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Vulvovaginal candidosis: contemporary challenges and the future of prophylactic and therapeutic approaches

Chew SY, Than LT

Mycoses, 2016 May;59(5):262-73.
PMID: 26765516 DOI: 10.1111/myc.12455

Vulvovaginal candidosis (VVC) is a common gynaecological disorder that is delineated by the inflammation of vaginal wall and it is caused by the opportunistic fungal pathogen Candida species. In fact, three out of every four women will experience at least one occasion of VVC during some point in their lives. Although uncomplicated VVC is relatively harmless, the complicated VVC such as recurrent attack often creates restlessness and depression in the patients, thus greatly affects their quality of life. Managements of VVC are usually associated with the use of antimycotic suppositories, topical cream or oral agents. These antimycotic agents are either available over-the-counter or prescribed by the clinicians. In recent decades, the rise of clinical challenges such as the increased prevalence of resistant Candida strains, recurrent VVC infection and adverse effects of multidrug interactions have necessitated the development of novel therapeutic or prophylactic options to combat the complicated VVC in the future. In this review, we discuss the current antimycotic treatments available for Candida vaginitis and the problems that exist in these seemingly effective treatments. Besides, we attempt to contemplate some of the future and prospective strategies surrounding the development of alternative therapeutic and prophylactic options in treating and preventing complicated VVC respectively.
Detection of 10 medically important Candida species by seminested polymerase chain reaction

Than LT, Chong PP, Ng KP, Seow HF

Diagn Microbiol Infect Dis, 2012 Feb;72(2):196-8.
PMID: 22154674 DOI: 10.1016/j.diagmicrobio.2011.10.008

A seminested PCR detecting ten medically important Candida species were achieved. Analytical sensitivity and specificity were not compromised.
Fulltext Detection of medically important Candida species by absolute quantitation real-time polymerase chain reaction

Than LT, Chong PP, Ng KP, Seow HF

Jundishapur J Microbiol, 2015 Jan;8(1):e14940.
PMID: 25789129 DOI: 10.5812/jjm.14940

The number of invasive candidiasis cases has risen especially with an increase in the number of immunosuppressed and immunocom promised patients. The early detection of Candida species which is specific and sensitive is important in determining the correct administration of antifungal drugs to patients.
Fulltext Pulmonary papillary adenocarcinoma with Aspergillus versicolor infection in a dog

Maniam R, Selvarajah GT, Mazlan M, Lung Than LT

Med Mycol Case Rep, 2018 Mar;19:25-29.
PMID: 29234587 DOI: 10.1016/j.mmcr.2017.11.005

Papillary adenocarcinoma of the lungs is the most common primary lung adenocarcinoma, with the feature of papillary-like structure formation by cells. A dog was presented with the primary complaint of vomiting, hyporexia and increased respiratory effort. Thoracic radiography revealed increased soft tissue radiopacity of the right cranial lung lobe suggestive of possible consolidation or collapsed lung lobe, with generalised miliary nodular pattern throughout the other lung fields. The dog was euthanized humanely and necropsy was performed. Histopathology confirmed the diagnosis of primary pulmonary lung neoplasm (papillary adenocarcinoma) with Aspergillus versicolor infection identified through fungal culture and PCR. There have been several reports on humans and dogs with fungal infections that often mimic or coexist with pulmonary neoplasm. This is the first documented report of A. versicolor isolated from a lung neoplasm in a dog in Malaysia.
Fulltext Probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 exhibit strong antifungal effects against vulvovaginal candidiasis-causing Candida glabrata isolates

Chew SY, Cheah YK, Seow HF, Sandai D, Than LT

J Appl Microbiol, 2015 May;118(5):1180-90.
PMID: 25688886 DOI: 10.1111/jam.12772

This study investigates the antagonistic effects of the probiotic strains Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 against vulvovaginal candidiasis (VVC)-causing Candida glabrata.
Fractional exhaled nitric oxide (FeNO) among office workers in an academic institution, Malaysia - associations with asthma, allergies and office environment

Lim FL, Hashim Z, Md Said S, Than LT, Hashim JH, Norbäck D

J Asthma, 2016 Mar;53(2):170-8.
PMID: 26300213 DOI: 10.3109/02770903.2015.1077861

OBJECTIVE: There are few studies on fractional exhaled nitric oxide (FeNO) and respiratory symptoms among adults in tropical areas. The aim was to study associations between FeNO and selected personal factors, respiratory symptoms, allergies, office characteristics and indoor office exposures among office workers (n = 460) from a university in Malaysia.
METHODS: Information on health was collected by a questionnaire, skin prick test and FeNO measurement. Temperature, relative air humidity, carbon monoxide and carbon dioxide were measured in the offices. Settled dust was vacuumed in the offices and analyzed for endotoxin, (1,3)-β-glucan and house dust mites allergens, namely Dermatophagoides pteronyssinus (Der p 1) and Dermatophagoides farinae (Der f 1). Two-level linear mixed models and multiple logistic regression were used to analyze the associations.
RESULTS: One-fourth (25.9%) of the office workers had elevated FeNO level (≥ 25 ppb) and 61.5% had HDM, cat, seafood or pollen allergy. Male gender (p < 0.001), current smoking (p = 0.037), height (p < 0.001) and atopy (p < 0.001) were associated with FeNO. The amount of vacuumed dust was associated with FeNO among atopic subjects (p = 0.009). Asthma and rhinitis symptoms were associated with FeNO (p < 0.05), especially among atopic subjects. In particular, a combination of atopy and elevated FeNO were associated with doctor-diagnosed asthma (p < 0.001), rhinitis (p < 0.001) and airway symptoms last 12 months (p < 0.001).
CONCLUSION: Gender, smoking, height and atopy are important risk factors for elevated FeNO levels. A combination of allergy testing and FeNO measurement could be useful in respiratory illness epidemiology studies and patient investigations in tropical areas.
KEYWORDS: Adults; Malaysia; allergy; office; respiratory symptoms; rhinitis; tropical areas
Fulltext Phylogenetic and Transcripts Profiling of Glucose Sensing Related Genes in Candida glabrata

Ng TS, Mohd Desa MN, Sandai D, Chong PP, Than LT

Jundishapur J Microbiol, 2015 Nov;8(11):e25177.
PMID: 26855740 DOI: 10.5812/jjm.25177

BACKGROUND: The sensing mechanism of glucose in Saccharomyces cerevisiae is well studied. However, such information is scarcely found in other yeast species such as Candida glabrata.
OBJECTIVES: This study aimed to identify the glucose sensing pathway related genes of C. glabrata and to analyze the regulation pattern of these genes in response to different surrounding glucose concentrations through the quantitative real time polymerase chain reaction (qRT-PCR).
MATERIALS AND METHODS: Phylogenetic analysis was carried out on predicted amino acid sequences of C. glabrata and S. cerevisiae to compare their degree of similarity. In addition, the growth of C. glabrata in response to different amounts of glucose (0%, 0.01%, 0.1%, 1% and 2%) was evaluated via the spot dilution assay on prepared agar medium. Besides, the SNF3 and RGT2, which act as putative glucose sensors, and the RGT1 and MIG1, which act as putative transcriptional regulators and selected downstream hexose transporters (HXTs), were analysed through qRT-PCR analysis for the gene expression level under different glucose concentrations.
RESULTS: Comparative analysis of predicted amino acids in the phylogenetic tree showed high similarity between C. glabrata and S cerevisiae. Besides, C. glabrata demonstrated the capability to grow in glucose levels as low as 0.01% in the spot dilution assay. In qRT-PCR analysis, differential expressions were observed in selected genes when C. glabrata was subjected to different glucose concentrations.
CONCLUSIONS: The constructed phylogenetic tree suggests the close evolutionary relationship between C. glabrata and S. cerevisiae. The capability of C. glabrata to grow in extremely low glucose environments and the differential expression of selected glucose-sensing related genes suggested the possible role of these genes in modulating the growth of C. glabrata in response to different glucose concentrations. This study helps deepen our understanding of the glucose sensing mechanism in C. glabrata and serves to provide fundamental data that may assist in unveiling this mechanism as a potential drug target.
In vitro modulation of probiotic bacteria on the biofilm of Candida glabrata

Chew SY, Cheah YK, Seow HF, Sandai D, Than LT

Anaerobe, 2015 Aug;34:132-8.
PMID: 26028405 DOI: 10.1016/j.anaerobe.2015.05.009

A conspicuous new concept of pathogens living as the microbial societies in the human host rather than free planktonic cells has raised considerable concerns among scientists and clinicians. Fungal biofilms are communities of cells that possess distinct characteristic such as increased resistance to the immune defence and antimycotic agents in comparison to their planktonic cells counterpart. Therefore, inhibition of the biofilm may represent a new paradigm for antifungal development. In this study, we aim to evaluate the in vitro modulation of vulvovaginal candidiasis (VVC)-causing Candida glabrata biofilms using probiotic lactobacilli strains. Probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 were shown to have completely inhibited C. glabrata biofilms and the results were corroborated by scanning electron microscopy (SEM), which revealed scanty structures of the mixed biofilms of C. glabrata and probiotic lactobacilli strains. In addition, biofilm-related C. glabrata genes EPA6 and YAK1 were downregulated in response to the probiotic lactobacilli challenges. The present study suggested that probiotic L. rhamnosus GR-1 and L. reuteri RC-14 strains inhibited C. glabrata biofilm by partially impeding the adherence of yeast cells and the effect might be contributed by the secretory compounds produced by these probiotic lactobacilli strains. Further investigations are required to examine and identify the biofilm inhibitory compounds and the mechanism of probiotic actions of these lactobacilli strains.
Sick building syndrome (SBS) among office workers in a Malaysian university--Associations with atopy, fractional exhaled nitric oxide (FeNO) and the office environment

Lim FL, Hashim Z, Md Said S, Than LT, Hashim JH, Norbäck D

Sci Total Environ, 2015 Dec 1;536:353-61.
PMID: 26225741 DOI: 10.1016/j.scitotenv.2015.06.137

There are few studies on sick building syndrome (SBS) including clinical measurements for atopy and fractional exhaled nitric oxide (FeNO). Our aim was to study associations between SBS symptoms, selected personal factors, office characteristics and indoor office exposures among office workers from a university in Malaysia. Health data were collected by a questionnaire (n=695), skin prick test (SPT) (n=463) and FeNO test (n=460). Office settled dust was vacuumed and analyzed for endotoxin, (1,3)-β-glucan and house dust mites (HDM) allergens group 1 namely Dermatophagoides pteronyssinus (Der p 1) and Dermatophagoides farinae (Der f 1). Office indoor temperature, relative air humidity (RH), carbon monoxide (CO) and carbon dioxide (CO2) were measured by a direct reading instrument. Associations were studied by two-levels multiple logistic regression with mutual adjustment and stratified analysis. The prevalence of weekly dermal, mucosal and general symptoms was 11.9%, 16.0% and 23.0% respectively. A combination of SPT positivity (allergy to HDM or cat) and high FeNO level (≥25 ppb) was associated with dermal (p=0.002), mucosal (p<0.001) and general symptoms (p=0.05). Der f1 level in dust was associated with dermal (p<0.001), mucosal (p<0.001) and general (p=0.02) symptoms. Among those with allergy to D. farinae, associations were found between Der f 1 levels in dust and dermal (p=0.003), mucosal (p=0.001) and general symptoms (p=0.007). Office-related symptoms were associated with Der f 1 levels in dust (p=0.02), low relative air humidity (p=0.04) and high office temperature (p=0.05). In conclusion, a combination of allergy to cat or HDM and high FeNO is a risk factor for SBS symptoms. Der f 1 allergen in dust can be a risk factor for SBS in the office environment, particularly among those sensitized to Der f 1 allergen.
Fulltext Asthma, Airway Symptoms and Rhinitis in Office Workers in Malaysia: Associations with House Dust Mite (HDM) Allergy, Cat Allergy and Levels of House Dust Mite Allergens in Office Dust

Lim FL, Hashim Z, Than LT, Md Said S, Hisham Hashim J, Norbäck D

PLoS One, 2015;10(4):e0124905.
PMID: 25923543 DOI: 10.1371/journal.pone.0124905

A prevalence study was conducted among office workers in Malaysia (N= 695). The aim of this study was to examine associations between asthma, airway symptoms, rhinitis and house dust mites (HDM) and cat allergy and HDM levels in office dust. Medical data was collected by a questionnaire. Skin prick tests were performed for HDM allergens (Dermatophagoides pteronyssinus, Dermatophagoides farinae) and cat allergen Felis domesticus. Indoor temperature and relative air humidity (RH) were measured in the offices and vacuumed dust samples were analyzed for HDM allergens. The prevalence of D. pteronyssinus, D. farinae and cat allergy were 50.3%, 49.0% and 25.5% respectively. Totally 9.6% had doctor-diagnosed asthma, 15.5% had current wheeze and 53.0% had current rhinitis. The Der p 1 (from D. pteronyssinus) and Der f 1 (from D. farinae) allergens levels in dust were 556 ng/g and 658 ng/g respectively. Statistical analysis was conducted by multilevel logistic regression, adjusting for age, gender, current smoking, HDM or cat allergy, home dampness and recent indoor painting at home. Office workers with HDM allergy had more wheeze (p= 0.035), any airway symptoms (p= 0.032), doctor-diagnosed asthma (p= 0.005), current asthma (p= 0.007), current rhinitis (p= 0.021) and rhinoconjuctivitis (p< 0.001). Cat allergy was associated with wheeze (p= 0.021), wheeze when not having a cold (p= 0.033), any airway symptoms (p= 0.034), doctor-diagnosed asthma (p= 0.010), current asthma (p= 0.020) and nasal allergy medication (p= 0.042). Der f 1 level in dust was associated with daytime breathlessness (p= 0.033) especially among those with HDM allergy. Der f 1 levels were correlated with indoor temperature (p< 0.001) and inversely correlated with RH (p< 0.001). In conclusion, HDM and cat allergies were common and independently associated with asthma, airway symptoms and rhinitis. Der f 1 allergen can be a risk factor for daytime breathlessness.
Fulltext Predictors of severe leptospirosis: a multicentre observational study from Central Malaysia

Philip N, Lung Than LT, Shah AM, Yuhana MY, Sekawi Z, Neela VK

BMC Infect Dis, 2021 Oct 19;21(1):1081.
PMID: 34666707 DOI: 10.1186/s12879-021-06766-5

BACKGROUND: Leptospirosis is a re-emerging disease with vast clinical presentations, that ranges from subclinical or mild to severe and fatal outcomes. Leptospirosis can be managed well if diagnosed earlier, however, similar clinical presentations by several other febrile illnesses or co-infections, and laboratory diagnostic challenges due to the biphasic nature of the illness, often result in mis- or underdiagnosis, thereby lead to severe illness. Identification of clinical predictors for the severe form of the disease plays a crucial role in reducing disease complication and mortality. Therefore, we aimed to determine the clinical predictors associated with severe illness among leptospirosis patients from Central Malaysia through a prospective multicenter observational study.
METHODS: A prospective multicenter observational study was performed on patients admitted for clinically suspected leptospirosis. Three hospitals namely Hospital Serdang, Hospital Tengku Ampuan Rahimah and Hospital Teluk Intan were included in the study. Among a total of 165 clinically suspected leptospirosis patients, 83 confirmed cases were investigated for clinical predictors for severe illness. Qualitative variables were performed using χ2 and the relationship between mild and severe cases was evaluated using logistic regression. Multivariable logistic regression was used to predict the independent variable for severity.
RESULTS: Among the 83 patients, 50 showed mild disease and 33 developed severe illness. The mean age of the patients was 41.92 ± 17.99 and most were males (n = 54, 65.06%). We identified mechanical ventilation, acute kidney injury, septic shock, creatinine level of > 1.13 mg/dL, urea > 7 mmol/L, alanine aminotransferase > 50 IU, aspartate aminotransferase > 50 IU, and platelet 50 IU and platelet
Metagenomic and proteomic approaches in elucidating aflatoxin B1 detoxification mechanisms of probiotic Lactobacillus casei Shirota towards intestine

Liew WP, Sabran MR, Than LT, Abd-Ghani F

Food Chem Toxicol, 2022 Feb;160:112808.
PMID: 34998910 DOI: 10.1016/j.fct.2022.112808

The modulation of gut microbiota and proteome due to aflatoxin B1 (AFB1) by probiotics remains unclear. This study investigated the alterations of gut microbiota and proteome in AFB1-exposed rats treated with probiotic Lactobacillus casei Shirota (Lcs). Forty male Sprague Dawley rats were randomly divided into five groups (n = 8) comprised control, AFB1, AFB1+activated charcoal, AFB1+Lcs, and Lcs groups. The rats were subjected to different treatments via oral gavage for four weeks. Urine and serum were collected for the measurement of AFB1 biomarkers and organs were harvested for histological analysis. Metagenomic sequencing was performed on fecal samples to profile gut microbiota. Besides, AFB1 most affected organ i.e. jejunum was subjected to proteomic analysis. The results indicated that Lcs intervention significantly reduced AFB1 biomarkers. H&E-stained intestine showed Lcs alleviated AFB1-induced inflammation and abnormal cell growth, particularly at the jejunum. Although AFB1 increased potentially pathogenic bacteria and reduced beneficial bacteria abundance in feces, the microbiota composition was normalized with Lcs treatment. The gut proteome analysis of the jejunum sample showed several pathways of AFB1 toxicity, wherein Lcs treatment demonstrated its protective effect. It is concluded that metagenomic and proteomic approaches are useful tools to understand AFB1-Lcs interaction and detoxification mechanism in the gut.
Fulltext The Effects of Indoor Pollutants Exposure on Allergy and Lung Inflammation: An Activation State of Neutrophils and Eosinophils in Sputum

Mohd Isa KN, Hashim Z, Jalaludin J, Lung Than LT, Hashim JH

Int J Environ Res Public Health, 2020 07 28;17(15).
PMID: 32731346 DOI: 10.3390/ijerph17155413

BACKGROUND: To explore the inflammation phenotypes following indoor pollutants exposure based on marker expression on eosinophils and neutrophils with the application of chemometric analysis approaches.
METHODS: A cross-sectional study was undertaken among secondary school students in eight suburban and urban schools in the district of Hulu Langat, Selangor, Malaysia. The survey was completed by 96 students at the age of 14 by using the International Study of Asthma and Allergies in Children (ISAAC) and European Community Respiratory Health Survey (ECRHS) questionnaires. The fractional exhaled nitric oxide (FeNO) was measured, and an allergic skin prick test and sputum induction were performed for all students. Induced sputum samples were analysed for the expression of CD11b, CD35, CD63, and CD66b on eosinophils and neutrophils by flow cytometry. The particulate matter (PM2.5 and PM10), NO2, CO2, and formaldehyde were measured inside the classrooms.
RESULTS: Chemometric and regression results have clustered the expression of CD63 with PM2.5, CD11b with NO2, CD66b with FeNO levels, and CO2 with eosinophils, with the prediction accuracy of the models being 71.88%, 76.04%, and 76.04%, respectively. Meanwhile, for neutrophils, the CD63 and CD66b clustering with PM2.5 and CD11b with FeNO levels showed a model prediction accuracy of 72.92% and 71.88%, respectively.
CONCLUSION: The findings indicated that the exposure to PM2.5 and NO2 was likely associated with the degranulation of eosinophils and neutrophils, following the activation mechanisms that led to the inflammatory reactions.
Fulltext SNF3 as High Affinity Glucose Sensor and Its Function in Supporting the Viability of Candida glabrata under Glucose-Limited Environment

Ng TS, Chew SY, Rangasamy P, Mohd Desa MN, Sandai D, Chong PP, et al.

Front Microbiol, 2015;6:1334.
PMID: 26648919 DOI: 10.3389/fmicb.2015.01334

Candida glabrata is an emerging human fungal pathogen that has efficacious nutrient sensing and responsiveness ability. It can be seen through its ability to thrive in diverse range of nutrient limited-human anatomical sites. Therefore, nutrient sensing particularly glucose sensing is thought to be crucial in contributing to the development and fitness of the pathogen. This study aimed to elucidate the role of SNF3 (Sucrose Non Fermenting 3) as a glucose sensor and its possible role in contributing to the fitness and survivability of C. glabrata in glucose-limited environment. The SNF3 knockout strain was constructed and subjected to different glucose concentrations to evaluate its growth, biofilm formation, amphotericin B susceptibility, ex vivo survivability and effects on the transcriptional profiling of the sugar receptor repressor (SRR) pathway-related genes. The CgSNF3Δ strain showed a retarded growth in low glucose environments (0.01 and 0.1%) in both fermentation and respiration-preferred conditions but grew well in high glucose concentration environments (1 and 2%). It was also found to be more susceptible to amphotericin B in low glucose environment (0.1%) and macrophage engulfment but showed no difference in the biofilm formation capability. The deletion of SNF3 also resulted in the down-regulation of about half of hexose transporters genes (four out of nine). Overall, the deletion of SNF3 causes significant reduction in the ability of C. glabrata to sense limited surrounding glucose and consequently disrupts its competency to transport and perform the uptake of this critical nutrient. This study highlighted the role of SNF3 as a high affinity glucose sensor and its role in aiding the survivability of C. glabrata particularly in glucose limited environment.
The Role of Isocitrate Lyase (ICL1) in the Metabolic Adaptation of Candida albicans Biofilms

Ishola OA, Ting SY, Tabana YM, Ahmed MA, Yunus MA, Mohamed R, et al.

Jundishapur J Microbiol, 2016 Sep;9(9):e38031.
PMID: 27800147

A major characteristic of Candida biofilm cells that differentiates them from free-floating cells is their high tolerance to antifungal drugs. This high resistance is attributed to particular biofilm properties, including the accumulation of extrapolymeric substances, morphogenetic switching, and metabolic flexibility.
Metabolic adaptation via regulated enzyme degradation in the pathogenic yeast Candida albicans

Ting SY, Ishola OA, Ahmed MA, Tabana YM, Dahham S, Agha MT, et al.

J Mycol Med, 2017 Mar;27(1):98-108.
PMID: 28041812 DOI: 10.1016/j.mycmed.2016.12.002

The virulence of Candida albicans is dependent upon fitness attributes as well as virulence factors. These attributes include robust stress responses and metabolic flexibility. The assimilation of carbon sources is important for growth and essential for the establishment of infections by C. albicans. Previous studies showed that the C. albicans ICL1 genes, which encode the glyoxylate cycle enzymes isocitratelyase are required for growth on non-fermentable carbon sources such as lactate and oleic acid and were repressed by 2% glucose. In contrast to S. cerevsiae, the enzyme CaIcl1 was not destabilised by glucose, resulting with its metabolite remaining at high levels. Further glucose addition has caused CaIcl1 to lose its signal and mechanisms that trigger destabilization in response to glucose. Another purpose of this study was to test the stability of the Icl1 enzyme in response to the dietary sugars, fructose, and galactose. In the present study, the ICL1 mRNAs expression was quantified using Quantitative Real Time PCR, whereby the stability of protein was measured and quantified using Western blot and phosphoimager, and the replacing and cloning of ICL1 ORF by gene recombination and ubiquitin binding was conducted via co-immuno-precipitation. Following an analogous experimental approach, the analysis was repeated using S. cerevisiaeas a control. Both galactose and fructose were found to trigger the degradation of the ICL1 transcript in C. albicans. The Icl1 enzyme was stable following galactose addition but was degraded in response to fructose. C. albicans Icl1 (CaIcl1) was also subjected to fructose-accelerated degradation when expressed in S. cerevisiae, indicating that, although it lacks a ubiquitination site, CaIcl1 is sensitive to fructose-accelerated protein degradation. The addition of an ubiquitination site to CaIcl1 resulted in this enzyme becoming sensitive to galactose-accelerated degradation and increases its rate of degradation in the presence of fructose. It can be concluded that ubiquitin-independent pathways of fructose-accelerated enzyme degradation exist in C. albicans.

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