Entomologic and molecular investigation into Plasmodium vivax transmission in Singapore, 2009

<p>Abstract</p> <p>Background</p> <p>Singapore has been certified malaria free since November 1982 by the World Health Organization and despite occasional local transmission, the country has maintained the standing. In 2009, three clusters of malaria cases were reported in Singapore.</p> <p>Methods</p> <p>Epidemiological, entomological and molecular studies were carried out to investigate the three clusters, namely Mandai-Sungei Kadut, Jurong Island and Sembawang.</p> <p>Results</p> <p>A total of 29 malaria patients, with no recent travel history, were reported in the three clusters. Molecular analysis based on the <it>msp3α </it>and <it>msp1 </it>genes showed two independent local transmissions: one in Mandai-Sungei Kadut and another in Sembawang. Almost all cases within each cluster were epidemiologically linked. In Jurong Island cluster, epidemiological link remains uncertain, as almost all cases had a unique genetic profile. Only two cases shared a common profile and were found to be linked to the Mandai-Sungei Kadut cluster. Entomological investigation found <it>Anopheles sinensis </it>to be the predominant Anopheline in the two areas where local transmission of <it>P. vivax </it>was confirmed. <it>Anopheles sinensis </it>was found to be attracted to human bait and bites as early as 19:45 hrs. However, all <it>Anopheles </it>mosquitoes caught were negative for sporozoites and oocysts by dissection.</p> <p>Conclusion</p> <p>Investigation of <it>P. vivax </it>cases from the three cluster areas confirmed the occurrence of local transmission in two areas. Although <it>An. sinensis </it>was the predominant Anopheline found in areas with confirmed transmission, the vector/s responsible for the outbreaks still remains cryptic.</p

Loss of α-catenin elicits a cholestatic response and impairs liver regeneration

The liver is unique in its capacity to regenerate after injury, during which hepatocytes actively divide and establish cell-cell contacts through cell adhesion complexes. Here, we demonstrate that the loss of α-catenin, a well-established adhesion component, dramatically disrupts liver regeneration. Using a partial hepatectomy model, we show that regenerated livers from α-catenin knockdown mice are grossly larger than control regenerated livers, with an increase in cell size and proliferation. This increased proliferation correlated with increased YAP activation, implicating α-catenin in the Hippo/YAP pathway. Additionally, α-catenin knockdown mice exhibited a phenotype reminiscent of clinical cholestasis, with drastically altered bile canaliculi, elevated levels of bile components and signs of jaundice and inflammation. The disrupted regenerative capacity is a result of actin cytoskeletal disorganisation, leading to a loss of apical microvilli, dilated lumens in the bile canaliculi, and leaky tight junctions. This study illuminates a novel, essential role for α-catenin in liver regeneration

Association and clinical utility of NAT2 in the prediction of isoniazid-induced liver injury in Singaporean patients

10.1371/journal.pone.0186200PLOS ONE121

Correlation between HDL-cholesterol and remodeling index in patients with coronary artery disease: an intravascular ultrasound study

American Heart Association Annual Scientific Congres

Association and clinical utility of <i>NAT2</i> in the prediction of isoniazid-induced liver injury in Singaporean patients

<div><p>Background and aims</p><p>Isoniazid (INH) is part of the first-line-therapy for tuberculosis (TB) but can cause drug-induced liver injury (DILI). Several candidate single nucleotide polymorphisms (SNPs) have been previously identified but the clinical utility of these SNPs in the prediction of INH-DILI remains uncertain. The aim of this study was to assess the association between selected candidate SNPs and the risk of INH-DILI and to assess the clinical validity of associated variants in a Singaporean population.</p><p>Methods</p><p>This was a case-control study where 24 INH-DILI cases and 79 controls were recruited from the TB control unit in a tertiary hospital. Logistic regression was used to test for the association between candidate SNPs and INH-DILI. NAT2 acetylator status was inferred from genotypes and tested for association with INH-DILI. Finally, clinical validity measures were estimated for significant variants.</p><p>Results</p><p>Two SNPs in <i>NAT2</i> (rs1041983 and rs1495741) and NAT2 slow acetylators (SA) were significantly associated with INH-DILI (OR (95% CI) = 13.86 (4.30–44.70), 0.10 (0.03–0.33) and 9.98 (3.32–33.80), respectively). Based on an INH-DILI prevalence of 10%, the sensitivity, specificity, positive and negative predictive values of NAT2 SA were 75%, 78%, 28% and 97%, respectively. The population attributable fraction (PAF) and number needed to test (NNT) for NAT2 SA were estimated to be 0.67 and 4.08, respectively. A model with clinical and NAT2 acetylator status provided significantly better prediction for INH-DILI than a clinical model alone (area under receiver operating characteristic curve = 0.863 vs. 0.766, respectively, p = 0.027).</p><p>Conclusions</p><p>We show the association between NAT2 SA and INH-DILI in a Singaporean population and demonstrated its clinical utility in the prediction of INH-DILI.</p></div

Demographic and clinical characteristics of Singaporean patients diagnosed with TB and treated with INH.

<p>Demographic and clinical characteristics of Singaporean patients diagnosed with TB and treated with INH.</p

Pharmacogenomic association of <i>NAT2</i> variants in the Singaporean population.

<p>Pharmacogenomic association of <i>NAT2</i> variants in the Singaporean population.</p

Predictive value of NAT2 acetylator status.

<p>Predictive values were evaluated using receiver operating characteristic (ROC) curves and expressed as area-under-curve (AUC), which is a summary measure of the sensitivity and specificity. The clinical model (clin) consists of age, gender and self-reported ethnicity. SA: slow acetylators.</p

Risk allele frequency of associated <i>NAT2</i> variants by DILI grade.

<p>The frequencies of the risk variants (rs1041983 A, rs1495741 A and NAT2 SA) increase with DILI grade. There was only 1 patient with grade 4 DILI, who was homozygous for the non-risk variants. DILI: drug-induced liver injury, SA: slow acetylators.</p