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Fulltext Neglected Intestinal Parasites, Malnutrition and Associated Key Factors: A Population Based Cross-Sectional Study among Indigenous Communities in Sarawak, Malaysia

Rajoo Y, Ambu S, Lim YA, Rajoo K, Tey SC, Lu CW, et al.

PLoS One, 2017;12(1):e0170174.
PMID: 28095446 DOI: 10.1371/journal.pone.0170174

Intestinal parasitic infections (IPIs) have been recognized as one of the most significant causes of illness among disadvantaged communities. Many studies have been conducted on the prevalence of IPIs in Malaysia. However, these studies mostly focused on the indigenous groups in Peninsular Malaysia. The present study was conducted to provide the current baseline data on prevalence of IPIs, anaemia, malnutrition and associated risk factors among the indigenous communities in Sarawak, situation at northwest Borneo island of Malaysia. A cross sectional study was conducted among the longhouses communities. Stool samples were obtained and examined for the presence of IPIs using microscopy technique. Haemoglobin measurement was done using a portable haemoglobin analyzer. Malnutrition (i.e., stunting, underweight and wasting) was assessed using the WHO Anthro software. Statistical analysis was carried out using SPSS software. A total of 341participants took part in this study. The overall prevalence of IPIs was 57.5%. Multivariate analysis indicated that the absence of toilets (OR = 1.6; 95% CI = 1.1-2.7; p = 0.002) and close contact with animals (OR = 1.8; 95% CI = 1.3-2.9; p = 0.027) as significant predictors for IPIs. The incidence of anaemia was 36.4%. The incidence of underweight, wasting and stunting were 22.2%, 5.6% and 35.4%, respectively. Multivariate analysis demonstrated that low level of parental education attainment (OR = 1.9; 95% CI = 1.2-3.0; p = 0.006) was identified as significant predictor for anaemia. The incidence of wasting was significantly associated with mild anaemia (OR = 1.2; 95% CI = 0.9-1.7; p = 0.024). Low household income was identified as significant predictor for stunting (OR = 2.1; 95% CI = 9.8-22.2; p = 0.001) and underweight (OR = 1.9; 95% CI = 5.6-18.7; p = 0.037), respectively. Essentially, the present study highlighted that intestinal parasitic infections, anaemia and malnutrition are still prevalent among rural indigenous community in Sarawak. Improvement of socioeconomic status, periodic mass deworming, iron supplementation and health education program should be included in the control and prevention of public health strategies.
Fulltext Disease progression in Plasmodium knowlesi malaria is linked to variation in invasion gene family members

Ahmed AM, Pinheiro MM, Divis PC, Siner A, Zainudin R, Wong IT, et al.

PLoS Negl Trop Dis, 2014 Aug;8(8):e3086.
PMID: 25121807 DOI: 10.1371/journal.pntd.0003086

Emerging pathogens undermine initiatives to control the global health impact of infectious diseases. Zoonotic malaria is no exception. Plasmodium knowlesi, a malaria parasite of Southeast Asian macaques, has entered the human population. P. knowlesi, like Plasmodium falciparum, can reach high parasitaemia in human infections, and the World Health Organization guidelines for severe malaria list hyperparasitaemia among the measures of severe malaria in both infections. Not all patients with P. knowlesi infections develop hyperparasitaemia, and it is important to determine why. Between isolate variability in erythrocyte invasion, efficiency seems key. Here we investigate the idea that particular alleles of two P. knowlesi erythrocyte invasion genes, P. knowlesi normocyte binding protein Pknbpxa and Pknbpxb, influence parasitaemia and human disease progression. Pknbpxa and Pknbpxb reference DNA sequences were generated from five geographically and temporally distinct P. knowlesi patient isolates. Polymorphic regions of each gene (approximately 800 bp) were identified by haplotyping 147 patient isolates at each locus. Parasitaemia in the study cohort was associated with markers of disease severity including liver and renal dysfunction, haemoglobin, platelets and lactate, (r = ≥ 0.34, p = <0.0001 for all). Seventy-five and 51 Pknbpxa and Pknbpxb haplotypes were resolved in 138 (94%) and 134 (92%) patient isolates respectively. The haplotypes formed twelve Pknbpxa and two Pknbpxb allelic groups. Patients infected with parasites with particular Pknbpxa and Pknbpxb alleles within the groups had significantly higher parasitaemia and other markers of disease severity. Our study strongly suggests that P. knowlesi invasion gene variants contribute to parasite virulence. We focused on two invasion genes, and we anticipate that additional virulent loci will be identified in pathogen genome-wide studies. The multiple sustained entries of this diverse pathogen into the human population must give cause for concern to malaria elimination strategists in the Southeast Asian region.
The Function of HLA-B*13:01 Involved in the Pathomechanism of Dapsone-Induced Severe Cutaneous Adverse Reactions

Chen WT, Wang CW, Lu CW, Chen CB, Lee HE, Hung SI, et al.

J Invest Dermatol, 2018 07;138(7):1546-1554.
PMID: 29458119 DOI: 10.1016/j.jid.2018.02.004

Dapsone-induced hypersensitivity reactions may cause severe cutaneous adverse reactions, such as drug reaction with eosinophilia and systemic symptoms (DRESS). It has been reported that HLA-B*13:01 is strongly associated with dapsone-induced hypersensitivity reactions among leprosy patients. However, the phenotype specificity and detailed immune mechanism of HLA-B*13:01 remain unclear. We investigated the genetic predisposition, HLA-B*13:01 function, and cytotoxic T cells involved in the pathogenesis of dapsone-induced severe cutaneous adverse reactions. We enrolled patients from Taiwan and Malaysia with DRESS and maculopapular eruption with chronic inflammatory dermatoses. Our results showed that the HLA-B*13:01 allele was present in 85.7% (6/7) of patients with dapsone DRESS (odds ratio = 49.64, 95% confidence interval = 5.89-418.13; corrected P = 2.92 × 10-4) but in only 10.8% (73/677) of general population control individuals in Taiwan. The level of granulysin, the severe cutaneous adverse reaction-specific cytotoxic protein released from cytotoxic T cells, was increased in both the plasma of DRESS patients (36.14 ± 9.02 ng/ml, P < 0.05) and in vitro lymphocyte activation test (71.4%, 5/7 patients) compared with healthy control individuals. Furthermore, dapsone-specific cytotoxic T cells were significantly activated when co-cultured with HLA-B*13:01-expressing antigen presenting cells in the presence of dapsone (3.9-fold increase, compared with cells with no HLA-B*13:01 expression; P < 0.01). This study indicates that HLA-B*13:01 is strongly associated with dapsone DRESS and describes a functional role for the HLA-restricted immune mechanism induced by dapsone.
Whole genome sequencing identifies genetic variants associated with co-trimoxazole hypersensitivity in Asians

Wang CW, Tassaneeyakul W, Chen CB, Chen WT, Teng YC, Huang CY, et al.

J Allergy Clin Immunol, 2021 04;147(4):1402-1412.
PMID: 32791162 DOI: 10.1016/j.jaci.2020.08.003

BACKGROUND: Co-trimoxazole, a sulfonamide antibiotic, is used to treat a variety of infections worldwide, and it remains a common first-line medicine for prophylaxis against Pneumocystis jiroveci pneumonia. However, it can cause severe cutaneous adverse reaction (SCAR), including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms. The pathomechanism of co-trimoxazole-induced SCAR remains unclear.
OBJECTIVE: We aimed to investigate the genetic predisposition of co-trimoxazole-induced SCAR.
METHODS: We conducted a multicountry case-control association study that included 151 patients with of co-trimoxazole-induced SCAR and 4631 population controls from Taiwan, Thailand, and Malaysia, as well as 138 tolerant controls from Taiwan. Whole-genome sequencing was performed for the patients and population controls from Taiwan; it further validated the results from Thailand and Malaysia.
RESULTS: The whole-genome sequencing study (43 case patients vs 507 controls) discovered that the single-nucleotide polymorphism rs41554616, which is located between the HLA-B and MICA loci, had the strongest association with co-trimoxazole-induced SCAR (P = 8.2 × 10-9; odds ratio [OR] = 7.7). There were weak associations of variants in co-trimoxazole-related metabolizing enzymes (CYP2D6, GSTP1, GCLC, N-acetyltransferase [NAT2], and CYP2C8). A replication study using HLA genotyping revealed that HLA-B∗13:01 was strongly associated with co-trimoxazole-induced SCAR (the combined sample comprised 91 case patients vs 2545 controls [P = 7.2 × 10-21; OR = 8.7]). A strong HLA association was also observed in the case patients from Thailand (P = 3.2 × 10-5; OR = 3.6) and Malaysia (P = .002; OR = 12.8), respectively. A meta-analysis and phenotype stratification study further indicated a strong association between HLA-B∗13:01 and co-trimoxazole-induced drug reaction with eosinophilia and systemic symptoms (P = 4.2 × 10-23; OR = 40.1).
CONCLUSION: This study identified HLA-B∗13:01 as an important genetic factor associated with co-trimoxazole-induced SCAR in Asians.
The Medication Risk of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Asians: The Major Drug Causality and Comparison With the US FDA Label

Wang YH, Chen CB, Tassaneeyakul W, Saito Y, Aihara M, Choon SE, et al.

Clin. Pharmacol. Ther., 2019 01;105(1):112-120.
PMID: 29569740 DOI: 10.1002/cpt.1071

Specific ethnic genetic backgrounds are associated with the risk of Stevens-Johnson syndrome / toxic epidermal necrolysis (SJS/TEN) especially in Asians. However, there have been no large cohort, multiple-country epidemiological studies of medication risk related to SJS/TEN in Asian populations. Thus, we analyzed the registration databases from multiple Asian countries who were treated during 1998-2017. A total 1,028 SJS/TEN cases were identified with the algorithm of drug causality for epidermal necrolysis. Furthermore, those medications labeled by the US Food and Drug Administration (FDA) as carrying a risk of SJS/TEN were also compared with the common causes of SJS/TEN in Asian countries. Oxcarbazepine, sulfasalazine, COX-II inhibitors, and strontium ranelate were identified as new potential causes. In addition to sulfa drugs and beta-lactam antibiotics, quinolones were also a common cause. Only one acetaminophen-induced SJS was identified, while several medications (e.g., oseltamivir, terbinafine, isotretinoin, and sorafenib) labeled as carrying a risk of SJS/TEN by the FDA were not found to have caused any of the cases in the Asian countries investigated in this study.