Search results for: anti-tubercular therapy induced hepatotoxicity

Authors: Sarika Gupta, Harshika Khanna, Ajay K Verma, Surya Kant

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Background: Drug-resistant tuberculosis (DR-TB) is a growing health challenge to global TB control efforts. Pediatric DR-TB is one of the neglected infectious diseases. In our previously published report, we have notified an increased prevalence of DR-TB in the pediatric population at a tertiary health care centre in North India which was estimated as 17.4%, 15.1%, 18.4%, and 20.3% in (%) in the year 2018, 2019, 2020, and 2021. Limited evidence exists about a pattern of drug resistance, side effect profile and programmatic outcomes of Paediatric DR-TB treatment. Therefore, this study was done to find out the pattern of resistance, side effect profile and treatment outcome. Methodology: This was a prospective cohort study conducted at the nodal drug-resistant tuberculosis centre of a tertiary care hospital in North India from January 2021 to December 2022. Subjects included children aged between 0-18 years of age with a diagnosis of DR-TB, on the basis of GeneXpert (rifampicin [RIF] resistance detected), line probe assay and drug sensitivity testing (DST) of M. tuberculosis (MTB) grown on a culture of body fluids. Children were classified as monoresistant TB, polyresistant TB (resistance to more than 1 first-line anti-TB drug, other than both INH and RIF), MDR-TB, pre-XDR-TB and XDR-TB, as per the WHO classification. All the patients were prescribed DR TB treatment as per the standard guidelines, either shorter oral DR-TB regimen or a longer all-oral MDR/XDR-TB regimen (age below five years needed modification). All the patients were followed up for side effects of treatment once per month. The patient outcomes were categorized as good outcomes if they had completed treatment and cured or were improving during the course of treatment, while bad outcomes included death or not improving during the course of treatment. Results: Of the 50 pediatric patients included in the study, 34 were females (66.7%) and 16 were male (31.4%). Around 33 patients (64.7%) were suffering from pulmonary TB, while 17 (33.3%) were suffering from extrapulmonary TB. The proportions of monoresistant TB, polyresistant TB, MDR-TB, pre-XDR-TB and XDR-TB were 2.0%, 0%, 50.0%, 30.0% and 18.0%, respectively. Good outcome was reported in 40 patients (80.0%). The 10 bad outcomes were 7 deaths (14%) and 3 (6.0%) children who were not improving. Adverse events (single or multiple) were reported in all the patients, most of which were mild in nature. The most common adverse events were metallic taste 16(31.4%), rash and allergic reaction 15(29.4%), nausea and vomiting 13(26.0%), arthralgia 11 (21.6%) and alopecia 11 (21.6%). Serious adverse event of QTc prolongation was reported in 4 cases (7.8%), but neither arrhythmias nor symptomatic cardiac side effects occurred. Vestibular toxicity was reported in 2(3.9%), and psychotic symptoms in 4(7.8%). Hepatotoxicity, hypothyroidism, peripheral neuropathy, gynaecomastia, and amenorrhea were reported in 2 (4.0%), 4 (7.8%), 2 (3.9%), 1(2.0%), and 2 (3.9%) respectively. None of the drugs needed to be withdrawn due to uncontrolled adverse events. Conclusion: Paediatric DR TB treatment achieved favorable outcomes in a large proportion of children. DR TB treatment regimen drugs were overall well tolerated in this cohort.

Keywords: pediatric, drug-resistant, tuberculosis, adverse events, treatment

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Authors: F. Alaa Ali, S. A. Sherein Abdelgayed, S. Osama. EL-Tawil, M. Adel Bakeer

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Tartrazine is an organic azo dyes food additive widely used in foods, drugs, and cosmetics. The present study aimed to investigate the toxic effects of tartrazine on kidneys and liver biomarkers in addition to the investigation of oxidative stress and change of histopathological structure of liver and kidneys in 30 male rats. Tartrazine was orally administrated daily at dose 200 mg/ kg bw (1/ 10 LD₅₀) for sixty days. Serum and tissue samples were collected at the end of the experiment to investigate the underlying mechanism of tartrazine through assessment oxidative stress (Glutathione (GSH), Superoxide dismutase (SOD) and malondialdehyde (MDA) and biochemical markers (alanine aminotransferase (ALT), aspartate aminotransferase (AST), Total protein and Urea). Liver and kidneys tissue were collected and preserved in 10% formalin for histopathological examination. The obtained values were statistically analyzed by one way analysis of variance (ANOVA) followed by multiple comparison test. Biochemical analysis revealed that tartrazine induced significant increase in serum ALT, AST, total protein, urea level compared to control group. Tartrazine showed significant decrease in liver GSH and SOD where their values when compared to control group. Tartrazine induced increase in liver MDA compared to control group. Histopathology of the liver showed diffuse vacuolar degeneration in hepatic parenchyma, the portal area showed sever changes sever in hepatoportal blood vessels and in the bile ducts. The kidneys showed degenerated tubules at the cortex together with mononuclear leucocytes inflammatory cells infiltration. There is perivascular edema with inflammatory cell infiltration surrounding the congested and hyalinized vascular wall of blood vessel. The present study indicates that the subchronic effects of tartrazine have a toxic effect on the liver and kidneys together with induction of oxidative stress by formation of free radicals. Therefore, people should avoid the hazards of consuming tartrazine.

Keywords: albino rats, tartrazine, toxicity, pathology

Procedia PDF Downloads 357

Authors: Julia Kapr, Andrea Rossi, Haribaskar Ramachandran, Marius Pollet, Ilka Egger, Selina Dangeleit, Katharina Koch, Jean Krutmann, Ellen Fritsche

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It is widely acknowledged that animal models do not always represent human disease. Especially human brain development is difficult to model in animals due to a variety of structural and functional species-specificities. This causes significant discrepancies between predicted and apparent drug efficacies in clinical trials and their subsequent failure. Emerging alternatives based on 3D in vitro approaches, such as human brain spheres or organoids, may in the future reduce and ultimately replace animal models. Here, we present a human induced pluripotent stem cell (hiPSC)-based 3D neural in a vitro disease model for the Cockayne Syndrome B (CSB). CSB is a rare hereditary disease and is accompanied by severe neurologic defects, such as microcephaly, ataxia and intellectual disability, with currently no treatment options. Therefore, the aim of this study is to investigate the molecular and cellular defects found in neural hiPSC-derived CSB models. Understanding the underlying pathology of CSB enables the development of treatment options. The two CSB models used in this study comprise a patient-derived hiPSC line and its isogenic control as well as a CSB-deficient cell line based on a healthy hiPSC line (IMR90-4) background thereby excluding genetic background-related effects. Neurally induced and differentiated brain sphere cultures were characterized via RNA Sequencing, western blot (WB), immunocytochemistry (ICC) and multielectrode arrays (MEAs). CSB-deficiency leads to an altered gene expression of markers for autophagy, focal adhesion and neural network formation. Cell migration was significantly reduced and electrical activity was significantly increased in the disease cell lines. These data hint that the cellular pathologies is possibly underlying CSB. By induction of autophagy, the migration phenotype could be partially rescued, suggesting a crucial role of disturbed autophagy in defective neural migration of the disease lines. Altered autophagy may also lead to inefficient mitophagy. Accordingly, disease cell lines were shown to have a lower mitochondrial base activity and a higher susceptibility to mitochondrial stress induced by rotenone. Since mitochondria play an important role in neurotransmitter cycling, we suggest that defective mitochondria may lead to altered electrical activity in the disease cell lines. Failure to clear the defective mitochondria by mitophagy and thus missing initiation cues for new mitochondrial production could potentiate this problem. With our data, we aim at establishing a disease adverse outcome pathway (AOP), thereby adding to the in-depth understanding of this multi-faced disorder and subsequently contributing to alternative drug development.

Keywords: autophagy, disease modeling, in vitro, pluripotent stem cells

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Authors: Marie Bajnarová

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The core part of the research project is represented by taking a perspective on the role of an educator in Juvenile Institutional Centres. In accordance with the research questions, the research explores impact of the environment, situations, practices, attitudes, values and also experience of the respondents. Art activities minimize risky behaviours and contribute to a healthy lifestyle. They also help children and adolescents with conduct disorders develop positive social behaviour, psychosocial skills and cope with difficult life situations.

Keywords: Juvenile Detention Centres, drawing, conduct disorders, art therapy

Procedia PDF Downloads 284

Authors: Jeremy Bost, Matthew Brett, Jacob Flynn, Weihui Li

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One response during anaphylaxis is reduced blood pressure due to blood vessels relaxing and dilating. Epinephrine causes the blood vessels to constrict, which raises blood pressure to counteract the symptoms. When going through an allergic reaction, an Epinephrine injector is used to administer a shot of epinephrine intramuscularly. Epinephrine injectors have become an integral part of day-to-day life for people with allergies. Current Epinephrine injectors (EpiPen) are completely mechanical and have no sensors to monitor the vital signs of patients or give suggestions the optimal time for the shot. The EpiPens are also large and inconvenient to carry daily. The current price of an EpiPen is roughly 600$ for a pack of two. This makes carrying an EpiPen very expensive, especially when they need to be switched out when the epinephrine expires. This new design is in the form of a bracelet, which has the ability to inject epinephrine. The bracelet will be equipped with vital signs monitors that can aid the patient to sense the allergic reaction. The vital signs that would be of interest are blood pressure, heart rate and Electrodermal activity (EDA). The heart rate of the patient will be tracked by a photoplethysmograph (PPG) that is incorporated into the sensors. The heart rate is expected to increase during anaphylaxis. Blood pressure will be monitored through a radar sensor, which monitors the phase changes in electromagnetic waves as they reflect off of the blood vessel. EDA is under autonomic control. Allergen-induced anaphylaxis is caused by a release of chemical mediators from mast cells and basophils, thus changes the autonomic activity of the patient. So by measuring EDA, it will give the wearer an alert on how their autonomic nervous system is reacting. After the vital signs are collected, they will be sent to an application on a smartphone to be analyzed, which can then alert an emergency contact if the epinephrine injector on the bracelet is activated. Overall, this design creates a safer system by aiding the user in keeping track of their epinephrine injector, while making it easier to track their vital signs. Also, our design will be more affordable and more convenient to replace. Rather than replacing the entire product, only the needle and drug will be switched out and not the entire design.

Keywords: allergy, anaphylaxis, epinephrine, injector, vital signs monitor

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Authors: Rayhana Begum, Manju Sharma

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Careya arborea Roxb. belongs to the Lecythidaceae family, is traditionally used in tumors, anthelmintic, bronchitis, epileptic fits, astringents, inflammation, an antidote to snake-venom, skin disease, diarrhea, dysentery with bloody stools, dyspepsia, ulcer, toothache, and ear pain. The present study was focused on investigating the anti-arthritic effect of coumaroyl lupendioic acid, a new lupane-type triterpene from Careya arborea stem bark in the chronic inflammatory model and further assessing its possible mechanism on the modulation of inflammatory biomarkers. Arthritis was induced by injecting 0.1 ml of Complete Freund’s Adjuvant (5 mg/ml of heat killed Mycobacterium tuberculosis) into the subplantar region of the left hind paw. Treatment with coumaroyl lupendioic acid (10 and 20 mg/kg, p.o.) and reference drugs (indomethacin and dexamethasone at the dose of 5 mg/kg, p.o.) were started on the day of induction and continued up to 28 days. The progression of arthritis was evaluated by measuring paw volume, tibio tarsal joint diameters, and arthritic index. The effect of coumaroyl lupendioic acid (CLA) on the production PGE₂, NO, MPO, NF-κB, TNF-α, IL-1β, and IL-6 on serum level as well as inflamed paw tissue were also assessed. In addition, ankle joints and spleen were collected and prepared for histological examination. CLA in inflamed rats resulted in significant amelioration of paw edema, tibio-tarsal joint swelling and arthritic score as compared to CFA control group. The results indicated that CLA treated groups markedly decreased the levels of inflammatory mediators (PGE₂, NO, MPO and NF-κB levels) and down-regulated the production of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in paw tissue homogenates as well as in serum. However, the more pronounced effect was observed in the inflamed paw tissue homogenates. CLA also revealed a protective effect to the tibio-tarsal joint cartilage and spleen. These results suggest that coumaroyl lupendioic acid inhibits inflammation may be through the suppression of the cascade of proinflammatory mediators via the down-regulation of NF-ҡB.

Keywords: complete Freund’s adjuvant , Coumaroyl lupendioic acid, pro-inflammatory cytokines, prostaglandin E2

Procedia PDF Downloads 141

Authors: Nicola Milani, Carla Bellissimo, Davide Pogliana, Davide Panzin, Luca Garlaschelli, Giulia Facchinetti, Claudia Casson, Luca Marazzina, Andrea Sartori, Simone Rivaroli, Jeff Konin

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The patient is a 26 year-old male amateur football player from Milan, Italy; (81kg; 185cm; BMI 23.6 kg/m²). He sustained a non-contact anterior cruciate ligament tear to his right knee in June 2021. In September 2021, his right knee ligament was reconstructed using a semitendinosus graft. The injury occurred during a football match on natural grass with typical shoes on a warm day (32 degrees celsius). Playing as a defender he sustained the injury during a change of direction, where the foot was fixated on the grass. He felt pain and was unable to continue playing the match. The surgeon approved his rehabilitation to begin two weeks post-operative. The initial physiotherapist assessment determined performing two training sessions per day within the first three months. In the first three weeks, the pain was 4/10 on Numerical Rating Scale (NRS), no swelling, a range of motion was 0-110°, with difficulty fully extending his knee and minimal quadriceps activation. Crutches were discontinued at four weeks with improved walking. Active exercise, electrostimulator, physical therapy, massages, osteopathy, and passive motion were initiated. At week 6, he completed his first functional movement screen; the score was 16/21 with no pain and no swelling. At week 8, the isokinetic test showed a 23% differential deficit between the two legs in maximum strength (at 90°/s). At week 10, he improved to 15% of injury-induced deficit which suggested he was ready to start running. At week 12, the athlete sustained his first threshold test. At week 16, he performed his first return to sports movement assessment, which revealed a 10% stronger difference between the legs. At week 16, he had his second threshold test. At week 17, his first on-field test revealed a 5% differential deficit between the two legs in the hop test. At week 18, isokinetic test demonstrates that the uninjured leg was 7% stronger than the recovering leg in maximum strength (at 90°/s). At week 20, his second on-field test revealed a 2% difference in hop test; at week 21, his third isokinetic test demonstrated a difference of 5% in maximum strength (at 90°/s). At week 21, he performed his second return to sports movement assessment which revealed a 2% difference between the limbs. Since it was the end of the championship, the team asked him to partake in the playoffs; moreover the player was very motivated to participate in the playoffs also because he was the captain of the team. Together with the player and the team, we decided to let him play even though we were aware of a heightened risk of injury than what is reported in the literature because of two factors: biological recovery times and the results of the tests we performed. In the decision making process about the athlete’s recovery time, it is important to balance the information available from the literature with the desires of the patient to avoid frustration.

Keywords: ACL, football, rehabilitation, return to play

Procedia PDF Downloads 119

Authors: Mahla Azimi

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Introduction: Post-bladder catheter infection is a common and significant healthcare-associated infection that affects individuals with indwelling urinary catheters. These infections can lead to various complications, including urinary tract infections (UTIs), bacteremia, sepsis, and increased morbidity and mortality rates. This article aims to provide a comprehensive review of post-bladder catheter infections, including their causes, risk factors, clinical presentation, diagnosis, treatment options, and preventive measures. Causes and Risk Factors: Post-bladder catheter infections primarily occur due to the colonization of microorganisms on the surface of the urinary catheter. The most common pathogens involved are Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterococcus species. Several risk factors contribute to the development of these infections, such as prolonged catheterization duration, improper insertion technique, poor hygiene practices during catheter care, compromised immune system function in patients with underlying conditions or immunosuppressive therapy. Clinical Presentation: Patients with post-bladder catheter infections may present with symptoms such as fever, chills, malaise, suprapubic pain or tenderness, and cloudy or foul-smelling urine. In severe cases or when left untreated for an extended period of time, patients may develop more severe symptoms like hematuria or signs of systemic infection. Diagnosis: The diagnosis of post-bladder catheter infection involves a combination of clinical evaluation and laboratory investigations. Urinalysis is crucial in identifying pyuria (presence of white blood cells) and bacteriuria (presence of bacteria). A urine culture is performed to identify the causative organism(s) and determine its antibiotic susceptibility profile. Treatment Options: Prompt initiation of appropriate antibiotic therapy is essential in managing post-bladder catheter infections. Empirical treatment should cover common pathogens until culture results are available. The choice of antibiotics should be guided by local antibiogram data to ensure optimal therapy. In some cases, catheter removal may be necessary, especially if the infection is recurrent or associated with severe complications. Preventive Measures: Prevention plays a vital role in reducing the incidence of post-bladder catheter infections. Strategies include proper hand hygiene, aseptic technique during catheter insertion and care, regular catheter maintenance, and timely removal of unnecessary catheters. Healthcare professionals should also promote patient education regarding self-care practices and signs of infection. Conclusion: Post-bladder catheter infections are a significant healthcare concern that can lead to severe complications and increased healthcare costs. Early recognition, appropriate diagnosis, and prompt treatment are crucial in managing these infections effectively. Implementing preventive measures can significantly reduce the incidence of post-bladder catheter infections and improve patient outcomes. Further research is needed to explore novel strategies for prevention and management in this field.

Keywords: post-bladder catheter infection, urinary tract infection, bacteriuria, indwelling urinary catheters, prevention

Procedia PDF Downloads 81

Authors: A. K. Tursunova, O. V. Chebonenko, A. Zh. Amirkulova, A. O. Abaildayev, O. A. Sapko, Y. M. Dyo, A. Sh. Utarbaeva

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Fusarium solani and its variants cause root and stem rot of plants. Dry rot is the most common disease of potato tubers during storage. The causative agents of fusariosis in contact with plants behave as antagonists, growth stimulants or parasites. The diversity of host-parasite relationships is explained by the parasite’s ability to produce a wide spectrum of biologically active compounds including toxins, enzymes, oligosaccharides, antibiotic substances, enniatins and gibberellins. Many of these metabolites contribute to the creation of compatible relations; others behave as elicitors, inducing various protective responses in plants. An important part of the strategy for developing plant resistance against pathogens is the activation of protein synthesis to produce protective ‘pathogenesis-related’ proteins. The family of PR-proteins known to confer the most protective response is chitinases (EC 3.2.1.14, Cht) and β-1,3-glucanases (EC 3.2.1.39, Glu). PR-proteins also include a large multigene family of peroxidases (EC 1.11.1.7, Pod), and increased activity of Pod and expression of the Pod genes leads to the development of resistance to a broad class of pathogens. Despite intensive research on the role of PR-proteins, the question of their participation in the mechanisms of formation of the F.solani–S.tuberosum pathosуstem is not sufficiently studied. Our aim was to investigate the effect of different classes of F. solani metabolites on the activity of chitinase, β-1,3-glucanases and peroxidases in tubers of Solanum tuberosum. Metabolite culture filtrate (CF) and cytoplasmic components were fractionated by extraction of the mycelium with organic solvents, salting out techniques, dialysis, column chromatography and ultrafiltration. Protein, lipid, carbohydrate and polyphenolic fractions of fungal metabolites were derived. Using enzymatic hydrolysis we obtained oligo glycans from fungal cell walls with different molecular weights. The activity of the metabolites was tested using potato tuber discs (d = 16mm, h = 5mm). The activity of PR-proteins of tubers was analyzed in a time course of 2–24 hours. The involvement of the analysed metabolites in the modulation of both early non-specific and late related to pathogenesis reactions was demonstrated. The most effective inducer was isolated from the CF (fraction of total phenolic compounds including naphtazarins). Induction of PR-activity by this fraction was: chitinase - 340-360%, glucanase - 435-450%, soluble forms of peroxidase - 400-560%, related forms of peroxidase - 215-237%. High-inducing activity was observed by the chloroform and acetonitrile extracts of the mycelium (induction of chitinase and glucanase activity was 176-240%, of soluble and bound forms of peroxidase - 190-400%). The fraction of oligo glycans mycelium cell walls of 1.2 kDa induced chitinase and β-1,3-glucanase to 239-320%; soluble forms and related peroxidase to 198-426%. Oligo glycans cell walls of 5-10 kDa had a weak suppressor effect - chitinase (21-25%) and glucanase (25-28%) activity; had no effect on soluble forms of peroxidase, but induced to 250-270% activity related forms. The CF polysaccharides of 8.5 kDa and 3.1 kDa inhibited synchronously the glucanase and chitinase specific response in step (after 24 hours at 42-50%) and the step response induced nonspecific peroxidase activity: soluble forms 4.8 -5.2 times, associated forms 1.4-1.6 times.

Keywords: fusarium solani, PR-proteins, peroxidase, solanum tuberosum

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Authors: E. A. Krasikov

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As a main barrier against radioactivity outlet reactor pressure vessel (RPV) is a key component in terms of NPP safety. Therefore, present-day demands in RPV reliability enhance have to be met by all possible actions for RPV in-service embrittlement mitigation. Annealing treatment is known to be the effective measure to restore the RPV metal properties deteriorated by neutron irradiation. There are two approaches to annealing. The first one is so-called ‘dry’ high temperature (~475°C) annealing. It allows obtaining practically complete recovery, but requires the removal of the reactor core and internals. External heat source (furnace) is required to carry out RPV heat treatment. The alternative approach is to anneal RPV at a maximum coolant temperature which can be obtained using the reactor core or primary circuit pumps while operating within the RPV design limits. This low temperature «wet» annealing, although it cannot be expected to produce complete recovery, is more attractive from the practical point of view especially in cases when the removal of the internals is impossible. The first RPV «wet» annealing was done using nuclear heat (US Army SM-1A reactor). The second one was done by means of primary pumps heat (Belgian BR-3 reactor). As a rule, there is no recovery effect up to annealing and irradiation temperature difference of 70°C. It is known, however, that along with radiation embrittlement neutron irradiation may mitigate the radiation damage in metals. Therefore, we have tried to test the possibility to use the effect of radiation-induced ductilization in ‘wet’ annealing technology by means of nuclear heat utilization as heat and neutron irradiation sources at once. In support of the above-mentioned conception the 3-year duration reactor experiment on 15Cr3NiMoV type steel with preliminary irradiation at operating PWR at 270°C and following extra irradiation (87 h at 330°C) at IR-8 test reactor was fulfilled. In fact, embrittlement was partly suppressed up to value equivalent to 1,5 fold neutron fluence decrease. The degree of recovery in case of radiation enhanced annealing is equal to 27% whereas furnace annealing results in zero effect under existing conditions. Mechanism of the radiation-induced damage mitigation is proposed. It is hoped that «wet » annealing technology will help provide a better management of the RPV degradation as a factor affecting the lifetime of nuclear power plants which, together with associated management methods, will help facilitate safe and economic long-term operation of PWRs.

Keywords: controlling, embrittlement, radiation, steel, wet annealing

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Authors: Yazan S. Khaled, Shazana Shamsuddin, Jim Tiernan, Mike McPherson, Thomas Hughes, Paul Millner, David G. Jayne

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Introduction: There is a need for real-time imaging of colorectal cancer (CRC) to allow tailored surgery to the disease stage. Fluorescence guided laparoscopic imaging of primary colorectal cancer and the draining lymphatics would potentially bring stratified surgery into clinical practice and realign future CRC management to the needs of patients. Fluorescent nanoparticles can offer many advantages in terms of intra-operative imaging and therapy (theranostic) in comparison with traditional soluble reagents. Nanoparticles can be functionalised with diverse reagents and then targeted to the correct tissue using an antibody or Affimer (artificial binding protein). We aimed to develop and test fluorescent silica nanoparticles and targeted against CRC using an anti-carcinoembryonic antigen (CEA) Affimer (Aff). Methods: Anti-CEA and control Myoglobin Affimer binders were subcloned into the expressing vector pET11 followed by transformation into BL21 Star™ (DE3) E.coli. The expression of Affimer binders was induced using 0.1 mM isopropyl β-D-1-thiogalactopyranoside (IPTG). Cells were harvested, lysed and purified using nickle chelating affinity chromatography. The photosensitiser Foslip (soluble analogue of 5,10,15,20-Tetra(m-hydroxyphenyl) chlorin) was incorporated into the core of silica nanoparticles using water-in-oil microemulsion technique. Anti-CEA or control Affs were conjugated to silica nanoparticles surface using sulfosuccinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (sulfo SMCC) chemical linker. Binding of CEA-Aff or control nanoparticles to colorectal cancer cells (LoVo, LS174T and HC116) was quantified in vitro using confocal microscopy. Results: The molecular weights of the obtained band of Affimers were ~12.5KDa while the diameter of functionalised silica nanoparticles was ~80nm. CEA-Affimer targeted nanoparticles demonstrated 9.4, 5.8 and 2.5 fold greater fluorescence than control in, LoVo, LS174T and HCT116 cells respectively (p < 0.002) for the single slice analysis. A similar pattern of successful CEA-targeted fluorescence was observed in the maximum image projection analysis, with CEA-targeted nanoparticles demonstrating 4.1, 2.9 and 2.4 fold greater fluorescence than control particles in LoVo, LS174T, and HCT116 cells respectively (p < 0.0002). There was no significant difference in fluorescence for CEA-Affimer vs. CEA-Antibody targeted nanoparticles. Conclusion: We are the first to demonstrate that Foslip-doped silica nanoparticles conjugated to anti-CEA Affimers via SMCC allowed tumour cell-specific fluorescent targeting in vitro, and had shown sufficient promise to justify testing in an animal model of colorectal cancer. CEA-Affimer appears to be a suitable targeting molecule to replace CEA-Antibody. Targeted silica nanoparticles loaded with Foslip photosensitiser is now being optimised to drive photodynamic killing, via reactive oxygen generation.

Keywords: colorectal cancer, silica nanoparticles, Affimers, antibodies, imaging

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Authors: Neslihan Demirci, Serdar Durdağı

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Mycobacterium tuberculosis is still a worldwide disease-causing agent that, according to WHO, led to the death of 1.5 million people from tuberculosis (TB) in 2020. The bacteria reside in macrophages located specifically in the lung. There is a known quadruple drug therapy regimen for TB consisting of isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB). Over the past 60 years, there have been great contributions to treatment options, such as recently approved delamanid (OPC67683) and bedaquiline (TMC207/R207910), targeting mycolic acid and ATP synthesis, respectively. Also, there are natural compounds that can block the tryptophanyl-tRNA synthetase (TrpRS) enzyme, chuangxinmycin, and indolmycin. Yet, already the drug resistance is reported for those agents. In this study, the newly released TrpRS enzyme structure is investigated for potential inhibitor drugs from already synthesized molecules to help the treatment of resistant cases and to propose an alternative drug for the quadruple drug therapy of tuberculosis. Maestro, Schrodinger is used for docking and molecular dynamic simulations. In-house library containing ~8000 compounds among FDA-approved indole-containing compounds, a total of 57 obtained from the ChemBL were used for both ATP and tryptophan binding pocket docking. Best of indole-containing 57 compounds were subjected to hit expansion and compared later with virtual screening workflow (VSW) results. After docking, VSW was done. Glide-XP docking algorithm was chosen. When compared, VSW alone performed better than the hit expansion module. Best scored compounds were kept for ten ns molecular dynamic simulations by Desmond. Further, 100 ns molecular dynamic simulation was performed for elected molecules according to Z-score. The top three MMGBSA-scored compounds were subjected to steered molecular dynamic (SMD) simulations by Gromacs. While SMD simulations are still being conducted, ponesimod (for multiple sclerosis), vilanterol (β₂ adrenoreceptor agonist), and silodosin (for benign prostatic hyperplasia) were found to have a significant affinity for tuberculosis TrpRS, which is the propulsive force for the urge to expand the research with in vitro studies. Interestingly, top-scored ponesimod has been reported to have a side effect that makes the patient prone to upper respiratory tract infections.

Keywords: drug repurposing, molecular dynamics, tryptophanyl-tRNA synthetase, tuberculosis

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Authors: M. R. Aher, R. B. Laware, G. S. Asane, B. S. Kuchekar

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Objective: Studies have shown that a new combination therapy with Artemisinin derivatives and curcumin is unique, with potential advantages over known ACTs. In present study an attempt was made to prepare microparticulate drug delivery system of Curcumin-Zn complex and evaluate it in combination with artemether for antimalarial activity. Material and method: Curcumin Zn complex was prepared and encapsulated using sodium alginate. Microparticles thus obtained are further coated with various enteric polymers at different coating thickness to control the release. Microparticles are evaluated for encapsulation efficiency, drug loading and in vitro drug release. Roentgenographic Studies was conducted in rabbits with BaSO 4 tagged formulation. Optimized formulation was screened for antimalarial activity using P. berghei-infected mice survival test and % paracetemia inhibition, alone (three oral dose of 5mg/day) and in combination with arthemether (i.p. 500, 1000 and 1500µg). Curcumin-Zn(II) was estimated in serum after oral administration to rats by using spectroflurometry. Result: Microparticles coated with Cellulose acetate phthalate showed most satisfactory and controlled release with 479 min time for 60% drug release. X-ray images taken at different time intervals confirmed the retention of formulation in GI tract. Estimation of curcumin in serum by spectroflurometry showed that drug concentration is maintained in the blood for longer time with tmax of 6 hours. The survival time (40 days post treatment) of mice infected with P. berghei was compared to survival after treatment with either Curcumin-Zn(II) microparticles artemether combination, curcumin-Zn complex and artemether. Oral administration of Curcumin-Zn(II)-artemether prolonged the survival of P.berghei-infected mice. All the mice treated with Curcumin-Zn(II) microparticles (5mg/day) artemether (1000µg) survived for more than 40 days and recovered with no detectable parasitemia. Administration of Curcumin-Zn(II) artemether combination reduced the parasitemia in mice by more than 90% compared to that in control mice for the first 3 days after treatment. Conclusion: Antimalarial activity of the curcumin Zn-artemether combination was more pronounced than mono therapy. A single dose of 1000µg of artemether in curcumin-Zn combination gives complete protection in P. berghei-infected mice. This may reduce the chances of drug resistance in malaria management.

Keywords: formulation, microparticulate drug delivery, antimalarial, pharmaceutics

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Authors: Abubakar Maitama Yusuf Hotoro, Olokpo Israel Olofu, Yusuf U. Tarauni, Mudassir A. Umar, Aliyu A, Dahiru Garba Diso, Usman H. Jamoh, M. Sale

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The study assessed the impact of environmental pollution on groundwater potential at Tudun Murtala waste land fill using electrical resistivity, induced polarization and Physiochemical methods. The study area is located between latitude 12.023678N and longitude 8.573676 E. Geophysical data were collected at maximum length of 140m along twelve profiles using ABEM Terrameter SAS 1000. Results from the Geophysical analysis showed that the profiles were underlain by three lithological layers; the top layer consisting of Loamy and Sand soils, alluvium, granite, shale and sandstone. The second and third layers were predominantly made of weathered and fractured basements respectively. The potential groundwater water bearing zones of the study area occurred at VES2, VES4, VES5, VES6 and VES7. The thicknesses of the sounding points were found to be 20.8m at VES2; 25.2m at VES4; 13.2m at VES5; 50.8m at VES6 and 13.3m at VES7. The corresponding depths for the sounding points were 20.8m at VES2; 27.9m at VES4; 26.7m at VES5; 51.6m at VES6 and 24.9m at VES7 respectively. The Physiochemical study of selected groundwater samples assessed parameters such as the Electrical Conductivity, EC (288dS/m to 1365dS/m), TDS (170.8mg/L to 820mg/L) Pb (0.546mg/l to 0.629mg/l), Cu (-0.001mg/l to 0.004mg/l), and Cd (0.031mg/l to 0.092mg/l). The physiochemical results showed that the groundwater around the dumpsite may have been contaminated, especially in Dumpsite Hole 1 and Hole 2 at VES4 and VES6 respectively. There are indications for suspected leachate mitigation around the two VES points. Even though, the pH values of 6.4 and 6.2 at the two sounding points were considered to be within the permissible pH range (6.5 to 6.8). The values of other elements present in the groundwater for the samples at other VES points were found to be above permissible WHO and Nigerian Standards for Drinking Water.

Keywords: resistivity induced polarization, chargeability, landfill, leachate, contamination

Procedia PDF Downloads 62

Authors: Luís R. Silva, Catarina Bento, Ana C. Gonçalves, Fábio Jesus, Branca M. Silva

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Nowadays, the general population is more and more concerned about nutrition and the health implications of an unbalanced diet. Current knowledge regarding the health benefits and antioxidant properties of certain foods such as fruits and vegetables has gained the interest of both the general public and scientific community. Peach (Prunus persica (L.) Batsch) is one of the most consumed fruits worldwide, with low sugar contents and a broad range of nutrients essential to the normal functioning of the body. Six different peach cultivars from the Fundão region in Portugal were evaluated regarding their phenolic composition by LC-DAD and biological activity. The prepared extracts’ capacity to scavenge free-radicals was tested through the stable free radical DPPH• and nitric oxide (•NO). Additionally, antidiabetic potential and protective effects against peroxyl radical (ROO•) induced damage to erythrocytes were also tested. LC-DAD analysis allowed the identification of 17 phenolic compounds, among which 5-O-caffeoylquinic acids and 3-O-caffeoylquinic acids are pointed out as the most abundant. Regarding the antioxidant activity, all cultivars displayed concentration-dependent free-radical scavenging activity against both nitrogen species and DPPH•. In respect to α-glucosidase inhibitory activity, Royal Magister and Royal Glory presented the highest inhibitory activity (IC50 = 11.7 ± 1.4 and 17.1 ± 1.7 μg/mL, respectively), nevertheless all six cultivars presented higher activity than the control acarbose. As for the protective effect of Royal Lu extract on the oxidative damage induced in erythrocytes by ROO•, the results were quite promising showing inhibition IC50 values of 110.0 ± 4.5 μg/mL and 83.8 ± 6.5 μg/mL for hemolysis and hemoglobin oxidation, respectively. The demonstrated activity is of course associated to the peaches’ phenolic profile, rich in phenolic acids and flavonoids with high hydrogen donating capacity. These compounds have great industrial interest for the manufacturing of natural products. The following step would naturally be the extraction and isolation from the plant tissues and large-scale production through biotechnology techniques.

Keywords: antioxidants, functional food, phenolic compounds, peach

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Authors: Cristina Núñez, Rufina Bastida, Elena Labisbal, Alejandro Macías, María T. Pereira, José M. Vila

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A highly selective quinoline-based fluorescent sensor L was designed in order to functionalize gold nanoparticles (GNPs@L). The cytotoxicity of compound L and GNPs@L on the MCF-7 breast cancer cells was explored and it was observed that L and GNPs@L compounds induced apoptosis in MCF-7 cancer cells. The cellular uptake of the hybrid system GNPs@L was studied using confocal laser scanning microscopy (CLSM).

Keywords: cytotoxicity, fluorescent probes, nanoparticles, quinoline

Procedia PDF Downloads 382

Authors: Sweta Pandey, Samridhi Dhyani, Susmita Chaudhuri

Abstract:

Klebsiella pneumoniae causes a wide range of infections, including urinary tract infections, sepsis, bacteremia, pneumonia, and liver abscesses. The emergence of multi-drug resistance in this bacterium led to a major setback for clinical management. WHO also endorsed a need for finding alternative therapy to antibiotics for the treatment of these infections. Development of vaccines and passive antibody therapy has been proven as a potent alternative to antibiotics in the case of MDR, XDR, and PDR Klebsiella infections. Siderophore receptors have been demonstrated to be overexpressed for the internalization of iron siderophore complexes during infections in most Gram-negative bacteria. For the present study, immune response to siderophore receptors to establish this protein as a potential immunogen for the development of therapeutic leads was explored. Clinical strains of Klebsiella pneumoniae were grown in iron-deficient conditions, and the iron-regulated outer membrane proteins were extracted and characterized through mass spectrometry for specific identification. The gene for identified protein was cloned in pET- 28a vector and expressed in E. coli. The native protein and the recombinant protein were isolated and purified and used as antigens for the generation of immune response in BALB/c mice. The native protein of Klebsiella pneumoniae grown in iron-deficient conditions was identified as FepA (Ferrienterobactin receptor) and other siderophore receptors. This 80 kDa protein generated an immune response in BALB/c mice. The antiserum from mice after subsequent booster doses was collected and showed binding with FepA protein in western blot and phagocytic uptake of the K. pneumoniae in the presence antiserum from immunized mice also observed from the animal studies after bacterial challenge post immunisation in mice have shown bacterial clearance. The antiserum from mice showed binding and clearance of the Klebsiella pneumoniae bacteria in vitro and in vivo. These antigens used for generating an active immune response in mice can further be used for therapeutic monoclonal antibody development against Klebsiella pneumoniae infections.

Keywords: antiserum, FepA, Klebsiella pneumoniae, multi drug resistance, siderophore receptor

Procedia PDF Downloads 102

Authors: R. H. Begaydarova, B. Zh. Kultanov, B. T. Esilbaeva, G. E. Nasakaeva, Y. Yukhnevich, G. K. Alshynbekova, A. E. Dyusembaeva

Abstract:

Background: The level of middle molecules of peptides (MMP) allows to evaluate the severity and prognosis of the disease and is a criterion for the effectiveness of the treatment. The detection the products of lipidperoxidation cascade, such as conjugated dienes, malondialdehyde in biological material, has an important role in the development of pathogenesis, the diagnosis and prognosis in different parasitic diseases. Purpose of the study was to evaluate the state of endogenous intoxication and indicators of lipid peroxidation in patients with giardiasis before and after treatment. Materials and methods: Endogenous intoxication was evaluated in patients with giardiasis in the level of middle molecules of peptides (MMP) in the blood. The amount of MMP and products of lipid peroxidation were determined in the blood of 198 patients with giardiasis, 129 of them were women (65%), 69 were men (35%). The MMP level was detected for comparison in the blood of 84 healthy volunteers. The lipid peroxidation were determined in 40 healthy men and women without giardiasis and history of chronic diseases. Data were processed by conventional methods of variation statistics, we calculated the arithmetic mean (M) and standard dispersion (m). t-test (t) was used to assess differences. Results: The level of MMP in the blood was significantly higher in patients with giardiasis in comparison with group of healthy men and women. MMP concentration in the blood of women with Giardia was 2.5 times greater than that of the comparison groups of women. The level of MMP exceeds more than 6 times in men with giardiasis. The decrease in the intensity of endogenous intoxication was two weeks after antigiardia therapy, both men and women. According to the study, a statistically significant increase in the level of all the studied parameters lipid peroxidation cascade was observed in the blood of men with giardiasis, with the exception of the total primary production (NGN). The treatment of giardiasis helped to stabilize the level of almost all metabolites of lipid peroxidation cascade. The exception was level of malondialdehyde, it was significantly elevated to compare with the control group and after treatment. Conclusion: Thus, the MMP level was significantly higher in blood of patients with giardiasis than in comparison group. This is evidence of severe endogenous intoxication caused by giardia infection. The accumulation of primary and secondary products of lipid peroxidation was observed in the blood of men and women. These processes tend to be more active in men than in women. Antigiardiasis therapy contributed to the normalization of almost all the studied indicators of lipid peroxidation in the blood of participants, except the level malondialdehyde in the blood of men.

Keywords: enzymes of antioxidant protection, giardiasis, blood, treatment

Procedia PDF Downloads 238

Authors: Hager Elsheikh, Juliane Glaubitz, Frank Ulrich Weiss, Matthias Sendler

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Aim: Acute pancreatitis (AP) and chronic pancreatitis (CP) are both accompanied by a prominent immune response which influences the course of disease. Whereas during AP the pro-inflammatory immune response dominates, during CP a fibroinflammatory response regulates organ remodeling. The transcription factor signal transducer and activator of transcription 6 (STAT6) is a crucial part of the Type 2 immune response. Here we investigate the role of STAT6 in a mouse model of AP and CP. Material and Methods: AP was induced by hourly repetitive i.p. injections of caerulein (50µg/kg/bodyweight) in C57Bl/6 J and STAT6-/- mice. CP was induced by repetitive caerulein injections 6 times a day, 3 days a week over 4 weeks. Disease severity was evaluated by serum amylase/lipase measurement, H&E staining of pancreas. Pancreatic infiltrate was characterized by immunofluorescent labeling of CD68, CD206, CCR2, CD4 and CD8. Pancreas fibrosis was evaluated by Azan blue staining. qRT-PCR was performed of Arg1, Nos2, Il6, Il1b, Col3a, Socs3 and Ym1. Affymetrix chip array analyses were done to illustrate the IL4/IL13/STAT6 signaling in bone marrow derived macrophages. Results: AP severity is mitigated in STAT6-/- mice, as shown by decreased serum amylase and lipase, as well as histological damage. CP mice surprisingly showed only slightly reduced fibrosis of the pancreas. Also staining of CD206 a classical marker of alternatively activated macrophages showed no decrease of M2-like polarization in the absence of STAT6. In contrast, transcription profile analysis in BMDM showed complete blockade of the IL4/IL13 pathway in STAT6-/- animals. Conclusion: STAT6 signaling pathway is protective during AP and mitigates the pancreatic damage. During chronic pancreatitis the IL4/IL13 – STAT6 axisis involved in organ fibrogenesis. Notably, fibrosis is not dependent on a single signaling pathway, and alternative macrophage activation is also complex and involves different subclasses (M2a, M2b, M2c and M2d) which could be independent of the IL4/IL13 STAT6 axis.

Keywords: chronic pancreatitis, macrophages, IL4/IL13, Type immune response

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Authors: Christina Williams, Mehari Weldemariam, Ann M. Farese, Thomas J. MacVittie, Maureen A. Kane

Abstract:

Radiation exposure results in dose-dependent and time-dependent multi-organ damage. Drug development of medical countermeasures (MCM) for radiation-induced injury occurs under the FDA Animal Rule because human efficacy studies are not ethical or feasible. The FDA Animal Rule requires the representation of both sexes and describes several uses for biomarkers in MCM drug development studies. Currently, MCMs are limited and there is no FDA-approved biomarker for any radiation injury. Sex as a variable is essential to identifying biomarkers and developing effective MCMs for acute radiation exposure (ARS) and delayed effects of acute radiation exposure (DEARE). These studies aim to address the death of information on sex differences that have not been determined by studies that included only male, single-sex cohorts. Studies have reported differences in radiosensitivity according to sex. As such, biomarker discovery for radiation-induced damage must consider sex as a variable. This study evaluated the plasma proteomic profile of Rhesus macaque non-human primates after different exposures and doses, as well as time points after radiation. Exposures and doses included total body irradiation between 5-7.5 Gy and partial body irradiation with 5% bone marrow sparing at 9, 9.5 and 10 Gy. Timepoints after irradiation included days 1, 3, 60, and 180, which encompassed both acute radiation syndromes and delayed effects of acute radiation exposure. Bottom-up proteomic analyses of plasma included equal numbers of males and females. In the control animals, few proteomic differences are observed between the sexes. In the irradiated animals, there are a few sex differences, with changes mostly consisting of proteins upregulated in the female animals. Multiple canonical pathways were upregulated in irradiated animals relative to the control animals when subjected to pathway analysis, but differential responses between the sexes are limited. These data provide critical baseline differences according to sex and establish sex differences in non-human primate models relevant to drug development of MCM under the FDA Animal Rule.

Keywords: ionizing radiation, sex differences, plasma proteomics, biomarker discovery

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Authors: Hosam Abdelhady

Abstract:

Filming the behaviors of individual DNA molecules in their environment when they interact with individual medicinal nano-polymers in a molecular scale has opened the door to understand the effect of the molecular shape, size, and incubation time with nanocarriers on optimizing the design of robust genetic Nano molecules able to resist the enzymatic degradation, enter the cell, reach to the nucleus and kill individual cancer cells in their environment. To this end, we will show how we applied the 4D AFM as a guide to finetune the design of genetic nanoparticles and to film the effects of these nanoparticles on the nanomechanical and morphological profiles of individual cancer cells.

Keywords: AFM, dendrimers, nanoparticles, DNA, gene therapy, imaging

Procedia PDF Downloads 73

Authors: Zuzanna Miodonska, Michal Krecichwost, Pawel Badura

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Sigmatism (lisping) is a speech disorder in which sibilant consonants are mispronounced. The diagnosis of this phenomenon is usually based on the auditory assessment. However, the progress in speech analysis techniques creates a possibility of developing computer-aided sigmatism diagnosis tools. The aim of the study is to statistically verify whether specific acoustic features of sibilant sounds may be related to pronunciation correctness. Such knowledge can be of great importance while implementing classifiers and designing novel tools for automatic sibilants pronunciation evaluation. The study covers analysis of various speech signal measures, including features proposed in the literature for the description of normative sibilants realization. Amplitudes and frequencies of three fricative formants (FF) are extracted based on local spectral maxima of the friction noise. Skewness, kurtosis, four normalized spectral moments (SM) and 13 mel-frequency cepstral coefficients (MFCC) with their 1st and 2nd derivatives (13 Delta and 13 Delta-Delta MFCC) are included in the analysis as well. The resulting feature vector contains 51 measures. The experiments are performed on the speech corpus containing words with selected sibilant sounds (/ʃ, ʒ/) pronounced by 60 preschool children with proper pronunciation or with natural pathologies. In total, 224 /ʃ/ segments and 191 /ʒ/ segments are employed in the study. The Mann-Whitney U test is employed for the analysis of stigmatism and normative pronunciation. Statistically, significant differences are obtained in most of the proposed features in children divided into these two groups at p < 0.05. All spectral moments and fricative formants appear to be distinctive between pathology and proper pronunciation. These metrics describe the friction noise characteristic for sibilants, which makes them particularly promising for the use in sibilants evaluation tools. Correspondences found between phoneme feature values and an expert evaluation of the pronunciation correctness encourage to involve speech analysis tools in diagnosis and therapy of sigmatism. Proposed feature extraction methods could be used in a computer-assisted stigmatism diagnosis or therapy systems.

Keywords: computer-aided pronunciation evaluation, sigmatism diagnosis, speech signal analysis, statistical verification

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Authors: Iman Farasat, Howard M. Salis

Abstract:

The CRISPR/Cas9 system has revolutionized genome engineering by enabling site-directed and high-throughput genome editing, genome insertion, and gene knockdowns in several species, including bacteria, yeast, flies, worms, and human cell lines. This technology has the potential to enable human gene therapy to treat genetic diseases and cancer at the molecular level; however, the current CRISPR/Cas9 system suffers from seemingly sporadic off-target genome mutagenesis that prevents its use in gene therapy. A comprehensive mechanistic model that explains how the CRISPR/Cas9 functions would enable the rational design of the guide-RNAs responsible for target site selection while minimizing unexpected genome mutagenesis. Here, we present the first quantitative model of the CRISPR/Cas9 genome mutagenesis system that predicts how guide-RNA sequences (crRNAs) control target site selection and cleavage activity. We used statistical thermodynamics and law of mass action to develop a five-step biophysical model of cas9 cleavage, and examined it in vivo and in vitro. To predict a crRNA's binding specificities and cleavage rates, we then compiled a nearest neighbor (NN) energy model that accounts for all possible base pairings and mismatches between the crRNA and the possible genomic DNA sites. These calculations correctly predicted crRNA specificity across 5518 sites. Our analysis reveals that cas9 activity and specificity are anti-correlated, and, the trade-off between them is the determining factor in performing an RNA-mediated cleavage with minimal off-targets. To find an optimal solution, we first created a scheme of safe-design criteria for Cas9 target selection by systematic analysis of available high throughput measurements. We then used our biophysical model to determine the optimal Cas9 expression levels and timing that maximizes on-target cleavage and minimizes off-target activity. We successfully applied this approach in bacterial and mammalian cell lines to reduce off-target activity to near background mutagenesis level while maintaining high on-target cleavage rate.

Keywords: biophysical model, CRISPR, Cas9, genome editing

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Authors: Ji-Chan Jang

Abstract:

Tuberculosis is still major health problem because there is an increase of multidrug-resistant and extensively drug-resistant forms of the disease. Therefore, the most urgent clinical need is to discover potent agents and develop novel drug combination capable of reducing the duration of MDR and XDR tuberculosis therapy. Three reference strains H37Rv, CDC1551, W-Beijing GC1237 and six clinical isolates of MDRTB were tested to daptomycin in the range of 0.013 to 256 mg/L. Daptomycin is resistant to all tested M. tuberculosis strains not only laboratory strains but also clinical MDR strains that were isolated at different source. Daptomycin will not be an antibiotic of choice for treating infection of Gram positive atypical slowly growing M. tuberculosis.

Keywords: tuberculosis, daptomycin, resistance, Mycobacterium tuberculosis

Procedia PDF Downloads 385

Authors: Fernanda Piculo, Giovana Vesentini, Gabriela Marini, Debora Cristina Damasceno, Angelica Mercia Pascon Barbosa, Marilza Vieira Cunha Rudge

Abstract:

Introduction: Women with previous gestational diabetes mellitus (GDM) were significantly more likely to have urinary incontinence (UI) and pelvic floor muscle dysfunction compared to non-diabetic women two years after a cesarean section. Additional results demonstrated that induced diabetes causes detrimental effects on pregnant rat urethral muscle. These results indicate the need for exploration of the mechanistic role of a recovery factor in female UI. Chemokine ligand 7 (CCL7) was significantly over expressed in rat serum, urethral and vaginal tissues immediately following induction of stress UI in a rat model simulating birth trauma. CCL7 over expression has shown potency for stimulating targeted stem cell migration and provide a translational link (clinical measurement) which further provide opportunities for treatment. The aim of this study was to investigate the CCL7 levels profile in diabetic pregnant women with urinary incontinence during pregnancy over the first year postpartum. Methods: This study was conducted in the Perinatal Diabetes Research Center of the Botucatu Medical School/UNESP, and was approved by the Research Ethics Committee of the Institution (CAAE: 20639813.0.0000.5411). The diagnosis of GDM was established between 24th and 28th gestational weeks, by the 75 g-OGTT test according to ADA’s criteria. Urinary incontinence was defined according to the International Continence Society and the CCL7 levels was measured by ELISA (R&D Systems, Catalog Number DCC700). Two hundred twelve women were classified into four study groups: normoglycemic continent (NC), normoglycemic incontinent (NI), diabetic continent (DC) and diabetic incontinent (DI). They were evaluated at six-time-points: 12-18, 24-28 and 34-38 gestational weeks, 24-48 hours, 6 weeks and 6-12 months postpartum. Results: At 12-18 weeks, it was possible to consider only two groups, continent and incontinent, because at this early gestational period has not yet been the diagnosis of GDM. The group with GDM and UI (DI group) showed lower levels of CCL7 in all time points during pregnancy and postpartum, compared to normoglycemic groups (NC and NI), indicating that these women have not recovered from child birth induced UI during the 6-12 months postpartum compared to their controls, and that the progression of UI and/or lack of recovery throughout the first postpartum year can be related with lower levels of CCL7. Instead, serum CCL7 was significantly increased in the NC group. Taken together, these findings of overexpression of CCL7 in the NC group and decreased levels in the DI group, could confirm that diabetes delays the recovery from child birth induced UI, and that CCL7 could potentially be used as a serum marker of injury. Conclusion: This study demonstrates lower levels of CCL7 in the DI group during pregnancy and postpartum and suggests that the progression of UI in diabetic women and/or lack of recovery throughout the first postpartum year can be related with low levels of CCL7. This provides a translational potential where CCL7 measurement could be used as a surrogate for injury after delivery. Successful controlled CCL7 mediated stem cell homing to the lower urinary tract could one day introduce the potential for non-operative treatment or prevention of stress urinary incontinence.

Keywords: CCL7, gestational diabetes, pregnancy, urinary incontinence

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Authors: Ananya Gupta, Sangeeta Bhaskar

Abstract:

Mycobacterium indicus pranii (MIP) is a saprophytic mycobacterium. It is a predecessor of M. avium complex (MAC). Whole genome analysis and growth kinetics studies have placed MIP in between pathogenic and non-pathogenic species. It shares significant antigenic repertoire with M. tuberculosis and have unique immunomodulatory properties. MIP provides better protection than BCG against pulmonary tuberculosis in animal models. Immunization with MIP by aerosol route provides significantly higher protection as compared to immunization by subcutaneous (s.c.) route. However, mechanism behind differential protection has not been studied. In this study, using mice model we have evaluated and compared the M.tb specific immune response in lung compartments (airway lumen / lung interstitium) as well as spleen following MIP immunization via nasal (i.n.) and s.c. route. MIP i.n. vaccination resulted in increased seeding of memory T cells (CD4+ and CD8+ T-cells) in the airway lumen. Frequency of CD4+ T cells expressing Th1 migratory marker (CXCR3) and activation marker (CD69) were also high in airway lumen of MIP i.n. group. Significantly high ex vivo secretion of cytokines- IFN-, IL-12, IL-17 and TNF- from cells of airway luminal spaces provides evidence of antigen-specific lung immune response, besides generating systemic immunity comparable to MIP s.c. group. Analysis of T cell response on per cell basis revealed that antigen specific T-cells of MIP i.n. group were functionally superior as higher percentage of these cells simultaneously secreted IFN-gamma, IL-2 and TNF-alpha cytokines as compared to MIP s.c. group. T-cells secreting more than one of the cytokines simultaneously are believed to have robust effector response and crucial for protection, compared with single cytokine secreting T-cells. Adoptive transfer of airway luminal T-cells from MIP i.n. group into trachea of naive B6 mice revealed that MIP induced CD8 T-cells play crucial role in providing long term protection. Thus the study demonstrates that MIP intranasal vaccination induces M.tb specific memory T-cells in the airway lumen that results in an early and robust recall response against M.tb infection.

Keywords: airway lumen, Mycobacterium indicus pranii, Th1 migratory markers, vaccination

Procedia PDF Downloads 187

Authors: Elsa Reethu, S. Karthik Babu, N. Syed

Abstract:

Background: Studies in the past focused on the additional benefits of action observation in improving upper and lower limb functions and improving activities of daily living when administered along with conventional therapy. Nevertheless, there is a paucity of literature proving the effects of motor imagery of truncal exercise in improving trunk control in patients with stroke. Aims/purpose: To study the effect of motor imagery of truncal exercises on trunk function and balance in early stroke. Methods: A total of 24 patients were included in the study. 12 were included in the experimental group and 12 were included in control group Trunk function was measured using Trunk Control Test (TCT), Trunk Impairment Scale Verheyden (TIS Verheyden) and Trunk Impairment Scale Fujiwara (TIS Fujiwara). The balance was assessed using Brunel Balance Assessment (BBA) and Tinetti POMA. For the experimental group, each session was for 30 minutes of physical exercises and 15 minutes of motor imagery, once a day, six times a week for 3 weeks and prior to the exercise session, patients viewed a video tape of all the trunk exercises to be performed for 15minutes. The control group practiced the trunk exercises alone for the same duration. Measurements were taken before, after and 4 weeks after intervention. Results: The effect of treatment in motor imagery group showed better improvement when compared with control group when measured after 3 weeks on values of static sitting balance, dynamic balance, total TIS (Verheyden) score, BBA, Tinetti balance and gait with a large effect size of 0.86, 1.99, 1.69, 1.06, 1.63 and 0.97 respectively. The moderate effect size was seen in values of TIS Fujiwara (0.58) and small effect size was seen on TCT (0.12) and TIS coordination component (0.13).at the end of 4 weeks after intervention, the large effect size was identified on values of dynamic balance (2.06), total TIS score (1.59) and Tinetti balance (1.24). The moderate effect size was observed on BBA (0.62) and Tinetti gait (0.72). Conclusion: Trunk motor imagery is effective in improving trunk function and balance in patients with stroke and has a carryover effect in the aspects of mobility. The therapy gain that was observed during the time of discharge was seen to be maintained at the follow-up levels.

Keywords: stroke, trunk rehabilitation, trunk function, balance, motor imagery

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Authors: Qing Liu, Jean-fabien Capsal, Claude Richard

Abstract:

In this current contribution, authors are dedicated to investigate influence of the crystal lamellae orientation on electromechanical behaviors of relaxor ferroelectric Poly (vinylidene fluoride –trifluoroethylene -chlorotrifluoroethylene) (P(VDF-TrFE-CTFE)) films by control of polymer microstructure, aiming to picture the full map of structure-property relationship. In order to define their crystal orientation films, terpolymer films were fabricated by solution-casting, stretching and hot-pressing process. Differential scanning calorimetry, impedance analyzer, and tensile strength techniques were employed to characterize crystallographic parameters, dielectric permittivity, and elastic Young’s modulus respectively. In addition, large electrical induced out-of-plane electrostrictive strain was obtained by cantilever beam mode. Consequently, as-casted pristine films exhibited surprisingly high electrostrictive strain 0.1774% due to considerably small value of elastic Young’s modulus although relatively low dielectric permittivity. Such reasons contributed to large mechanical elastic energy density. Instead, due to 2 folds increase of elastic Young’s modulus and less than 50% augmentation of dielectric constant, fully-crystallized film showed weak electrostrictive behavior and mechanical energy density as well. And subjected to mechanical stretching process, Film C exhibited stronger dielectric constant and out-performed electrostrictive strain over Film B because edge-on crystal lamellae orientation induced by uniaxially mechanical stretch. Hot-press films were compared in term of cooling rate. Rather large electrostrictive strain of 0.2788% for hot-pressed Film D in quenching process was observed although its dielectric permittivity equivalent to that of pristine as-casted Film A, showing highest mechanical elastic energy density value of 359.5 J/m^3. In hot-press cooling process, dielectric permittivity of Film E saw values at 48.8 concomitant with ca.100% increase of Young’s modulus. Films with intermediate mechanical energy density were obtained.

Keywords: crystal orientation, electrostroctive strain, mechanical energy density, permittivity, relaxor ferroelectric

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Authors: Simran Kaur, Paul J. Van Geel

Abstract:

A coupled Thermal-Mechanical-Biological (TMB) model was developed for the analysis of impacts of temperatures on waste stabilization at a Municipal Solid Waste (MSW) landfill in Quebec, Canada using COMSOL Multiphysics, a finite element-based software. For waste placed in landfills in Northern climates during winter months, it can take months or even years before the waste approaches ideal temperatures for biodegradation to occur. Therefore, the proposed model links biodegradation induced strain in MSW to waste temperatures and corresponding heat generation rates as a result of anaerobic degradation. This provides a link between the thermal-biological and mechanical behavior of MSW. The thermal properties of MSW are further linked to density which is tracked and updated in the mechanical component of the model, providing a mechanical-thermal link. The settlement of MSW is modelled based on the concept of viscoelasticity. The specific viscoelastic model used is a single Kelvin – Voight viscoelastic body in which the finite element response is controlled by the elastic material parameters – Young’s Modulus and Poisson’s ratio. The numerical model was validated with 10 years of temperature and settlement data collected from a landfill in Ste. Sophie, Quebec. The coupled TMB modelling framework, which simulates placement of waste lifts as they are placed progressively in the landfill, allows for optimization of several thermal and mechanical parameters throughout the depth of the waste profile and helps in better understanding of temperature dependence of MSW stabilization. The model is able to illustrate how waste placed in the winter months can delay biodegradation-induced settlement and generation of landfill gas. A delay in waste stabilization will impact the utilization of the approved airspace prior to the placement of a final cover and impact post-closure maintenance. The model provides a valuable tool to assess different waste placement strategies in order to increase airspace utilization within landfills operating under different climates, in addition to understanding conditions for increased gas generation for recovery as a green and renewable energy source.

Keywords: coupled model, finite element modeling, landfill, municipal solid waste, waste stabilization

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Authors: David Bakker, Nikki Rickard

Abstract:

Smartphone apps hold immense potential as mental health and wellbeing tools. Support can be made easily accessible and can be used in real-time while users are experiencing distress. Furthermore, data can be collected to enable machine learning and automated tailoring of support to users. While many apps have been developed for mental health purposes, few have adhered to evidence-based recommendations and even fewer have pursued experimental validation. This paper details the development and experimental evaluation of an app, MoodMission, that aims to provide support for low moods and anxiety, help prevent clinical depression and anxiety disorders, and serve as an adjunct to professional clinical supports. MoodMission was designed to deliver cognitive behavioural therapy for specifically reported problems in real-time, momentary interactions. Users report their low moods or anxious feelings to the app along with a subjective units of distress scale (SUDS) rating. MoodMission then provides a choice of 5-10 short, evidence-based mental health strategies called Missions. Users choose a Mission, complete it, and report their distress again. Automated tailoring, gamification, and in-built data collection for analysis of effectiveness was also included in the app’s design. The development process involved construction of an evidence-based behavioural plan, designing of the app, building and testing procedures, feedback-informed changes, and a public launch. A randomized controlled trial (RCT) was conducted comparing MoodMission to two other apps and a waitlist control condition. Participants completed measures of anxiety, depression, well-being, emotional self-awareness, coping self-efficacy and mental health literacy at the start of their app use and 30 days later. At the time of submission (November 2016) over 300 participants have participated in the RCT. Data analysis will begin in January 2017. At the time of this submission, MoodMission has over 4000 users. A repeated-measures ANOVA of 1390 completed Missions reveals that SUDS (0-10) ratings were significantly reduced between pre-Mission ratings (M=6.20, SD=2.39) and post-Mission ratings (M=4.93, SD=2.25), F(1,1389)=585.86, p < .001, np2=.30. This effect was consistent across both low moods and anxiety. Preliminary analyses of the data from the outcome measures surveys reveal improvements across mental health and wellbeing measures as a result of using the app over 30 days. This includes a significant increase in coping self-efficacy, F(1,22)=5.91, p=.024, np2=.21. Complete results from the RCT in which MoodMission was evaluated will be presented. Results will also be presented from the continuous outcome data being recorded by MoodMission. MoodMission was successfully developed and launched, and preliminary analysis suggest that it is an effective mental health and wellbeing tool. In addition to the clinical applications of MoodMission, the app holds promise as a research tool to conduct component analysis of psychological therapies and overcome restraints of laboratory based studies. The support provided by the app is discrete, tailored, evidence-based, and transcends barriers of stigma, geographic isolation, financial limitations, and low health literacy.

Keywords: anxiety, app, CBT, cognitive behavioural therapy, depression, eHealth, mission, mobile, mood, MoodMission

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