, bio-based product, Delphi method

Procedia PDF Downloads 250