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Dengue in Southeast Asia: epidemiological characteristics and strategic challenges in disease prevention
Ooi, Eng-Eong;Gubler, Duane J.;
Cadernos de Saúde Pública , 2009, DOI: 10.1590/S0102-311X2009001300011
Abstract: dengue emerged as a public health burden in southeast asia during and following the second world war and has become increasingly important, with progressively longer and more frequent cyclical epidemics of dengue fever/dengue hemorrhagic fever. despite this trend, surveillance for this vector-borne viral disease remains largely passive in most southeast asian countries, without adequate laboratory support. we review here the factors that may have contributed to the changing epidemiology of dengue in southeast asia as well as challenges of disease prevention. we also discuss a regional approach to active dengue virus surveillance, focusing on urban areas where the viruses are maintained, which may be a solution to limited financial resources since most of the countries in the region have developing economies. a regional approach would also result in a greater likelihood of success in disease prevention since the large volume of human travel is a major factor contributing to the geographical spread of dengue viruses.
IL-1β, IL-6, and RANTES as Biomarkers of Chikungunya Severity
Lisa F. P. Ng, Angela Chow, Yong-Jiang Sun, Dyan J. C. Kwek, Poh-Lian Lim, Frederico Dimatatac, Lee-Ching Ng, Eng-Eong Ooi, Khar-Heng Choo, Zhisheng Her, Philippe Kourilsky, Yee-Sin Leo
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0004261
Abstract: Background Little is known about the immunopathogenesis of Chikungunya virus. Circulating levels of immune mediators and growth factors were analyzed from patients infected during the first Singaporean Chikungunya fever outbreak in early 2008 to establish biomarkers associated with infection and/or disease severity. Methods and Findings Adult patients with laboratory-confirmed Chikungunya fever infection, who were referred to the Communicable Disease Centre/Tan Tock Seng Hospital during the period from January to February 2008, were included in this retrospective study. Plasma fractions were analyzed using a multiplex-microbead immunoassay. Among the patients, the most common clinical features were fever (100%), arthralgia (90%), rash (50%) and conjunctivitis (40%). Profiles of 30 cytokines, chemokines, and growth factors were able to discriminate the clinical forms of Chikungunya from healthy controls, with patients classified as non-severe and severe disease. Levels of 8 plasma cytokines and 4 growth factors were significantly elevated. Statistical analysis showed that an increase in IL-1β, IL-6 and a decrease in RANTES were associated with disease severity. Conclusions This is the first comprehensive report on the production of cytokines, chemokines, and growth factors during acute Chikungunya virus infection. Using these biomarkers, we were able to distinguish between mild disease and more severe forms of Chikungunya fever, thus enabling the identification of patients with poor prognosis and monitoring of the disease.
A human in vitro model system for investigating genome-wide host responses to SARS coronavirus infection
Lisa FP Ng, Martin L Hibberd, Eng-Eong Ooi, Kin-Fai Tang, Soek-Ying Neo, Jenny Tan, Karuturi R Krishna Murthy, Vinsensius B Vega, Jer-Ming Chia, Edison T Liu, Ee-Chee Ren
BMC Infectious Diseases , 2004, DOI: 10.1186/1471-2334-4-34
Abstract: PBMCs from normal healthy donors were inoculated in vitro with SARS-CoV and the viral replication kinetics was studied by real-time quantitative assays. SARS-CoV specific gene expression changes were examined by high-density oligonucleotide array analysis.We observed that SARS-CoV was capable of infecting and replicating in PBMCs and the kinetics of viral replication was variable among the donors. SARS-CoV antibody binding assays indicated that SARS specific antibodies inhibited SARS-CoV viral replication. Array data showed monocyte-macrophage cell activation, coagulation pathway upregulation and cytokine production together with lung trafficking chemokines such as IL8 and IL17, possibly activated through the TLR9 signaling pathway; that mimicked clinical features of the disease.The identification of human blood mononuclear cells as a direct target of SARS-CoV in the model system described here provides a new insight into disease pathology and a tool for investigating the host response and mechanisms of pathogenesis.The causative agent for SARS has been identified as a novel coronavirus [1-3] with genome sequence revealing no strong homology to existing known coronaviruses [4-6]. Coronaviruses belong to the family of enveloped viruses called Coronaviridae, and have the largest known single-stranded viral RNA genomes (27 to 32 kb). Coronaviruses, have both "early" and "late" phases of gene expression. Regulatory proteins are synthesized as "early" non-structural proteins, while the structural proteins are synthesized as "late" proteins. "Late" structural proteins are usually required in greater amounts thus, there is a necessity to regulate the expression of the viral genes quantitatively. After the viral entry via endocytosis or through specific receptors, the 5'-end of the viral genome is translated directly giving rise to twenty-three viral proteins, including the RNA dependent RNA polymerase (RdRp), and other functional products involved in transcription, replica
Serum Proteome and Cytokine Analysis in a Longitudinal Cohort of Adults with Primary Dengue Infection Reveals Predictive Markers of DHF
Yadunanda Kumar ,Cui Liang,Zheng Bo,Jagath C. Rajapakse,Eng Eong Ooi,Steven R. Tannenbaum
PLOS Neglected Tropical Diseases , 2012, DOI: 10.1371/journal.pntd.0001887
Abstract: Background Infections caused by dengue virus are a major cause of morbidity and mortality in tropical and subtropical regions of the world. Factors that control transition from mild forms of disease such as dengue fever (DF) to more life-threatening forms such as dengue hemorrhagic fever (DHF) are poorly understood. Consequently, there are no reliable methods currently available for early triage of DHF patients resulting in significant over-hospitalization. Methodology/Principal Findings We have systematically examined the proteome, cytokines and inflammatory markers in sera from 62 adult dengue patients (44 DF; 18 DHF) with primary DENV infection, at three different times of infection representing the early febrile, defervescence and convalescent stages. Using fluorescent bioplex assays, we measured 27 cytokines in these serum samples. Additionally, we used multiple mass spectrometry methods for iTRAQ-based comparative analysis of serum proteome as well as measurements of protein adducts- 3-nitrotyrosine and 3-chlorotyrosine as surrogate measures of free radical activity. Using multiple methods such as OPLS, MRMR and MSVM-RFE for multivariate feature selection and classification, we report molecular markers that allow prediction of primary DHF with sensitivity and specificity of >80%. Conclusions/Significance This report constitutes a comprehensive analysis of molecular signatures of dengue disease progression and will help unravel mechanisms of dengue disease progression. Our analysis resulted in the identification of markers that may be useful for early prediction of DHF during the febrile phase. The combination of highly sensitive analytical methods and novel statistical approaches described here forms a robust platform for biomarker discovery.
Production of Infectious Dengue Virus in Aedes aegypti Is Dependent on the Ubiquitin Proteasome Pathway
Milly M. Choy?,October M. Sessions?,Duane J. Gubler?,Eng Eong Ooi
PLOS Neglected Tropical Diseases , 2015, DOI: 10.1371/journal.pntd.0004227
Abstract: Dengue virus (DENV) relies on host factors to complete its life cycle in its mosquito host for subsequent transmission to humans. DENV first establishes infection in the midgut of Aedes aegypti and spreads to various mosquito organs for lifelong infection. Curiously, studies have shown that infectious DENV titers peak and decrease thereafter in the midgut despite relatively stable viral genome levels. However, the mechanisms that regulate this decoupling of infectious virion production from viral RNA replication have never been determined. We show here that the ubiquitin proteasome pathway (UPP) plays an important role in regulating infectious DENV production. Using RNA interference studies, we show in vivo that knockdown of selected UPP components reduced infectious virus production without altering viral RNA replication in the midgut. Furthermore, this decoupling effect could also be observed after RNAi knockdown in the head/thorax of the mosquito, which otherwise showed direct correlation between infectious DENV titer and viral RNA levels. The dependence on the UPP for successful DENV production is further reinforced by the observed up-regulation of key UPP molecules upon DENV infection that overcome the relatively low expression of these genes after a blood meal. Collectively, our findings indicate an important role for the UPP in regulating DENV production in the mosquito vector.
Innate Immune Responses of Pulmonary Epithelial Cells to Burkholderia pseudomallei Infection
Siew Hoon Sim, Yichun Liu, Dongling Wang, Vidhya Novem, Suppiah Paramalingam Sivalingam, Tuck Weng Thong, Eng Eong Ooi, Gladys Tan
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0007308
Abstract: Background Burkholderia pseudomallei, a facultative intracellular pathogen, causes systemic infection in humans with high mortality especially when infection occurs through an infectious aerosol. Previous studies indicated that the epithelial cells in the lung are an active participant in host immunity. In this study, we aimed to investigate the innate immune responses of lung epithelial cells against B. pseudomallei. Methodology and Principal Findings Using a murine lung epithelial cell line, primary lung epithelial cells and an inhalational murine infection model, we characterized the types of innate immunity proteins and peptides produced upon B. pseudomallei infection. Among a wide panel of immune components studied, increased levels of major pro-inflammatory cytokines IL-6 and TNFα, chemokine MCP-1, and up-regulation of secretory leukocyte protease inhibitor (SLPI) and chemokine (C-C motif) ligand 20 (CCL20) were observed. Inhibition assays using specific inhibitors suggested that NF-κB and p38 MAPK pathways were responsible for these B. pseudomallei-induced antimicrobial peptides. Conclusions Our findings indicate that the respiratory epithelial cells, which form the majority of the cells lining the epithelial tract and the lung, have important roles in the innate immune response against B. pseudomallei infection.
Reconstructing historical changes in the force of infection of dengue fever in Singapore: implications for surveillance and control
Egger,Joseph R; Ooi,Eng Eong; Kelly,David W; Woolhouse,Mark E; Davies,Clive R; Coleman,Paul G;
Bulletin of the World Health Organization , 2008, DOI: 10.1590/S0042-96862008000300011
Abstract: objective: to reconstruct the historical changes in force of dengue infection in singapore, and to better understand the relationship between control of aedes mosquitoes and incidence of classic dengue fever. methods: seroprevalence data were abstracted from surveys performed in singapore from 1982 to 2002. these data were used to develop two mathematical models of age seroprevalence. in the first model, force of infection was allowed to vary independently each year, while in the second it was described by a polynomial function. model-predicted temporal trends were analysed using linear regression. time series techniques were employed to investigate periodicity in predicted forces of infection, dengue fever incidence and mosquito breeding. findings: force of infection estimates showed a significant downward trend from 1966, when vector control was instigated. force of infection estimates from both models reproduced significant increases in the percentage and average age of the population susceptible to dengue infections. importantly, the year-on-year model independently predicted a five to six year periodicity that was also displayed by clinical incidence but absent from the aedes household index. conclusion: we propose that the rise in disease incidence was due in part to a vector-control-driven reduction in herd immunity in older age groups that are more susceptible to developing clinical dengue.
Hypertonic Saline Reduces Vascular Leakage in a Mouse Model of Severe Dengue
Grace Kai Xin Tan, Jowin Kai Wei Ng, Kar Wai Tan, Veronique Angeli, Shabbir Moochhala, Eng Eong Ooi, Sylvie Alonso
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0061621
Abstract: Dengue (DEN) is a mosquito-borne viral disease and represents a serious public health threat and an economical burden throughout the tropics. Dengue clinical manifestations range from mild acute febrile illness to severe DEN hemorrhagic fever/DEN shock syndrome (DHF/DSS). Currently, resuscitation with large volumes of isotonic fluid remains the gold standard of care for DEN patients who develop vascular leakage and shock. Here, we investigated the ability of small volume of hypertonic saline (HTS) suspensions to control vascular permeability in a mouse model of severe DEN associated with vascular leakage. Several HTS treatment regimens were considered and our results indicated that a single bolus of 7.5% NaCl at 4 mL per kg of body weight administered at the onset of detectable vascular leakage rapidly and significantly reduced vascular leak for several days after injection. This transient reduction of vascular leakage correlated with reduced intestine and liver damage with restoration of the hepatic functions, and resulted in delayed death of the infected animals. Mechanistically, we showed that HTS did not directly impact on the viral titers but resulted in lower immune cells counts and decreased systemic levels of soluble mediators involved in vascular permeability. In addition, we demonstrated that neutrophils do not play a critical role in DEN-associated vascular leakage and that the therapeutic effect of HTS is not mediated by its impact on the neutrophil counts. Together our data indicate that HTS treatment can transiently but rapidly reduce dengue-associated vascular leakage, and support the findings of a recent clinical trial which evaluated the efficacy of a hypertonic suspension to impact on vascular permeability in DSS children.
Molecular Analysis of Serum and Bronchoalveolar Lavage in a Mouse Model of Influenza Reveals Markers of Disease Severity That Can Be Clinically Useful in Humans
Yadunanda Kumar, Cui Liang, Gino V. Limmon, Li Liang, Bevin P. Engelward, Eng Eong Ooi, Jianzhu Chen, Steven R. Tannenbaum
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0086912
Abstract: Background Management of influenza, a major contributor to the worldwide disease burden, is complicated by lack of reliable methods for early identification of susceptible individuals. Identification of molecular markers that can augment existing diagnostic tools for prediction of severity can be expected to greatly improve disease management capabilities. Methodology/Principal Findings We have analyzed cytokines, proteome flux and protein adducts in bronchoalveolar lavage (BAL) and sera from mice infected with influenza A virus (PR8 strain) using a previously established non-lethal model of influenza infection. Through detailed cytokine and protein adduct measurements of murine BAL, we first established the temporal profile of innate and adaptive responses as well as macrophage and neutrophil activities in response to influenza infection. A similar analysis was also performed with sera from a longitudinal cohort of influenza patients. We then used an iTRAQ-based, comparative serum proteome analysis to catalog the proteome flux in the murine BAL during the stages correlating with “peak viremia,” “inflammatory damage,” as well as the “recovery phase.” In addition to activation of acute phase responses, a distinct class of lung proteins including surfactant proteins was found to be depleted from the BAL coincident with their “appearance” in the serum, presumably due to leakage of the protein following loss of the integrity of the lung/epithelial barrier. Serum levels of at least two of these proteins were elevated in influenza patients during the febrile phase of infection compared to healthy controls or to the same patients at convalescence. Conclusions/Significance The findings from this study provide a molecular description of disease progression in a mouse model of influenza and demonstrate its potential for translation into a novel class of markers for measurement of acute lung injury and improved case management.
Proteasome Inhibition Suppresses Dengue Virus Egress in Antibody Dependent Infection
Milly M. Choy?,Summer L. Zhang?,Vivian V. Costa?,Hwee Cheng Tan?,Sophie Horrevorts?,Eng Eong Ooi
PLOS Neglected Tropical Diseases , 2015, DOI: 10.1371/journal.pntd.0004058
Abstract: The mosquito-borne dengue virus (DENV) is a cause of significant global health burden, with an estimated 390 million infections occurring annually. However, no licensed vaccine or specific antiviral treatment for dengue is available. DENV interacts with host cell factors to complete its life cycle although this virus-host interplay remains to be fully elucidated. Many studies have identified the ubiquitin proteasome pathway (UPP) to be important for successful DENV production, but how the UPP contributes to DENV life cycle as host factors remains ill defined. We show here that proteasome inhibition decouples infectious virus production from viral RNA replication in antibody-dependent infection of THP-1 cells. Molecular and imaging analyses in β-lactone treated THP-1 cells suggest that proteasome function does not prevent virus assembly but rather DENV egress. Intriguingly, the licensed proteasome inhibitor, bortezomib, is able to inhibit DENV titers at low nanomolar drug concentrations for different strains of all four serotypes of DENV in primary monocytes. Furthermore, bortezomib treatment of DENV-infected mice inhibited the spread of DENV in the spleen as well as the overall pathological changes. Our findings suggest that preventing DENV egress through proteasome inhibition could be a suitable therapeutic strategy against dengue.
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