Evaluation of preferences of women and healthcare professionals in Singapore for implementation of noninvasive prenatal testing for Down syndrome

INTRODUCTION: Invasive prenatal diagnosis (IPD) has long been used to prenatally diagnose Down syndrome (DS), but is associated with a small risk of miscarriage. Meanwhile, noninvasive prenatal testing (NIPT) is a highly sensitive screening test using cell-free DNA in maternal blood for detection of DS that removes the risk of miscarriage, but confers a small risk of false-positive and false-negative results. Their implementations into clinical practice require an understanding of stakeholder preferences. METHODS: A total of 69 health professionals (HPs) and 301 women took part in a discrete choice experiment (DCE) in which preferences for four prenatal test attributes (accuracy, time of results, risk of miscarriage and amount of information provided) were assessed, and conditional logit regression was used to analyse data. Data on demographics and ranked preferences for test attributes were collected, and a direct choice between NIPT, IPD or neither test was given. RESULTS: Women showed a preference for test safety, whereas HPs prioritised test accuracy above all other attributes. When offered a direct choice between NIPT, IPD or neither test, women aged over 35 years, those with previous miscarriage or who knew a child with DS were more likely to choose NIPT than IPD. Chinese women preferred NIPT whereas Indian women preferred IPD. CONCLUSION: Our data highlight the need for patient-specific counselling, taking into account previous experiences and cultural factors. Since women and HPs prioritise different test attributes, it is essential that HPs recognise these differences in order to provide non-biased counselling

Use of an Anaerobic Chamber Environment for the Assay of Endogenous Cellular Protein-Tyrosine Phosphatase Activities

Protein-tyrosine phosphatases (PTPases) have a catalytic cysteine residue whose reduced state is integral to the reaction mechanism. Since exposure to air can artifactually oxidize this highly reactive thiol, PTPase assays have typically used potent reducing agents to reactivate the enzymes present; however, this approach does not allow for the measurement of the endogenous PTPase activity directly isolated from the in vivo cellular environment. Here we provide a method for using an anaerobic chamber to preserve the activity of the total PTPase complement in a tissue lysate or of an immunoprecipitated PTPase homolog to characterize their endogenous activation state. Comparison with a sample treated with biochemical reducing agents allows the determination of the activatable (reducible) fraction of the endogenous PTPase pool

State based model of long-term potentiation and synaptic tagging and capture

Recent data indicate that plasticity protocols have not only synapse-specific but also more widespread effects. In particular, in synaptic tagging and capture (STC), tagged synapses can capture plasticity-related proteins, synthesized in response to strong stimulation of other synapses. This leads to long-lasting modification of only weakly stimulated synapses. Here we present a biophysical model of synaptic plasticity in the hippocampus that incorporates several key results from experiments on STC. The model specifies a set of physical states in which a synapse can exist, together with transition rates that are affected by high- and low-frequency stimulation protocols. In contrast to most standard plasticity models, the model exhibits both early- and late-phase LTP/D, de-potentiation, and STC. As such, it provides a useful starting point for further theoretical work on the role of STC in learning and memory

Phylogeography and Taxonomy of Trypanosoma brucei

Trypanosoma brucei, the parasite causing human African trypanosomiasis (sleeping sickness) across sub-Saharan Africa is traditionally split into three subspecies: T. b. gambiense (Tbg), causing a chronic form of human disease in West and Central Africa; T. b. rhodesiense (Tbr), causing an acute form of human disease in East and Southern Africa; and T. b. brucei (Tbb), which is restricted to animals. Tbg is further split into Tbg group 1 and Tbg group 2. Better understanding the evolutionary relationships between these groups may help to shed light on the epidemiology of sleeping sickness. Here, we used three different types of genetic markers to investigate the phylogeographic relationships among the four groups across a large portion of their range. Our results confirm the distinctiveness of Tbg group 1 while highlighting the extremely close relationships among the other three taxa. In particular, Tbg group 2 was closely related to Tbb, while Tbr appeared to be a variant of Tbb, differing only in its phenotype of human infectivity. The wide geographic distribution of the gene conferring human infectivity (SRA) and the fact that it is readily exchanged among lineages of T. brucei in eastern Africa suggests that human-infective trypanosomes have access to an extensive gene pool with which to respond to selective pressures such as drugs

Direct and indirect effects of Johne's disease on farm and animal productivity in an Irish dairy herd

Johne's disease (JD) is caused by infection with the organism Mycobacterium avium spp. paratuberculosis, leading to chronic diarrhoea and ill thrift in adult cattle. JD is considered to adversely affect farm performance and profitability. This retrospective case study was undertaken on a single commercial dairy herd in the south west of Ireland. Animal production records were interrogated to assess the effect of JD on milk yield (total kg per lactation), somatic cell count (the geometric mean over the lactation), reasons for culling, cull price and changes in herd parity structure over time. JD groups were defined using clinical signs and test results. One control animal was matched to each case animal on parity number and year. Specific lactations (clinical, pre-clinical and test-positive only) from 1994 to 2004 were compared between JD case and control cows. A significantly lower milk yield (1259.3 kg/lactation) was noted from cows with clinical JD in comparison to their matched control group. Clinical animals had an average cull price of €516 less than animals culled without signs of clinical disease. In contrast, little effect was noted for sub-clinical infections. These direct effects of JD infections, in combination with increased culling for infertility and increasing replacement rates, had a negative impact on farm production. Results from this study provide preliminary information regarding the effects of JD status on both herd and animal-level performance in Ireland

The Functional DRD3 Ser9Gly Polymorphism (rs6280) Is Pleiotropic, Affecting Reward as Well as Movement

Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [11C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis

Common genetic variants of the ion channel transient receptor potential membrane melastatin 6 and 7 (TRPM6 and TRPM7), magnesium intake, and risk of type 2 diabetes in women

<p>Abstract</p> <p>Background</p> <p>Ion channel transient receptor potential membrane melastatin 6 and 7 (TRPM6 and TRPM7) play a central role in magnesium homeostasis, which is critical for maintaining glucose and insulin metabolism. However, it is unclear whether common genetic variation in <it>TRPM6 </it>and <it>TRPM7 </it>contributes to risk of type 2 diabetes.</p> <p>Methods</p> <p>We conducted a nested case-control study in the Women's Health Study. During a median of 10 years of follow-up, 359 incident diabetes cases were diagnosed and matched by age and ethnicity with 359 controls. We analyzed 20 haplotype-tagging single nucleotide polymorphisms (SNPs) in <it>TRPM6 </it>and 5 common SNPs in <it>TRPM7 </it>for their association with diabetes risk.</p> <p>Results</p> <p>Overall, there was no robust and significant association between any single SNP and diabetes risk. Neither was there any evidence of association between common <it>TRPM6 </it>and <it>TRPM7 </it>haplotypes and diabetes risk. Our haplotype analyses suggested a significant risk of type 2 diabetes among carriers of both the rare alleles from two non-synomous SNPs in <it>TRPM6 </it>(Val1393Ile in exon 26 [rs3750425] and Lys1584Glu in exon 27 [rs2274924]) when their magnesium intake was lower than 250 mg per day. Compared with non-carriers, women who were carriers of the haplotype 1393Ile-1584Glu had an increased risk of type 2 diabetes (OR, 4.92, 95% CI, 1.05–23.0) only when they had low magnesium intake (<250 mg/day).</p> <p>Conclusion</p> <p>Our results provide suggestive evidence that two common non-synonymous <it>TRPM6 </it>coding region variants, Ile1393Val and Lys1584Glu polymorphisms, might confer susceptibility to type 2 diabetes in women with low magnesium intake. Further replication in large-scale studies is warranted.</p

Results based on 124 cases of breast cancer and 97 controls from Taiwan suggest that the single nucleotide polymorphism (SNP309) in the MDM2 gene promoter is associated with earlier onset and increased risk of breast cancer

<p>Abstract</p> <p>Background</p> <p>It has been suggested that the single nucleotide polymorphism 309 (SNP309, T -> G) in the promoter region of the MDM2 gene is important for tumor development; however, with regards to breast cancer, inconsistent associations have been reported worldwide. It is speculated that these conflicting results may have arisen due to different patient subgroups and ethnicities studied. For the first time, this study explores the effect of the MDM2 SNP309 genotype on Taiwanese breast cancer patients.</p> <p>Methods</p> <p>Genomic DNA was obtained from the whole blood of 124 breast cancer patients and 97 cancer-free healthy women living in Taiwan. MDM2 SNP309 genotyping was carried out by restriction fragment length polymorphism (RFLP) assay. The multivariate logistic regression and the Kaplan-Meier method were used for analyzing the risk association and significance of age at diagnosis among different MDM2 SNP309 genotypes, respectively.</p> <p>Results</p> <p>Compared to the TT genotype, an increased risk association with breast cancer was apparent for the GG genotype (OR = 3.05, 95% CI = 1.04 to 8.95), and for the TG genotype (OR = 2.12, 95% CI = 0.90 to 5.00) after adjusting for age, cardiovascular disease/diabetes, oral contraceptive usage, and body mass index, which exhibits significant difference between cases and controls. Furthermore, the average ages at diagnosis for breast cancer patients were 53.6, 52 and 47 years for those harboring TT, TG and GG genotypes, respectively. A significant difference in median age of onset for breast cancer between GG and TT+TG genotypes was obtained by the log-rank test (p = 0.0067).</p> <p>Conclusion</p> <p>Findings based on the current sample size suggest that the MDM2 SNP309 GG genotype may be associated with both the risk of breast cancer and an earlier age of onset in Taiwanese women.</p

Lack of association between genetic polymorphisms within DUSP12 - ATF6 locus and glucose metabolism related traits in a Chinese population

<p>Abstract</p> <p>Background</p> <p>Genome-wide linkage studies in multiple ethnic populations found chromosome 1q21-q25 was the strongest and most replicable linkage signal in the human chromosome. Studies in Pima Indian, Caucasians and African Americans identified several SNPs in <it>DUSP12 </it>and <it>ATF6</it>, located in chromosome 1q21-q23, were associated with type 2 diabetes.</p> <p>Methods</p> <p>We selected 19 single nucleotide polymorphisms (SNPs) that could tag 98% of the SNPs with minor allele frequencies over 0.1 within <it>DUSP12-ATF6 </it>region. These SNPs were genotyped in a total of 3,700 Chinese Han subjects comprising 1,892 type 2 diabetes patients and 1,808 controls with normal glucose regulation.</p> <p>Results</p> <p>None of the SNPs and haplotypes showed significant association to type 2 diabetes in our samples. No association between the SNPs and quantitative traits was observed either.</p> <p>Conclusions</p> <p>Our data suggests common SNPs within <it>DUSP12</it>-<it>ATF6 </it>locus may not play a major role in glucose metabolism in the Chinese.</p

High-throughput processing and normalization of one-color microarrays for transcriptional meta-analyses

<p>Abstract</p> <p>Background</p> <p>Microarray experiments are becoming increasingly common in biomedical research, as is their deposition in publicly accessible repositories, such as Gene Expression Omnibus (GEO). As such, there has been a surge in interest to use this microarray data for meta-analytic approaches, whether to increase sample size for a more powerful analysis of a specific disease (e.g. lung cancer) or to re-examine experiments for reasons different than those examined in the initial, publishing study that generated them. For the average biomedical researcher, there are a number of practical barriers to conducting such meta-analyses such as manually aggregating, filtering and formatting the data. Methods to automatically process large repositories of microarray data into a standardized, directly comparable format will enable easier and more reliable access to microarray data to conduct meta-analyses.</p> <p>Methods</p> <p>We present a straightforward, simple but robust against potential outliers method for automatic quality control and pre-processing of tens of thousands of single-channel microarray data files. GEO GDS files are quality checked by comparing parametric distributions and quantile normalized to enable direct comparison of expression level for subsequent meta-analyses.</p> <p>Results</p> <p>13,000 human 1-color experiments were processed to create a single gene expression matrix that subsets can be extracted from to conduct meta-analyses. Interestingly, we found that when conducting a global meta-analysis of gene-gene co-expression patterns across all 13,000 experiments to predict gene function, normalization had minimal improvement over using the raw data.</p> <p>Conclusions</p> <p>Normalization of microarray data appears to be of minimal importance on analyses based on co-expression patterns when the sample size is on the order of thousands microarray datasets. Smaller subsets, however, are more prone to aberrations and artefacts, and effective means of automating normalization procedures not only empowers meta-analytic approaches, but aids in reproducibility by providing a standard way of approaching the problem.</p> <p>Data availability: matrix containing normalized expression of 20,813 genes across 13,000 experiments is available for download at . Source code for GDS files pre-processing is available from the authors upon request.</p