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Fulltext Plasmodium-infected erythrocytes induce secretion of IGFBP7 to form type II rosettes and escape phagocytosis

Lee WC, Russell B, Sobota RM, Ghaffar K, Howland SW, Wong ZX, et al.

Elife, 2020 Feb 18;9.
PMID: 32066522 DOI: 10.7554/eLife.51546

In malaria, rosetting is described as a phenomenon where an infected erythrocyte (IRBC) is attached to uninfected erythrocytes (URBC). In some studies, rosetting has been associated with malaria pathogenesis. Here, we have identified a new type of rosetting. Using a step-by-step approach, we identified IGFBP7, a protein secreted by monocytes in response to parasite stimulation, as a rosette-stimulator for Plasmodium falciparum- and P. vivax-IRBC. IGFBP7-mediated rosette-stimulation was rapid yet reversible. Unlike type I rosetting that involves direct interaction of rosetting ligands on IRBC and receptors on URBC, the IGFBP7-mediated, type II rosetting requires two additional serum factors, namely von Willebrand factor and thrombospondin-1. These two factors interact with IGFBP7 to mediate rosette formation by the IRBC. Importantly, the IGFBP7-induced type II rosetting hampers phagocytosis of IRBC by host phagocytes.
Fulltext The Impact of Geographical Variation in Plasmodium knowlesi Apical Membrane Protein 1 (PkAMA-1) on Invasion Dynamics of P. knowlesi

Ng YL, Lee WC, Lau YL, Fong MY

Trop Med Infect Dis, 2023 Jan 10;8(1).
PMID: 36668963 DOI: 10.3390/tropicalmed8010056

Plasmodium knowlesi has emerged as an important zoonotic parasite that causes persistent symptomatic malaria in humans. The signs and symptoms of malaria are attributed to the blood stages of the parasites, which start from the invasion of erythrocytes by the blood stage merozoites. The apical membrane protein 1 (AMA-1) plays an important role in the invasion. In this study, we constructed and expressed recombinant PkAMA-1 domain II (PkAMA-1-DII) representing the predominant haplotypes from Peninsular Malaysia and Malaysian Borneo and raised specific antibodies against the recombinant proteins in rabbits. Despite the minor amino acid sequence variation, antibodies raised against haplotypes from Peninsular Malaysia and Malaysian Borneo demonstrated different invasion inhibition (46.81% and 39.45%, respectively) to P. knowlesi A1-H.1, a reference strain derived from Peninsular Malaysia. Here, we demonstrated how a minor variation in a conserved parasite protein could cast a significant impact on parasite invasion biology, suggesting a complex host-switching of P. knowlesi from different locations. This may challenge the implementation of a standardized One Health approach against the transmission of knowlesi malaria.
Fulltext Moxifloxacin-warfarin interaction

Yew KL, Lee WC

Med J Malaysia, 2012 Aug;67(4):420-1.
PMID: 23082454 MyJurnal
Functional and immunological mapping of domains of the reticulocyte binding protein, Plasmodium vivax PvRBP2a

Tay MZ, Tang W, Lee WC, Ong ASM, Novera W, Malleret B, et al.

J Infect Dis, 2024 Mar 05.
PMID: 38441336 DOI: 10.1093/infdis/jiae111

We previously described a novel Plasmodium vivax invasion mechanism into human reticulocytes via the PvRBP2a-CD98 receptor-ligand pair. We assessed the PvRBP2a epitopes involved in CD98 binding and recognised by antibodies from infected patients using linear epitope mapping. We identified two epitope clusters mediating PvRBP2a-CD98 interaction. One cluster named cluster B (PvRBP2a431-448, TAALKEKGKLLANLYNKL) was the target of antibody responses in P. vivax-infected humans. Peptides from each cluster were able to prevent live parasite invasion of human reticulocytes. These results provide new insights for development of a malaria blood stage vaccine against P. vivax.
Fulltext Seroprevalence of Toxoplasma gondii Infection in Refugee and Migrant Pregnant Women along the Thailand-Myanmar Border

van Enter BJD, Lau YL, Ling CL, Watthanaworawit W, Sukthana Y, Lee WC, et al.

Am J Trop Med Hyg, 2017 Jul;97(1):232-235.
PMID: 28719309 DOI: 10.4269/ajtmh.16-0999

Toxoplasma gondii primary infection in pregnancy is associated with poor obstetric outcomes. This study aimed to determine the seroprevalence of Toxoplasma infection in pregnant migrant and refugee women from Myanmar attending antenatal care in Thailand. A random selection of 199 residual blood samples from first antenatal screen in 2014-2015 was tested for Toxoplasma IgG and IgM antibodies. Seroprevalence of Toxoplasma infection was 31.7% (95% confidence interval = 25.6-38.4). Avidity testing in the three positive IgM cases indicated all were past infections. Multiparity (≥ 3 children) was significantly associated with higher Toxoplasma seropositivity rates. Seroprevalence of T. gondii infection in this pregnant population is similar to the only other report from Myanmar, where multiparity was also identified as a significant association. Toxoplasma infection is important in pregnant women. Nevertheless, in this marginalized population, this infection may be given less priority, due to resource constraints in providing the most basic components of safe motherhood programs.
Fulltext Rosetting Responses of Plasmodium-infected Erythrocytes to Antimalarials

Lee WC, Russell B, Lau YL, Nosten F, Rénia L

Am J Trop Med Hyg, 2022 Apr 11;106(6):1670-4.
PMID: 35405642 DOI: 10.4269/ajtmh.21-1229

In malaria, rosetting is a phenomenon involving the cytoadherence of uninfected erythrocytes to infected erythrocytes (IRBC) harboring the late erythrocytic stage of Plasmodium spp. Recently, artesunate-stimulated rosetting has been demonstrated to confer a survival advantage to P. falciparum late-stage IRBC. This study investigated the rosetting response of P. falciparum and P. vivax clinical isolates to ex vivo antimalarial treatments. Brief exposure of IRBC to chloroquine, mefloquine, amodiaquine, quinine, and lumefantrine increased the rosetting rates of P. falciparum and P. vivax. Furthermore, the ex vivo combination of artesunate with mefloquine and piperaquine also resulted in increased the rosetting rates. Drug-mediated rosette-stimulation has important implications for the therapeutic failure of rapidly cleared drugs such as artesunate. However, further work is needed to establish the ramifications of increased rosetting rates by drugs with longer half-lifves, such as chloroquine, mefloquine, and piperaquine.
A robust background correction algorithm for forensic bloodstain imaging using mean-based contrast adjustment

Lee WC, Khoo BE, Abdullah AFL

Sci Justice, 2016 May;56(3):201-209.
PMID: 27162018 DOI: 10.1016/j.scijus.2016.01.001

Background correction algorithm (BCA) is useful in enhancing the visibility of images captured in crime scenes especially those of untreated bloodstains. Successful implementation of BCA requires all the images to have similar brightness which often proves a problem when using automatic exposure setting in a camera. This paper presents an improved background correction algorithm (BCA) that applies mean-based contrast adjustment as a pre-correction step to adjust the mean brightness of images to be similar before implementing BCA. The proposed modification, namely mean-based adaptive BCA (mABCA) was tested on various image samples captured under different illuminations such as 385 nm, 415 nm and 458 nm. We also evaluated mABCA of two wavelengths (415 nm and 458 nm) and three wavelengths (415 nm, 380 nm and 458 nm) in enhancing untreated bloodstains on different surfaces. The proposed mABCA is found to be more robust in processing images captured in different brightness and thus overcomes the main issue faced in the original BCA.
Fulltext Functional and molecular surveillance of Helicobacter pylori antibiotic resistance in Kuala Lumpur

Teh X, Khosravi Y, Lee WC, Leow AH, Loke MF, Vadivelu J, et al.

PLoS One, 2014;9(7):e101481.
PMID: 25003707 DOI: 10.1371/journal.pone.0101481

Helicobacter pylori is the etiological agent for diseases ranging from chronic gastritis and peptic ulcer disease to gastric adenocarcinoma and primary gastric B-cell lymphoma. Emergence of resistance to antibiotics possesses a challenge to the effort to eradicate H. pylori using conventional antibiotic-based therapies. The molecular mechanisms that contribute to the resistance of these strains have yet to be identified and are important for understanding the evolutional pattern and selective pressure imposed by the environment.
Fulltext Is there a risk of suburban transmission of malaria in Selangor, Malaysia?

Braima KA, Sum JS, Ghazali AR, Muslimin M, Jeffery J, Lee WC, et al.

PLoS One, 2013;8(10):e77924.
PMID: 24194901 DOI: 10.1371/journal.pone.0077924

BACKGROUND: The suburban transmission of malaria in Selangor, Malaysia's most developed and populous state still remains a concern for public health in this region. Despite much successful control efforts directed at its reduction, sporadic cases, mostly brought in by foreigners have continued to occur. In addition, cases of simian malaria caused by Plasmodium knowlesi, some with fatal outcome have caused grave concern to health workers. The aim of this study was to investigate the possibility of local malaria transmission in suburban regions of Selangor, which are adjacent to secondary rainforests.
FINDINGS: A malaria survey spanning 7 years (2006 - 2012) was conducted in Selangor. A total of 1623 laboratory confirmed malaria cases were reported from Selangor's nine districts. While 72.6% of these cases (1178/1623) were attributed to imported malaria (cases originating from other countries), 25.5% (414/1623) were local cases and 1.9% (31/1623) were considered as relapse and unclassified cases combined. In this study, the most prevalent infection was P. vivax (1239 cases, prevalence 76.3%) followed by P. falciparum (211, 13.0%), P. knowlesi (75, 4.6%), P. malariae (71, 4.4%) and P. ovale (1, 0.06%). Mixed infections comprising of P. vivax and P. falciparum were confirmed (26, 1.6%). Entomological surveys targeting the residences of malaria patients' showed that the most commonly trapped Anopheles species was An. maculatus. No oocysts or sporozoites were found in the An. maculatus collected. Nevertheless, the possibility of An. maculatus being the malaria vector in the investigated locations was high due to its persistent occurrence in these areas.
CONCLUSIONS: Malaria cases reported in this study were mostly imported cases. However the co-existence of local cases and potential Plasmodium spp. vectors should be cause for concern. The results of this survey reflect the need of maintaining closely monitored malaria control programs and continuous extensive malaria surveillance in Peninsula Malaysia.
Fulltext Giemsa-stained wet mount based method for reticulocyte quantification: a viable alternative in resource limited or malaria endemic settings

Lee WC, Russell B, Lau YL, Fong MY, Chu C, Sriprawat K, et al.

PLoS One, 2013;8(4):e60303.
PMID: 23565221 DOI: 10.1371/journal.pone.0060303

The quantity of circulating reticulocytes is an important indicator of erythropoietic activity in response to a wide range of haematological pathologies. While most modern laboratories use flow cytometry to quantify reticulocytes, most field laboratories still rely on 'subvital' staining. The specialist 'subvital' stains, New Methylene Blue (NMB) and Brilliant Crésyl Blue are often difficult to procure, toxic, and show inconsistencies between batches. Here we demonstrate the utility of Giemsa's stain (commonly used microbiology and parasitology) in a 'subvital' manner to provide an accurate method to visualize and count reticulocytes in blood samples from normal and malaria-infected individuals.
Fulltext Deciphering the Draft Genome of Toxoplasma gondii RH Strain

Lau YL, Lee WC, Gudimella R, Zhang G, Ching XT, Razali R, et al.

PLoS One, 2016;11(6):e0157901.
PMID: 27355363 DOI: 10.1371/journal.pone.0157901

Toxoplasmosis is a widespread parasitic infection by Toxoplasma gondii, a parasite with at least three distinct clonal lineages. This article reports the whole genome sequencing and de novo assembly of T. gondii RH (type I representative strain), as well as genome-wide comparison across major T. gondii lineages. Genomic DNA was extracted from tachyzoites of T. gondii RH strain and its identity was verified by PCR and LAMP. Subsequently, whole genome sequencing was performed, followed by sequence filtering, genome assembly, gene annotation assignments, clustering of gene orthologs and phylogenetic tree construction. Genome comparison was done with the already archived genomes of T. gondii. From this study, the genome size of T. gondii RH strain was found to be 69.35Mb, with a mean GC content of 52%. The genome shares high similarity to the archived genomes of T. gondii GT1, ME49 and VEG strains. Nevertheless, 111 genes were found to be unique to T. gondii RH strain. Importantly, unique genes annotated to functions that are potentially critical for T. gondii virulence were found, which may explain the unique phenotypes of this particular strain. This report complements the genomic archive of T. gondii. Data obtained from this study contribute to better understanding of T. gondii and serve as a reference for future studies on this parasite.
Fulltext Draft Genomes of Anopheles cracens and Anopheles maculatus: Comparison of Simian Malaria and Human Malaria Vectors in Peninsular Malaysia

Lau YL, Lee WC, Chen J, Zhong Z, Jian J, Amir A, et al.

PLoS One, 2016;11(6):e0157893.
PMID: 27347683 DOI: 10.1371/journal.pone.0157893

Anopheles cracens has been incriminated as the vector of human knowlesi malaria in peninsular Malaysia. Besides, it is a good laboratory vector of Plasmodium falciparum and P. vivax. The distribution of An. cracens overlaps with that of An. maculatus, the human malaria vector in peninsular Malaysia that seems to be refractory to P. knowlesi infection in natural settings. Whole genome sequencing was performed on An. cracens and An. maculatus collected here. The draft genome of An. cracens was 395 Mb in size whereas the size of An. maculatus draft genome was 499 Mb. Comparison with the published Malaysian An. maculatus genome suggested the An. maculatus specimen used in this study as a different geographical race. Comparative analyses highlighted the similarities and differences between An. cracens and An. maculatus, providing new insights into their biological behavior and characteristics.
Fulltext Phylogenetic study of six species of Anopheles mosquitoes in Peninsular Malaysia based on inter-transcribed spacer region 2 (ITS2) of ribosomal DNA

Sum JS, Lee WC, Amir A, Braima KA, Jeffery J, Abdul-Aziz NM, et al.

Parasit Vectors, 2014;7:309.
PMID: 24993022 DOI: 10.1186/1756-3305-7-309

Molecular techniques are invaluable for investigation on the biodiversity of Anopheles mosquitoes. This study aimed at investigating the spatial-genetic variations among Anopheles mosquitoes from different areas of Peninsular Malaysia, as well as deciphering evolutionary relationships of the local Anopheles mosquitoes with the mosquitoes from neighbouring countries using the anopheline ITS2 rDNA gene.
Fulltext Draft genome of Brugia pahangi: high similarity between B. pahangi and B. malayi

Lau YL, Lee WC, Xia J, Zhang G, Razali R, Anwar A, et al.

Parasit Vectors, 2015;8:451.
PMID: 26350613 DOI: 10.1186/s13071-015-1064-2

Efforts to completely eradicate lymphatic filariasis from human population may be challenged by the emergence of Brugia pahangi as another zoonotic lymphatic filarial nematode. In this report, a genomic study was conducted to understand this species at molecular level.
Fulltext Rheopathologic Consequence of Plasmodium vivax Rosette Formation

Zhang R, Lee WC, Lau YL, Albrecht L, Lopes SC, Costa FT, et al.

PLoS Negl Trop Dis, 2016 08;10(8):e0004912.
PMID: 27509168 DOI: 10.1371/journal.pntd.0004912

Malaria parasites dramatically alter the rheological properties of infected red blood cells. In the case of Plasmodium vivax, the parasite rapidly decreases the shear elastic modulus of the invaded RBC, enabling it to avoid splenic clearance. This study highlights correlation between rosette formation and altered membrane deformability of P. vivax-infected erythrocytes, where the rosette-forming infected erythrocytes are significantly more rigid than their non-rosetting counterparts. The adhesion of normocytes to the PvIRBC is strong (mean binding force of 440pN) resulting in stable rosette formation even under high physiological shear flow stress. Rosetting may contribute to the sequestration of PvIRBC schizonts in the host microvasculature or spleen.
Fulltext Clarifying the debate on population-based screening for breast cancer with mammography: A systematic review of randomized controlled trials on mammography with Bayesian meta-analysis and causal model

Chen TH, Yen AM, Fann JC, Gordon P, Chen SL, Chiu SY, et al.

Medicine (Baltimore), 2017 Jan;96(3):e5684.
PMID: 28099330 DOI: 10.1097/MD.0000000000005684

BACKGROUND: The recent controversy about using mammography to screen for breast cancer based on randomized controlled trials over 3 decades in Western countries has not only eclipsed the paradigm of evidence-based medicine, but also puts health decision-makers in countries where breast cancer screening is still being considered in a dilemma to adopt or abandon such a well-established screening modality.
METHODS: We reanalyzed the empirical data from the Health Insurance Plan trial in 1963 to the UK age trial in 1991 and their follow-up data published until 2015. We first performed Bayesian conjugated meta-analyses on the heterogeneity of attendance rate, sensitivity, and over-detection and their impacts on advanced stage breast cancer and death from breast cancer across trials using Bayesian Poisson fixed- and random-effect regression model. Bayesian meta-analysis of causal model was then developed to assess a cascade of causal relationships regarding the impact of both attendance and sensitivity on 2 main outcomes.
RESULTS: The causes of heterogeneity responsible for the disparities across the trials were clearly manifested in 3 components. The attendance rate ranged from 61.3% to 90.4%. The sensitivity estimates show substantial variation from 57.26% to 87.97% but improved with time from 64% in 1963 to 82% in 1980 when Bayesian conjugated meta-analysis was conducted in chronological order. The percentage of over-detection shows a wide range from 0% to 28%, adjusting for long lead-time. The impacts of the attendance rate and sensitivity on the 2 main outcomes were statistically significant. Causal inference made by linking these causal relationships with emphasis on the heterogeneity of the attendance rate and sensitivity accounted for the variation in the reduction of advanced breast cancer (none-30%) and of mortality (none-31%). We estimated a 33% (95% CI: 24-42%) and 13% (95% CI: 6-20%) breast cancer mortality reduction for the best scenario (90% attendance rate and 95% sensitivity) and the poor scenario (30% attendance rate and 55% sensitivity), respectively.
CONCLUSION: Elucidating the scenarios from high to low performance and learning from the experiences of these trials helps screening policy-makers contemplate on how to avoid errors made in ineffective studies and emulate the effective studies to save women lives.
Fulltext Highly Crosslinked Polyethylene Tibial Post Fracture in the Unafflicted Limb of a Patient with Unilateral Lower Limb Poliomyelitis: A Case Report

Lee WC, Wee L

Malays Orthop J, 2019 Mar;13(1):42-44.
PMID: 31001383 DOI: 10.5704/MOJ.1903.008

We present a unique case of tibial post fracture of a posterior-stabilised total knee arthroplasty (PS-TKA) using highly crosslinked polyethylene (HXLPE) in the unafflicted limb of a patient who had poliomyelitis. The tibial post is an upright structure perpendicular to the PE insert articular surface which articulates with the cam of the femoral component to prevent excessive posterior translation of the tibia. We explore the choice of PS polyethylene (PE) inserts in patients with neuromuscular disorders (NMD). A 74-year old gentleman presented with recurrent knee pain seven years after the index PS-TKA with HXLPE. The TKA was performed on the unafflicted left limb (contralateral to the weak side affected by poliomyelitis). The posterior drawer test was positive. During the single-stage revision surgery, the HXLPE tibial post was noted to be broken. The liner was replaced with a thicker non-HXLPE. The patient achieved an excellent outcome at one-year post-surgery. This is the first report of HXLPE tibial post fracture in the unaffected knee of a patient with NMD affecting the lower limb. The HXLPE's reduced resistance to fatigue crack propagation might not be suitable in PS-TKA where there might be focal stress points on the tibial post, which was amplified in this case as it was the limb that the patient most depended on. When managing end-stage osteoarthritis with TKA in the unafflicted knee of a patient with NMD causing lower limb weakness, the selection of polyethylene material in PS-TKA may need more consideration than previously thought.
Fulltext More Evidence for Teriparatide after Fixation of Atypical Femoral Fractures: Report of Four Cases

Lee WC, Chua T

Malays Orthop J, 2021 Mar;15(1):138-140.
PMID: 33880163 DOI: 10.5704/MOJ.2103.023

Atypical femoral fractures (AFF) have low union rates. The use of teriparatide has been advocated for the post-operative healing of AFF, but the evidence is limited to case reports and some series due to its low incidence. We present a case series of four female patients to support the use of teriparatide after the surgical fixation of their AFF. Three of the patients had a complete AFF and one had an incomplete fracture. Their mean age was 70 (52 - 87) years, mean body mass index 24.6 (18.3 - 29.3), mean bone mineral density T-score of -2.3 (-4.8/-1.0), with a prior history of anti-resorptive therapy with bisphosphonates and denosumab. Teriparatide was started at an average of 8 (2-18) days post-fixation, with 20mcg daily for six months. Immediate full weight-bearing was permitted in three patients, while one was non-weight bearing for two months. The mean time to union was 12 (10 - 14) weeks. No side effects were observed over a mean follow-up of 58 (50 - 72) weeks. The use of teriparatide facilitated the quick union of AFF after surgical fixation. It appeared to be safe and promoted fracture healing in AFF.
Fulltext Acute respiratory distress syndrome and acute renal failure from Plasmodium ovale infection with fatal outcome

Lau YL, Lee WC, Tan LH, Kamarulzaman A, Syed Omar SF, Fong MY, et al.

Malar J, 2013;12:389.
PMID: 24180319 DOI: 10.1186/1475-2875-12-389

Plasmodium ovale is one of the causative agents of human malaria. Plasmodium ovale infection has long been thought to be non-fatal. Due to its lower morbidity, P. ovale receives little attention in malaria research.
Fulltext Hyperparasitaemic human Plasmodium knowlesi infection with atypical morphology in peninsular Malaysia

Lee WC, Chin PW, Lau YL, Chin LC, Fong MY, Yap CJ, et al.

Malar J, 2013;12:88.
PMID: 23496970 DOI: 10.1186/1475-2875-12-88

Plasmodium knowlesi is a potentially life-threatening zoonotic malaria parasite due to its relatively short erythrocytic cycle. Microscopic identification of P. knowlesi is difficult, with "compacted parasite cytoplasm" being one of the important identifying keys. This report is about a case of hyperparasitaemic human P. knowlesi infection (27% parasitaemia) with atypical amoeboid morphology. A peninsular Malaysian was admitted to the hospital with malaria. He suffered anaemia and acute kidney function impairment. Microscopic examination, assisted by nested PCR and sequencing confirmed as P. knowlesi infection. With anti-malarial treatment and several medical interventions, patient survived and recovered. One-month medical follow-up was performed after recovery and no recrudescence was noted. This case report highlights the extreme hyperparasitaemic setting, the atypical morphology of P. knowlesi in the patient's erythrocytes, as well as the medical interventions involved in this successfully treated case.

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