Browse publications by year: 2018

  1. Rostam MA, Shajimoon A, Kamato D, Mitra P, Piva TJ, Getachew R, et al.
    J. Pharmacol. Exp. Ther., 2018 04;365(1):156-164.
    PMID: 29438988 DOI: 10.1124/jpet.117.244483
    Transforming growth factor-β (TGF-β) is a pleiotropic growth factor implicated in the development of atherosclerosis for its role in mediating glycosaminoglycan (GAG) chain hyperelongation on the proteoglycan biglycan, a phenomenon that increases the binding of atherogenic lipoproteins in the vessel wall. Phosphorylation of the transcription factor Smad has emerged as a critical step in the signaling pathways that control the synthesis of biglycan, both the core protein and the GAG chains. We have used flavopiridol, a well-known cyclin-dependent kinase inhibitor, to study the role of linker region phosphorylation in the TGF-β-stimulated synthesis of biglycan. We used radiosulfate incorporation and SDS-PAGE to assess proteoglycan synthesis, real-time polymerase chain reaction to assess gene expression, and chromatin immunoprecipitation to assess the binding of Smads to the promoter region of GAG Synthesizing genes. Flavopiridol blocked TGF-β-stimulated synthesis of mRNA for the GAG synthesizing enzymes, and chondroitin 4-sulfotransferase (C4ST-1), chondroitin sulfate synthase-1 (ChSy-1) and TGF-β-mediated proteoglycans synthesis as well as GAG hyperelongation. Flavopiridol blocked TGF-β-stimulated Smad2 phosphorylation at both the serine triplet and the isolated threonine residue in the linker region. The binding of Smad to the promoter region of the C4ST-1 and ChSy-1 genes was stimulated by TGF-β, and this response was blocked by flavopiridol, demonstrating that linker region phosphorylated Smad can pass to the nucleus and positively regulate transcription. These results demonstrate the validity of the kinases, which phosphorylate the Smad linker region as potential therapeutic target(s) for the development of an agent to prevent atherosclerosis.
    MeSH terms: Cell Nucleus/drug effects*; Cell Nucleus/metabolism*; Flavonoids/pharmacology*; Glycosaminoglycans/metabolism; Humans; Muscle, Smooth, Vascular/cytology; Phosphorylation/drug effects; Piperidines/pharmacology*; Signal Transduction/drug effects; Gene Expression Regulation, Enzymologic/drug effects; Transforming Growth Factor beta/pharmacology*; Active Transport, Cell Nucleus/drug effects; Smad2 Protein/metabolism*; Smad2 Protein/chemistry*; Biglycan/biosynthesis*
  2. Hossain M, Islam A, Kamarul T, Hossain G
    BMC Pediatr, 2018 03 02;18(1):93.
    PMID: 29499670 DOI: 10.1186/s12887-018-1076-0
    BACKGROUND: Breastfeeding offers incredible health benefits to both child and mother. It is suggested by World Health Organization that an able mother should practice and maintain exclusive breastfeeding for first six months of her infant's life. The objective of this study was to determine the prevalence and factors associated with exclusive breastfeeding for first six months of an infant's life in Bangladesh.

    METHODS: Data was extracted from Bangladesh Demographic and Health Survey (BDHS-2014). BDHS-2014 collected data from 17,863 Bangladeshi married women in reproductive age from the entire country using two stages stratified cluster sampling. We included only mothers having at least one child currently aged not less than 6 months. Mothers who did not have child to breastfeed, some incomplete information and missing samples were excluded from the data set and consequently 3541 mothers were considered in the present study. Chi-square test, binary logistic regression models were used in this study.

    RESULTS: The prevalence of exclusive breastfeeding (EBF) for first six months of an infant's life in Bangladesh was 35.90%. Binary multivariable logistic regression model demonstrated that relatively less educated mothers were more likely to exclusively breastfeed their children than higher educated mothers. (AOR = 2.28, 95% CI: 1.05-4.93; p 

    MeSH terms: Adolescent; Adult; Bangladesh; Breast Feeding/psychology; Breast Feeding/statistics & numerical data*; Cross-Sectional Studies; Female; Humans; Infant; Infant, Newborn; Maternal Behavior*; Middle Aged; Socioeconomic Factors; Logistic Models; Young Adult
  3. Ismail BA, Kafy HT, Sulieman JE, Subramaniam K, Thomas B, Mnzava A, et al.
    Parasit Vectors, 2018 03 02;11(1):122.
    PMID: 29499751 DOI: 10.1186/s13071-018-2732-9
    BACKGROUND: Long-lasting insecticidal nets (LLINs) (with pyrethroids) and indoor residual spraying (IRS) are the cornerstones of the Sudanese malaria control program. Insecticide resistance to the principal insecticides in LLINs and IRS is a major concern. This study was designed to monitor insecticide resistance in Anopheles arabiensis from 140 clusters in four malaria-endemic areas of Sudan from 2011 to 2014. All clusters received LLINs, while half (n = 70), distributed across the four regions, had additional IRS campaigns.

    METHODS: Anopheles gambiae (s.l.) mosquitoes were identified to species level using PCR techniques. Standard WHO insecticide susceptibility bioassays were carried out to detect resistance to deltamethrin (0.05%), DDT (4%) and bendiocarb (0.1%). TaqMan assays were performed on random samples of deltamethrin-resistant phenotyped and pyrethrum spray collected individuals to determine Vgsc-1014 knockdown resistance mutations.

    RESULTS: Anopheles arabiensis accounted for 99.9% of any anopheline species collected across all sites. Bioassay screening indicated that mosquitoes remained susceptible to bendiocarb but were resistance to deltamethrin and DDT in all areas. There were significant increases in deltamethrin resistance over the four years, with overall mean percent mortality to deltamethrin declining from 81.0% (95% CI: 77.6-84.3%) in 2011 to 47.7% (95% CI: 43.5-51.8%) in 2014. The rate of increase in phenotypic deltamethrin-resistance was significantly slower in the LLIN + IRS arm than in the LLIN-only arm (Odds ratio 1.34; 95% CI: 1.02-1.77). The frequency of Vgsc-1014F mutation varied spatiotemporally with highest frequencies in Galabat (range 0.375-0.616) and New Halfa (range 0.241-0.447). Deltamethrin phenotypic-resistance correlated with Vgsc-1014F frequency.

    CONCLUSION: Combining LLIN and IRS, with different classes of insecticide, may delay pyrethroid resistance development, but the speed at which resistance develops may be area-specific. Continued monitoring is vital to ensure optimal management and control.

    MeSH terms: Animals; Anopheles/drug effects*; Anopheles/genetics; Biological Assay; Female; Insecticide Resistance/genetics*; Insecticides/pharmacology; Malaria/epidemiology; Malaria/prevention & control*; Mosquito Control*; Nitriles/pharmacology; Pyrethrins/pharmacology; Sudan/epidemiology; Insecticide-Treated Bednets; Mosquito Vectors/drug effects*; Mosquito Vectors/parasitology
  4. Teo BW, Zhang L, Guh JY, Tang SCW, Jha V, Kang DH, et al.
    Adv Chronic Kidney Dis, 2018 01;25(1):41-48.
    PMID: 29499886 DOI: 10.1053/j.ackd.2017.10.005
    The National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines recommended the Modification of Diet in Renal Disease study equation for estimating glomerular filtration rate (GFR) for the classification of CKD, but its accuracy was limited to North American patients with estimated GFR <60 mL/min per 1.73 m2 body surface area of European (White) or African (Black) descent. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) developed another equation for estimating GFR, derived from a population that included both participants without kidney disease and with CKD. But many ethnicities were inadequately represented. The International Society of Nephrology, Kidney Disease Improving Global Outcomes committee promulgated clinical practice guidelines, which recommended the CKD-EPI equation. Investigators in Asia subsequently assessed the performance of these GFR estimating equations-the Modification of Diet in Renal Disease study equation, the CKD-EPI equation (creatinine only), and the CKD-EPI equations (creatinine and cystatin C). In this review, we summarize the studies performed in Asia on validating or establishing new Asian ethnicity GFR estimating equations. We included both prospective and retrospective studies which used serum markers traceable to reference materials and focused the review of the performance of GFR estimation by comparisons with the GFR estimations obtained from the CKD-EPI equations.
    MeSH terms: Decision Support Techniques; Glomerular Filtration Rate*; Humans; Global Health; Reproducibility of Results; Practice Guidelines as Topic; Asian Continental Ancestry Group*; Renal Insufficiency, Chronic/diagnosis*; Renal Insufficiency, Chronic/ethnology*; Renal Insufficiency, Chronic/physiopathology
  5. Mostafa SA, Mustapha A, Mohammed MA, Ahmad MS, Mahmoud MA
    Int J Med Inform, 2018 04;112:173-184.
    PMID: 29500017 DOI: 10.1016/j.ijmedinf.2018.02.001
    Autonomous agents are being widely used in many systems, such as ambient assisted-living systems, to perform tasks on behalf of humans. However, these systems usually operate in complex environments that entail uncertain, highly dynamic, or irregular workload. In such environments, autonomous agents tend to make decisions that lead to undesirable outcomes. In this paper, we propose a fuzzy-logic-based adjustable autonomy (FLAA) model to manage the autonomy of multi-agent systems that are operating in complex environments. This model aims to facilitate the autonomy management of agents and help them make competent autonomous decisions. The FLAA model employs fuzzy logic to quantitatively measure and distribute autonomy among several agents based on their performance. We implement and test this model in the Automated Elderly Movements Monitoring (AEMM-Care) system, which uses agents to monitor the daily movement activities of elderly users and perform fall detection and prevention tasks in a complex environment. The test results show that the FLAA model improves the accuracy and performance of these agents in detecting and preventing falls.
    MeSH terms: Aged; Algorithms; Computer Simulation; Humans; Models, Theoretical*; Monitoring, Physiologic/methods*; Movement*; Pattern Recognition, Automated/methods*; Fuzzy Logic*
  6. Kalid N, Zaidan AA, Zaidan BB, Salman OH, Hashim M, Albahri OS, et al.
    J Med Syst, 2018 Mar 02;42(4):69.
    PMID: 29500683 DOI: 10.1007/s10916-018-0916-7
    This paper presents a new approach to prioritize "Large-scale Data" of patients with chronic heart diseases by using body sensors and communication technology during disasters and peak seasons. An evaluation matrix is used for emergency evaluation and large-scale data scoring of patients with chronic heart diseases in telemedicine environment. However, one major problem in the emergency evaluation of these patients is establishing a reasonable threshold for patients with the most and least critical conditions. This threshold can be used to detect the highest and lowest priority levels when all the scores of patients are identical during disasters and peak seasons. A practical study was performed on 500 patients with chronic heart diseases and different symptoms, and their emergency levels were evaluated based on four main measurements: electrocardiogram, oxygen saturation sensor, blood pressure monitoring, and non-sensory measurement tool, namely, text frame. Data alignment was conducted for the raw data and decision-making matrix by converting each extracted feature into an integer. This integer represents their state in the triage level based on medical guidelines to determine the features from different sources in a platform. The patients were then scored based on a decision matrix by using multi-criteria decision-making techniques, namely, integrated multi-layer for analytic hierarchy process (MLAHP) and technique for order performance by similarity to ideal solution (TOPSIS). For subjective validation, cardiologists were consulted to confirm the ranking results. For objective validation, mean ± standard deviation was computed to check the accuracy of the systematic ranking. This study provides scenarios and checklist benchmarking to evaluate the proposed and existing prioritization methods. Experimental results revealed the following. (1) The integration of TOPSIS and MLAHP effectively and systematically solved the patient settings on triage and prioritization problems. (2) In subjective validation, the first five patients assigned to the doctors were the most urgent cases that required the highest priority, whereas the last five patients were the least urgent cases and were given the lowest priority. In objective validation, scores significantly differed between the groups, indicating that the ranking results were identical. (3) For the first, second, and third scenarios, the proposed method exhibited an advantage over the benchmark method with percentages of 40%, 60%, and 100%, respectively. In conclusion, patients with the most and least urgent cases received the highest and lowest priority levels, respectively.
    MeSH terms: Chronic Disease; Data Interpretation, Statistical*; Decision Support Techniques*; Emergencies*; Heart Diseases/physiopathology*; Humans; Oxygen/blood; Stochastic Processes; Telemetry/methods*; Time Factors; Reproducibility of Results; Electrocardiography, Ambulatory; Blood Pressure Monitoring, Ambulatory; Monitoring, Ambulatory/methods*; Remote Sensing Technology
  7. Al Madfai F, Valah B, Zaidi STR, Wanandy T, Ming LC, Peterson GM, et al.
    J Clin Pharm Ther, 2018 Aug;43(4):530-535.
    PMID: 29500838 DOI: 10.1111/jcpt.12674
    WHAT IS KNOWN AND OBJECTIVE: Continuous infusion of dobutamine plays an important role in the management of patients with end-stage heart failure. Home infusion of dobutamine using a continuous ambulatory delivery device (CADD) facilitates the management of patients in their home, avoiding complications associated with long-term hospitalization. However, the stability of dobutamine in CADD is currently unknown. Therefore, this study investigated the physicochemical stability of dobutamine in CADDs at three different temperatures over various time points.

    METHODS: Six CADDs (three containing dobutamine 10 mg/mL in 0.9% sodium chloride and three containing dobutamine 10 mg/mL in 5% glucose) were prepared and stored at 4°C for 7 days, followed by 12 hours at 35°C and then for another 12 hours at 25°C. An aliquot (n = 3) was withdrawn aseptically at 0, 24, 48, 72, 96, 120, 144 and 168 hours when stored at 4°C, and at 0, 6 and 12 hours when stored at the other two temperatures. Each sample was analysed for dobutamine concentration using a stability-indicating high-performance liquid chromatography. All the samples were also evaluated for change in pH, colour and for particle content.

    RESULTS AND DISCUSSION: No evidence of particle formation, colour or pH change was observed throughout the study period. Dobutamine, when admixed with 0.9% sodium chloride or 5% glucose, was found to be chemically stable for at least 168 hours at 4°C and for another 12 hours at 35°C and for another 12 hours at 25°C.

    WHAT IS NEW AND CONCLUSIONS: Our findings will allow health professionals to provide a weekly supply of dobutamine-containing CADDs to patients for home infusions. Continuous infusion over a 24-hour period using one CADD per day will also decrease the number of exchanges required and thus reduce the risk of catheter-related bloodstream infections.

    MeSH terms: Dobutamine/administration & dosage; Dobutamine/chemistry*; Drug Packaging/methods; Drug Stability; Heart Failure/drug therapy; Humans; Infusion Pumps; Temperature; Drug Delivery Systems/methods
  8. Tan K, Chong MC, Subramaniam P, Wong LP
    Nurse Educ Today, 2018 May;64:180-189.
    PMID: 29500999 DOI: 10.1016/j.nedt.2017.12.030
    BACKGROUND: Outcome Based Education (OBE) is a student-centered approach of curriculum design and teaching that emphasize on what learners should know, understand, demonstrate and how to adapt to life beyond formal education. However, no systematic review has been seen to explore the effectiveness of OBE in improving the competencies of nursing students.

    OBJECTIVE: To appraise and synthesize the best available evidence that examines the effectiveness of OBE approaches towards the competencies of nursing students.

    DESIGN: A systematic review of interventional experimental studies.

    DATA SOURCES: Eight online databases namely CINAHL, EBSCO, Science Direct, ProQuest, Web of Science, PubMed, EMBASE and SCOPUS were searched.

    REVIEW METHODS: Relevant studies were identified using combined approaches of electronic database search without geographical or language filters but were limited to articles published from 2006 to 2016, handsearching journals and visually scanning references from retrieved studies. Two reviewers independently conducted the quality appraisal of selected studies and data were extracted.

    RESULTS: Six interventional studies met the inclusion criteria. Two of the studies were rated as high methodological quality and four were rated as moderate. Studies were published between 2009 and 2016 and were mostly from Asian and Middle Eastern countries. Results showed that OBE approaches improves competency in knowledge acquisition in terms of higher final course grades and cognitive skills, improve clinical skills and nursing core competencies and higher behavioural skills score while performing clinical skills. Learners' satisfaction was also encouraging as reported in one of the studies. Only one study reported on the negative effect.

    CONCLUSIONS: Although OBE approaches does show encouraging effects towards improving competencies of nursing students, more robust experimental study design with larger sample sizes, evaluating other outcome measures such as other areas of competencies, students' satisfaction, and patient outcomes are needed.

    MeSH terms: Clinical Competence*; Curriculum; Educational Measurement/methods*; Humans; Learning; Students, Nursing*
  9. Usman MS, Hussein MZ, Kura AU, Fakurazi S, Masarudin MJ, Ahmad Saad FF
    Molecules, 2018 Feb 24;23(2).
    PMID: 29495251 DOI: 10.3390/molecules23020500
    We have synthesized a graphene oxide (GO)-based theranostic nanodelivery system (GOTS) for magnetic resonance imaging (MRI) using naturally occurring protocatechuic acid (PA) as an anticancer agent and gadolinium (III) nitrate hexahydrate (Gd) as the starting material for a contrast agent,. Gold nanoparticles (AuNPs) were subsequently used as second diagnostic agent. The GO nanosheets were first prepared from graphite via the improved Hummer's protocol. The conjugation of the GO and the PA was done via hydrogen bonding and π-π stacking interactions, followed by surface adsorption of the AuNPs through electrostatic interactions. GAGPA is the name given to the nanocomposite obtained from Gd and PA conjugation. However, after coating with AuNPs, the name was modified to GAGPAu. The physicochemical properties of the GAGPA and GAGPAu nanohybrids were studied using various characterization techniques. The results from the analyses confirmed the formation of the GOTS. The powder X-ray diffraction (PXRD) results showed the diffractive patterns for pure GO nanolayers, which changed after subsequent conjugation of the Gd and PA. The AuNPs patterns were also recorded after surface adsorption. Cytotoxicity and magnetic resonance imaging (MRI) contrast tests were also carried out on the developed GOTS. The GAGPAu was significantly cytotoxic to the human liver hepatocellular carcinoma cell line (HepG2) but nontoxic to the standard fibroblast cell line (3T3). The GAGPAu also appeared to possess higher T1 contrast compared to the pure Gd and water reference. The GOTS has good prospects of serving as future theranostic platform for cancer chemotherapy and diagnosis.
    MeSH terms: Animals; Cell Line; Cell Survival/drug effects; Drug Carriers*; Drug Stability; Gadolinium/chemistry*; Gold/chemistry*; Graphite/chemistry*; Humans; Kinetics; Magnetic Resonance Imaging; Models, Molecular; Molecular Conformation; Oxides/chemistry*; Spectrum Analysis, Raman; X-Ray Diffraction; Drug Delivery Systems*; Spectroscopy, Fourier Transform Infrared; Nanostructures/ultrastructure; Nanostructures/chemistry; Mice; Metal Nanoparticles/ultrastructure; Metal Nanoparticles/chemistry*; Hydroxybenzoates/administration & dosage*; Hydroxybenzoates/chemistry; Drug Liberation
  10. Ishak N, Lajis AFB, Mohamad R, Ariff AB, Mohamed MS, Halim M, et al.
    Molecules, 2018 Feb 24;23(2).
    PMID: 29495254 DOI: 10.3390/molecules23020501
    The synthesis of kojic acid derivative (KAD) from kojic and palmitic acid (C16:0) in the presence of immobilized lipase from Rhizomucor miehei (commercially known as Lipozyme RMIM), was studied using a shake flask system. Kojic acid is a polyfunctional heterocycles that acts as a source of nucleophile in this reaction allowing the formation of a lipophilic KAD. In this study, the source of biocatalyst, Lipozyme RMIM, was derived from the lipase of Rhizomucor miehei immobilized on weak anion exchange macro-porous Duolite ES 562 by the adsorption technique. The effects of solvents, enzyme loading, reaction temperature, and substrate molar ratio on the reaction rate were investigated. In one-factor-at-a-time (OFAT) experiments, a high reaction rate (30.6 × 10-3 M·min-1) of KAD synthesis was recorded using acetone, enzyme loading of 1.25% (w/v), reaction time of 12 h, temperature of 50 °C and substrate molar ratio of 5:1. Thereafter, a yield of KAD synthesis was optimized via the response surface methodology (RSM) whereby the optimized molar ratio (fatty acid: kojic acid), enzyme loading, reaction temperature and reaction time were 6.74, 1.97% (w/v), 45.9 °C, and 20 h respectively, giving a high yield of KAD (64.47%). This condition was reevaluated in a 0.5 L stirred tank reactor (STR) where the agitation effects of two impellers; Rushton turbine (RT) and pitch-blade turbine (PBT), were investigated. In the STR, a very high yield of KAD synthesis (84.12%) was achieved using RT at 250 rpm, which was higher than the shake flask, thus indicating better mixing quality in STR. In a rheological study, a pseudoplastic behavior of KAD mixture was proposed for potential application in lotion formulation.
    MeSH terms: Acetone/chemistry; Calorimetry, Differential Scanning; Catalysis; Esterification; Kinetics; Lipase/chemistry*; Models, Chemical; Pyrones/chemical synthesis; Pyrones/chemistry*; Rheology; Solvents/chemistry*; Temperature; Thermodynamics; Thermogravimetry; Rhizomucor/chemistry*; Chemistry Techniques, Synthetic
  11. Nik Mansor NN, Leong TT, Safitri E, Futra D, Ahmad NS, Nasuruddin DN, et al.
    Sensors (Basel), 2018 Feb 26;18(3).
    PMID: 29495352 DOI: 10.3390/s18030686
    A tri-enzyme system consisting of choline kinase/choline oxidase/horseradish peroxidase was used in the rapid and specific determination of the biomarker for bacterial sepsis infection, secretory phospholipase Group 2-IIA (sPLA2-IIA). These enzymes were individually immobilized onto the acrylic microspheres via succinimide groups for the preparation of an electrochemical biosensor. The reaction of sPLA2-IIA with its substrate initiated a cascading enzymatic reaction in the tri-enzyme system that led to the final production of hydrogen peroxide, which presence was indicated by the redox characteristics of potassium ferricyanide, K₃Fe(CN)₆. An amperometric biosensor based on enzyme conjugated acrylic microspheres and gold nanoparticles composite coated onto a carbon-paste screen printed electrode (SPE) was fabricated and the current measurement was performed at a low potential of 0.20 V. This enzymatic biosensor gave a linear range 0.01-100 ng/mL (R² = 0.98304) with a detection limit recorded at 5 × 10-3 ng/mL towards sPLA2-IIA. Moreover, the biosensor showed good reproducibility (relative standard deviation (RSD) of 3.04% (n = 5). The biosensor response was reliable up to 25 days of storage at 4 °C. Analysis of human serum samples for sPLA2-IIA indicated that the biosensor has potential for rapid bacterial sepsis diagnosis in hospital emergency department.
    MeSH terms: Electrodes; Enzymes, Immobilized; Gold; Humans; Hydrogen Peroxide; Phospholipases; Reproducibility of Results; Biosensing Techniques*; Biomarkers; Sepsis; Metal Nanoparticles
  12. Patel RP, Jacob J, Sedeeq M, Ming LC, Wanandy T, Zaidi STR, et al.
    Clin Ther, 2018 04;40(4):664-667.
    PMID: 29496321 DOI: 10.1016/j.clinthera.2018.02.009
    PURPOSE: The aim was to investigate the stability of cefazolin in elastomeric infusion devices.

    METHODS: Elastomeric devices (Infusor LV) that contain cefazolin (3 g/240 mL and 6 g/240 mL) were prepared and stored at 4°C for 72 hours and then at 35°C for 12 hours, followed by 25°C for 12 hours. An aliquot was withdrawn at predefined time points and analyzed for the concentration of cefazolin. Samples were also assessed for changes in pH, solution color, and particle content.

    FINDINGS: Cefazolin retained acceptable chemical and physical stability over the studied storage period and conditions.

    IMPLICATIONS: These findings will allow the administration of cefazolin by the Infusor LV elastomeric device in the outpatient and remote settings.

  13. Nyon MP, Du L, Tseng CK, Seid CA, Pollet J, Naceanceno KS, et al.
    Vaccine, 2018 03 27;36(14):1853-1862.
    PMID: 29496347 DOI: 10.1016/j.vaccine.2018.02.065
    Middle East respiratory syndrome coronavirus (MERS-CoV) has infected at least 2040 patients and caused 712 deaths since its first appearance in 2012, yet neither pathogen-specific therapeutics nor approved vaccines are available. To address this need, we are developing a subunit recombinant protein vaccine comprising residues 377-588 of the MERS-CoV spike protein receptor-binding domain (RBD), which, when formulated with the AddaVax adjuvant, it induces a significant neutralizing antibody response and protection against MERS-CoV challenge in vaccinated animals. To prepare for the manufacture and first-in-human testing of the vaccine, we have developed a process to stably produce the recombinant MERS S377-588 protein in Chinese hamster ovary (CHO) cells. To accomplish this, we transfected an adherent dihydrofolate reductase-deficient CHO cell line (adCHO) with a plasmid encoding S377-588 fused with the human IgG Fc fragment (S377-588-Fc). We then demonstrated the interleukin-2 signal peptide-directed secretion of the recombinant protein into extracellular milieu. Using a gradually increasing methotrexate (MTX) concentration to 5 μM, we increased protein yield by a factor of 40. The adCHO-expressed S377-588-Fc recombinant protein demonstrated functionality and binding specificity identical to those of the protein from transiently transfected HEK293T cells. In addition, hCD26/dipeptidyl peptidase-4 (DPP4) transgenic mice vaccinated with AddaVax-adjuvanted S377-588-Fc could produce neutralizing antibodies against MERS-CoV and survived for at least 21 days after challenge with live MERS-CoV with no evidence of immunological toxicity or eosinophilic immune enhancement. To prepare for large scale-manufacture of the vaccine antigen, we have further developed a high-yield monoclonal suspension CHO cell line.
    MeSH terms: Animals; Epitopes/immunology; Epitopes/chemistry; Antigens, Viral/genetics*; Antigens, Viral/immunology*; Cricetulus; Genetic Engineering*; Genetic Vectors/genetics; Immunoglobulin Fc Fragments/genetics; Immunoglobulin Fc Fragments/immunology; Protein Processing, Post-Translational; Recombinant Proteins/genetics; Recombinant Proteins/immunology; Viral Vaccines/immunology*; Gene Expression*; CHO Cells; Coronavirus Infections/immunology*; Coronavirus Infections/prevention & control; Mice; Middle East Respiratory Syndrome Coronavirus/immunology*; Immunogenicity, Vaccine
  14. Strong AT, Sharma G, Nor Hanipah Z, Tu C, Brethauer SA, Schauer PR, et al.
    Surg Obes Relat Dis, 2018 05;14(5):700-706.
    PMID: 29496441 DOI: 10.1016/j.soard.2017.12.021
    BACKGROUND: Warfarin dosing after bariatric surgery may be influenced by alterations in gastrointestinal pH, transit time, absorptive surface area, gut microbiota, food intake, and adipose tissue.

    OBJECTIVES: The aim of this study was to describe trends in warfarin dosing after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG).

    SETTING: Single academic center.

    METHODS: All patients chronically on warfarin anticoagulation before RYGB or SG were retrospectively identified. Indications for anticoagulation, history of bleeding or thrombotic events, perioperative complications, and warfarin dosing were collected.

    RESULTS: Fifty-three patients (RYGB n = 31, SG n = 22) on chronic warfarin therapy were identified (56.6% female, mean 54.4 ± 11.7 yr of age). Of this cohort, 34.0% had prior venous thromboembolic events, 43.4% had atrial fibrillation, and 5.7% had mechanical cardiac valves. Preoperatively, the average daily dose of warfarin was similar in the RYGB group (8.3 ± 4.1 mg) and SG group (6.9 ± 2.8 mg). One month after surgery, mean daily dose of warfarin was reduced 24.1% in the RYGB group (P

    MeSH terms: Anticoagulants/administration & dosage*; Atrial Fibrillation/complications; Drug Administration Schedule; Female; Gastrectomy/methods; Heart Valve Prosthesis; Hemorrhage/complications; Humans; Male; Middle Aged; Obesity, Morbid/complications; Obesity, Morbid/surgery; Laparoscopy/methods*; Postoperative Care; Preoperative Care/methods; Retrospective Studies; Warfarin/administration & dosage*; Gastric Bypass/methods; International Normalized Ratio; Bariatric Surgery/methods*; Venous Thromboembolism/complications
  15. Jamar NH, Kritsiligkou P, Grant CM
    Sci Rep, 2018 03 01;8(1):3894.
    PMID: 29497115 DOI: 10.1038/s41598-018-22183-2
    Eukaryotic cells contain translation-associated mRNA surveillance pathways which prevent the production of potentially toxic proteins from aberrant mRNA translation events. We found that loss of mRNA surveillance pathways in mutants deficient in nonsense-mediated decay (NMD), no-go decay (NGD) and nonstop decay (NSD) results in increased protein aggregation. We have isolated and identified the proteins that aggregate and our bioinformatic analyses indicates that increased aggregation of aggregation-prone proteins is a general occurrence in mRNA surveillance mutants, rather than being attributable to specific pathways. The proteins that aggregate in mRNA surveillance mutants tend to be more highly expressed, more abundant and more stable proteins compared with the wider proteome. There is also a strong correlation with the proteins that aggregate in response to nascent protein misfolding and an enrichment for proteins that are substrates of ribosome-associated Hsp70 chaperones, consistent with susceptibility for aggregation primarily occurring during translation/folding. We also identified a significant overlap between the aggregated proteins in mRNA surveillance mutants and ageing yeast cells suggesting that translation-dependent protein aggregation may be a feature of the loss of proteostasis that occurs in aged cell populations.
    MeSH terms: Biochemical Phenomena; Endoribonucleases/metabolism; Eukaryotic Cells/metabolism; Ribosomes/metabolism; RNA, Messenger/genetics; RNA, Messenger/metabolism; Saccharomyces cerevisiae/metabolism; Protein Biosynthesis; HSP70 Heat-Shock Proteins/genetics; HSP70 Heat-Shock Proteins/metabolism; RNA Stability/genetics*; RNA Stability/physiology*; Saccharomyces cerevisiae Proteins/metabolism; Nonsense Mediated mRNA Decay/genetics; Protein Aggregates/physiology*
  16. Tay SS, Kuah MK, Shu-Chien AC
    Sci Rep, 2018 03 01;8(1):3874.
    PMID: 29497119 DOI: 10.1038/s41598-018-22157-4
    The front-end desaturases (Fads) are rate-limiting enzymes responsible for production of long-chain polyunsaturated fatty acids (LC-PUFA). The full spectrum of the transcriptional regulation of fads is still incomplete, as cloning of fads promoter is limited to a few species. Here, we described the cloning and characterisation of the zebrafish fads2 promoter. Using 5'-deletion and mutation analysis on this promoter, we identified a specific region containing the sterol regulatory element (SRE) which is responsible for the activation of the fads2 promoter. In tandem, two conserved CCAAT boxes were also present adjacent to the SRE and mutation of either of these binding sites attenuates the transcriptional activation of the fads2 promoter. An in vivo analysis employing GFP reporter gene in transiently transfected zebrafish embryos showed that this 1754 bp upstream region of the fads2 gene specifically directs GFP expression in the yolk syncytial layer (YSL) region. This indicates a role for LC-PUFA in the transport of yolk lipids through this tissue layer. In conclusion, besides identifying novel core elements for transcriptional activation in zebrafish fads2 promoter, we also reveal a potential role for fads2 or LC-PUFA in YSL during development.
    MeSH terms: Animals; Binding Sites; Cloning, Molecular/methods; Egg Yolk/metabolism; Fatty Acids/genetics; Fatty Acids/metabolism; Fatty Acids, Unsaturated/biosynthesis; Fatty Acids, Unsaturated/genetics; Promoter Regions, Genetic; Zebrafish/embryology*; Zebrafish/genetics*; Transcriptional Activation; Giant Cells/metabolism; Genes, Reporter; Gene Expression Regulation, Developmental; Transgenes; Fish Proteins/genetics; Fatty Acid Desaturases/genetics*; Fatty Acid Desaturases/metabolism
  17. Sandrasaigaran P, Algraittee SJR, Ahmad AR, Vidyadaran S, Ramasamy R
    Cytotechnology, 2018 Jun;70(3):1037-1050.
    PMID: 29497876 DOI: 10.1007/s10616-017-0182-4
    Mesenchymal stem cells (MSCs) exert potent immuno-regulatory activities on various immune cells and also differentiate into various mesodermal lineages besides retaining a distinct self-renewal ability. Such exclusive characteristics had enabled MSCs to be recognised as an ideal source for cell-based treatment in regenerative medicine and immunotherapy. Thus, considering MSCs for treating degenerative disease of organs with limited regenerative potential such as cartilage would serve as an ideal therapy. This study explored the feasibility of generating human cartilage-derived MSCs (hC-MSCs) from sports injured patients and characterised based on multipotent differentiation and immunosuppressive activities. Cartilage tissues harvested from a non-weight bearing region during an arthroscopy procedure were used to generate MSCs. Despite the classic morphology of fibroblast-like cells and a defined immunophenotyping, MSCs expressed early embryonic transcriptional markers (SOX2, REX1, OCT4 and NANOG) and differentiated into chondrocytes, adipocytes and osteocytes when induced accordingly. Upon co-culture with PHA-L activated T-cells, hC-MSCs suppressed the proliferation of the T-cells in a dose-dependent manner. Although, hC-MSCs did not alter the activation profile of T cells significantly, yet prevented the entering of activated T cells into S phase of the cell cycle by cell cycle arrest. The present study has strengthened the evidence of tissue-resident mesenchymal stem cells in human cartilage tissue. The endogenous MSCs could be an excellent tool in treating dysregulated immune response that associated with cartilage since hC-MSCs exerted both immunosuppressive and regenerative capabilities.
    MeSH terms: Arthroscopy; Cartilage; Cell Cycle; Cell Differentiation; Fibroblasts; Humans; Immunotherapy; Osteocytes; Phytohemagglutinins; Sports; T-Lymphocytes; Immunophenotyping; S Phase; Adipocytes; Coculture Techniques; Chondrocytes; Regenerative Medicine; Cell Proliferation; Cell Cycle Checkpoints; Mesenchymal Stromal Cells
  18. Abu Bakar N, Lefeber DJ, van Scherpenzeel M
    J Inherit Metab Dis, 2018 May;41(3):499-513.
    PMID: 29497882 DOI: 10.1007/s10545-018-0144-9
    Clinical glycomics comprises a spectrum of different analytical methodologies to analyze glycan structures, which provides insights into the mechanisms of glycosylation. Within clinical diagnostics, glycomics serves as a functional readout of genetic variants, and can form a basis for therapy development, as was described for PGM1-CDG. Integration of glycomics with genomics has resulted in the elucidation of previously unknown disorders of glycosylation, namely CCDC115-CDG, TMEM199-CDG, ATP6AP1-CDG, MAN1B1-CDG, and PGM1-CDG. This review provides an introduction into protein glycosylation and presents the different glycomics methodologies ranging from gel electrophoresis to mass spectrometry (MS) and from free glycans to intact glycoproteins. The role of glycomics in the diagnosis of congenital disorders of glycosylation (CDG) is presented, including a diagnostic flow chart and an overview of glycomics data of known CDG subtypes. The review ends with some future perspectives, showing upcoming technologies as system wide mapping of the N- and O-glycoproteome, intact glycoprotein profiling and analysis of sugar metabolism. These new advances will provide additional insights and opportunities to develop personalized therapy. This is especially true for inborn errors of metabolism, which are amenable to causal therapy, because interventions through supplementation therapy can directly target the pathogenesis at the molecular level.
    MeSH terms: Electrophoresis; Glycoproteins; Glycosylation; Polysaccharides; Mass Spectrometry; Congenital Disorders of Glycosylation; Glycomics
  19. Goh KL
    J Gastroenterol Hepatol, 2018 Jun;33(6):1177-1184.
    PMID: 29498759 DOI: 10.1111/jgh.14131
    The study of Helicobacter pylori in Malaysia has given several important insights into the epidemiology of the infection and pathogenesis of disease. Malaysia has a multiracial Asian population with three major Asian races living together-Malay, Chinese, and Indian. Races remain fairly distinct because of a paucity of interracial marriages. The "Racial Cohort Hypothesis" proposes that the infection occurs within racial groups rather than between. As such, the high prevalence among Indians (> 50%) and Chinese (40-50%) reflects the high prevalence in their countries of origin even though migration had taken place more than two generations before. The Malays have a comparatively low prevalence of about 10-20%. Despite the high prevalence of H. pylori, the Indians have a low gastric cancer incidence of less than 10 per 100 000 per year. This is in contrast to the Chinese who has an incidence in excess of 20 per 100 000 per year. We have called this the "Indian Enigma." The reason for this enigma is unclear and is the result of interaction between bacterial virulence factors, host susceptibility, and environmental factors. Phylogenetically, Chinese bacterial strains are distinct from Indians and Malays and are predominantly hpEastAsia/hsp EAsia. CagA EPIYA motifs among Chinese belong predominantly to the more virulent ABD motif. There is no clear distinguishing profile among host genetic factors. Environmental factors particularly diet may play an important role. Indians consume chilies and curries, which may be gastro protective, whereas Chinese consume more preserved and salted foods, which are thought to be carcinogenic.
    MeSH terms: China/ethnology; Disease Susceptibility; Environment*; Feeding Behavior*; Gastritis/microbiology*; Gastritis/epidemiology*; Humans; India/ethnology; Malaysia/ethnology; Malaysia/epidemiology; Phylogeny; Stomach Neoplasms/epidemiology; Cohort Studies; Prevalence; Helicobacter Infections*; Continental Population Groups*
  20. Chow PKH, Gandhi M, Tan SB, Khin MW, Khasbazar A, Ong J, et al.
    J Clin Oncol, 2018 07 01;36(19):1913-1921.
    PMID: 29498924 DOI: 10.1200/JCO.2017.76.0892
    Purpose Selective internal radiation therapy or radioembolization (RE) shows efficacy in unresectable hepatocellular carcinoma (HCC) limited to the liver. This study compared the safety and efficacy of RE and sorafenib in patients with locally advanced HCC. Patients and Methods SIRveNIB (selective internal radiation therapy v sorafenib), an open-label, investigator-initiated, phase III trial, compared yttrium-90 (90Y) resin microspheres RE with sorafenib 800 mg/d in patients with locally advanced HCC in a two-tailed study designed for superiority/detriment. Patients were randomly assigned 1:1 and stratified by center and presence of portal vein thrombosis. Primary end point was overall survival (OS). Efficacy analyses were performed in the intention-to-treat population and safety analyses in the treated population. Results A total of 360 patients were randomly assigned (RE, 182; sorafenib, 178) from 11 countries in the Asia-Pacific region. In the RE and sorafenib groups, 28.6% and 9.0%, respectively, failed to receive assigned therapy without significant cross-over to either group. Median OS was 8.8 and 10.0 months with RE and sorafenib, respectively (hazard ratio, 1.1; 95% CI, 0.9 to 1.4; P = .36). A total of 1,468 treatment-emergent adverse events (AEs) were reported (RE, 437; sorafenib, 1,031). Significantly fewer patients in the RE than sorafenib group had grade ≥ 3 AEs (36 of 130 [27.7%]) v 82 of 162 [50.6%]; P < .001). The most common grade ≥ 3 AEs were ascites (five of 130 [3.8%] v four of 162 [2.5%] patients), abdominal pain (three [2.3%] v two [1.2%] patients), anemia (zero v four [2.5%] patients), and radiation hepatitis (two [1.5%] v zero [0%] patients). Fewer patients in the RE group (27 of 130 [20.8%]) than in the sorafenib group (57 of 162 [35.2%]) had serious AEs. Conclusion In patients with locally advanced HCC, OS did not differ significantly between RE and sorafenib. The improved toxicity profile of RE may inform treatment choice in selected patients.
    MeSH terms: Anemia; Ascites; Brachytherapy; Hepatitis; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Microspheres; Portal Vein; Yttrium Radioisotopes; Abdominal Pain; Patient Selection; Cross-Over Studies; Intention to Treat Analysis
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