Tryptophan hydroxylase-2 (TPH2) is a newly identified second form of TPH responsible for serotonin synthesis in the brain and has been increasingly implicated as a contributor to the etiology of various psychiatric disorders. In this study, we have identified the constellation of polymorphisms in rhesus monkey TPH2 and investigated genotype/phenotype association as well as gene expression effects of specific polymorphisms. Genomic DNA was obtained from 247 rhesus monkeys, among which 24 had been previously examined for plasma cortisol level, dexamethasone suppression, and combined dexmethasone/ACTH challenge. Polymorphisms in all exons, splicing junctions and approximately 2 kb of the 5 0 -flanking region (5 0 -FR) of TPH2 were identified by sequencing. We identified 17 single nucleotide polymorphisms (SNPs) including two that are predictive of amino-acid change (25Pro > His and 75Gly > Ser, respectively), two mononucleotide repeats, one dinucleotide repeat, and one 159-bp insertion polymorphism. The 3 0 -UTR polymorphisms were significantly associated with hypothalamicpituitary-adrenal (HPA) axis activity, especially 2051A > C, which was strikingly correlated with plasma cortisol level in the morning only (F = 10.203, P = 0.001). Luciferase reporter gene assays showed that the 3 0 -UTR polymorphisms and haplotypes had a profound effect on in vitro gene expression. Accordingly, these investigations revealed that polymorphisms in 3 0 -UTR of rhesus monkey TPH2 modulate HPA axis function, presumably by affecting levels of TPH2 expression. Molecular Psychiatry (2006) 11, 914-928.

BackgroundDengue outbreaks are increasing in frequency over space and time, affecting people’s health and burdening resource-constrained health systems. The ability to detect early emerging outbreaks is key to mounting an effective response. The early warning and response system (EWARS) is a toolkit that provides countries with early-warning systems for efficient and cost-effective local responses. EWARS uses outbreak and alarm indicators to derive prediction models that can be used prospectively to predict a forthcoming dengue outbreak at district level.MethodsWe report on the development of the EWARS tool, based on users’ recommendations into a convenient, user-friendly and reliable software aided by a user’s workbook and its field testing in 30 health districts in Brazil, Malaysia and Mexico.Findings34 Health officers from the 30 study districts who had used the original EWARS for 7 to 10 months responded to a questionnaire with mainly open-ended questions. Qualitative content analysis showed that participants were generally satisfied with the tool but preferred open-access vs. commercial software. EWARS users also stated that the geographical unit should be the district, while access to meteorological information should be improved. These recommendations were incorporated into the second-generation EWARS-R, using the free R software, combined with recent surveillance data and resulted in higher sensitivities and positive predictive values of alarm signals compared to the first-generation EWARS. Currently the use of satellite data for meteorological information is being tested and a dashboard is being developed to increase user-friendliness of the tool. The inclusion of other Aedes borne viral diseases is under discussion.ConclusionEWARS is a pragmatic and useful tool for detecting imminent dengue outbreaks to trigger early response activities.

An IgG4 ELISA based on a novel recombinant antigen was evaluated for detection of Brugia malayi infection, using 2487 sera from various institutions: 2031 samples from Universiti Sains Malaysia, 276 blinded sera from 2 other institutions in Malaysia, 140 blinded sera from India and 40 blinded sera from Thailand. These sera were from various groups of individuals, i.e., microfilaraemics, chronic patients, endemic normals, non-endemic normals and individuals with other parasitic and bacterial infections. Based on a cut-off optical density reading of 0.300, the IgG4 ELISA demonstrated specificity rates of 95.6-100%, sensitivity rates of 96-100%, positive predictive values of 75-100% and negative predictive values of 98.9-100%. These evaluation studies demonstrated the high specificity and sensitivity of this test for the detection of active B. malayi infection. Thus, the IgG4 ELISA would be very useful as a tool in diagnosis and in elimination programmes for brugian filariasis.