Incorporation of a selective sigma-2 receptor ligand enhances uptake of liposomes by multiple cancer cells

Background: The sigma-2 receptor is an attractive target for tumor imaging and targeted therapy because it is overexpressed in multiple types of solid tumors, including prostate cancer, breast cancer, and lung cancer. SV119 is a synthetic small molecule that binds to sigma-2 receptors with high affinity and specificity. This study investigates the utility of SV119 in mediating the selective targeting of liposomal vectors in various types of cancer cells. Methods: SV119 was covalently linked with polyethylene glycol-dioleyl amido aspartic acid conjugate (PEG-DOA) to generate a novel functional lipid, SV119-PEG-DOA. This lipid was utilized for the preparation of targeted liposomes to enhance their uptake by cancer cells. Liposomes with various SV119 densities (0, 1, 3, and 5 mole%) were prepared and their cellular uptake was investigated in several tumor cell lines. In addition, doxorubicin (DOX) was loaded into the targeted and unmodified liposomes, and the cytotoxic effect on the DU-145 cells was evaluated by MTT assay. Results: Liposomes with or without SV119-PEG-DOA both have a mean diameter of approximately 90 nm and a neutral charge. The incorporation of SV119-PEG-DOA significantly increased the cellular uptake of liposomes by the DU-145, PC-3, A549, 201T, and MCF-7 tumor cells, which was shown by fluorescence microscopy and the quantitative measurement of fluorescence intensity. In contrast, the incorporation of SV119 did not increase the uptake of liposomes by the normal BEAS-2B cells. In a time course study, the uptake of SV119 liposomes by DU-145 cells was also significantly higher at each time point compared to the unmodified liposomes. Furthermore, the DOX-loaded SV119 liposomes showed significantly higher cytotoxicity to DU-145 cells compared to the DOX-loaded unmodified liposomes. Conclusion: SV119 liposomes were developed for targeted drug delivery to cancer cells. The targeting efficiency and specificity of SV119 liposomes to cancer cells was demonstrated in vitro. The results of this study suggest that SV119-modified liposomes might be a promising drug carrier for tumor-targeted delivery. © 2012 Zhang et al, publisher and licensee Dove Medical Press Ltd

Speciation by host switch in brood parasitic indigobirds

A growing body of empirical and theoretical work supports the plausibility of sympatric speciation(1-3), but there remain few examples in which all the essential components of the process are well understood. The African indigobirds Vidua spp. are host-specific brood parasites. Indigobird nestlings are reared along with host young, and mimic the mouth markings of their respective hosts(4-6). As adults, male indigobirds mimic host song(4-7), whereas females use these songs to choose both their mates and the nests they parasitize(8). These behavioural mechanisms promote the cohesion of indigobird populations associated with a given host species, and provide a mechanism for reproductive isolation after a new host is colonized. Here we show that all indigobird species are similar genetically, but are significantly differentiated in both mitochondrial haplotype and nuclear allele frequencies. These data support a model of recent sympatric speciation. In contrast to the cuckoo Cuculus canorus, in which only female lineages are faithful to specific hosts(9,10), host switches have led to speciation in indigobirds because both males and females imprint on their hosts(8,11).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62510/1/nature01863.pd

Online Sexual Partner Seeking as a Social Practice: Qualitative Evidence from the 4(th) British National Survey of Sexual Attitudes and Lifestyles (Natsal-4)

Once perceived as a means for those unsuccessful at traditional dating, online dating has become normalized as a way to seek sexual or romantic partners. In 2019, we interviewed 40 British adults on the role of digital technologies in their sexual lives; this paper draws on the accounts of 22 who had used such technologies for seeking partners. We analyzed qualitative accounts of online partner seeking as a social practice, drawing on a sample diverse in age, gender and sexual orientation, and informed by sexual script and social practice theory. Our theoretically informed analysis emphasized the multiple meanings and goals involved, the affordances of the technology and individuals’ skills. Our study provided several novel contributions. Young heterosexual people commonly used general social media, rather than dating apps, to meet partners; meeting partners often involved complex interplays between online and offline networks and encounters. Risks were defined not merely in relation to “risky others” but in terms of one’s own actions or attitudes. Participants deployed various skills in minimizing harms such as non-consensual sharing of intimate images, and used self-care skills such as setting limits to engagement

Health services research in the public healthcare system in Hong Kong: An analysis of over 1 million antihypertensive prescriptions between 2004-2007 as an example of the potential and pitfalls of using routinely collected electronic patient data

<b>Objectives</b> Increasing use is being made of routinely collected electronic patient data in health services research. The aim of the present study was to evaluate the potential usefulness of a comprehensive database used routinely in the public healthcare system in Hong Kong, using antihypertensive drug prescriptions in primary care as an example.<p></p> <b>Methods</b> Data on antihypertensive drug prescriptions were retrieved from the electronic Clinical Management System (e-CMS) of all primary care clinics run by the Health Authority (HA) in the New Territory East (NTE) cluster of Hong Kong between January 2004 and June 2007. Information was also retrieved on patients’ demographic and socioeconomic characteristics, visit type (new or follow-up), and relevant diseases (International Classification of Primary Care, ICPC codes). <p></p> <b>Results</b> 1,096,282 visit episodes were accessed, representing 93,450 patients. Patients’ demographic and socio-economic details were recorded in all cases. Prescription details for anti-hypertensive drugs were missing in only 18 patients (0.02%). However, ICPC-code was missing for 36,409 patients (39%). Significant independent predictors of whether disease codes were applied included patient age > 70 years (OR 2.18), female gender (OR 1.20), district of residence (range of ORs in more rural districts; 0.32-0.41), type of clinic (OR in Family Medicine Specialist Clinics; 1.45) and type of visit (OR follow-up visit; 2.39). <p></p> In the 57,041 patients with an ICPC-code, uncomplicated hypertension (ICPC K86) was recorded in 45,859 patients (82.1%). The characteristics of these patients were very similar to those of the non-coded group, suggesting that most non-coded patients on antihypertensive drugs are likely to have uncomplicated hypertension. <p></p> <b>Conclusion</b> The e-CMS database of the HA in Hong Kong varies in quality in terms of recorded information. Potential future health services research using demographic and prescription information is highly feasible but for disease-specific research dependant on ICPC codes some caution is warranted. In the case of uncomplicated hypertension, future research on pharmaco-epidemiology (such as prescription patterns) and clinical issues (such as side-effects of medications on metabolic parameters) seems feasible given the large size of the data set and the comparability of coded and non-coded patients

Whole-genome sequencing to understand the genetic architecture of common gene expression and biomarker phenotypes.

Initial results from sequencing studies suggest that there are relatively few low-frequency (<5%) variants associated with large effects on common phenotypes. We performed low-pass whole-genome sequencing in 680 individuals from the InCHIANTI study to test two primary hypotheses: (i) that sequencing would detect single low-frequency-large effect variants that explained similar amounts of phenotypic variance as single common variants, and (ii) that some common variant associations could be explained by low-frequency variants. We tested two sets of disease-related common phenotypes for which we had statistical power to detect large numbers of common variant-common phenotype associations-11 132 cis-gene expression traits in 450 individuals and 93 circulating biomarkers in all 680 individuals. From a total of 11 657 229 high-quality variants of which 6 129 221 and 5 528 008 were common and low frequency (<5%), respectively, low frequency-large effect associations comprised 7% of detectable cis-gene expression traits [89 of 1314 cis-eQTLs at P < 1 × 10(-06) (false discovery rate ∼5%)] and one of eight biomarker associations at P < 8 × 10(-10). Very few (30 of 1232; 2%) common variant associations were fully explained by low-frequency variants. Our data show that whole-genome sequencing can identify low-frequency variants undetected by genotyping based approaches when sample sizes are sufficiently large to detect substantial numbers of common variant associations, and that common variant associations are rarely explained by single low-frequency variants of large effect

New uses of the Migraine Screen Questionnaire (MS-Q): validation in the Primary Care setting and ability to detect hidden migraine. MS-Q in Primary Care

<p>Abstract</p> <p>Background</p> <p>PC plays an important role in early diagnosis of health disorders, particularly migraine, due to the financial impact of this disease for the society and its impact on patients' quality of life. The aim of the study was to validate the self-administered MS-Q questionnaire for detection of hidden migraine in the field of primary care (PC), and to explore its use in this setting.</p> <p>Methods</p> <p>Cross-sectional, observational, and multicentre study in subjects above 18 years of age patients attending PC centers (regardless of the reason for consultation). A MS-Q score ≥ 4 was considered possible migraine. Level of agreement with IHS criteria clinical diagnosis (kappa coefficient), and instrument's validity properties: sensitivity, specificity, positive (PPV) and negative (NPV) predictive values were determined. The ability of the instrument to identify possible new cases of migraine was calculated, as well as the ratio of hidden disease compared to the ratio obtained by IHS criteria.</p> <p>Results</p> <p>A total of 9,670 patients were included [48.9 ± 17.2 years (mean ± SD); 61.9% women], from 410 PC centers representative of the whole national territory. The clinical prevalence of migraine according to the IHS criteria was 24.7%, and 20.4% according to MS-Q: Kappa index of agreement 0.82 (p < 0.05). MS-Q sensitivity was 0.82 (95% CI, 0.81 - 0.84), specificity 0.97 (95% CI, 0.98 - 0.99), PPV 0.95 (95% CI, 0.94 - 0.96), and NPV 0.94 (95% CI, 0.93 - 0.95). No statistically significant differences were found in the percentages of patients with <it>de novo </it>and hidden migraine identified by MS-Q and by IHS criteria: 5.7% vs. 6.1% and 26.6% vs. 24.1%, respectively.</p> <p>Conclusions</p> <p>The results of the present study confirm the usefulness of the MS-Q questionnaire for the early detection and assessment of migraine in PC settings, and its ability to detect hidden migraine.</p

Statistical Power of Model Selection Strategies for Genome-Wide Association Studies

Genome-wide association studies (GWAS) aim to identify genetic variants related to diseases by examining the associations between phenotypes and hundreds of thousands of genotyped markers. Because many genes are potentially involved in common diseases and a large number of markers are analyzed, it is crucial to devise an effective strategy to identify truly associated variants that have individual and/or interactive effects, while controlling false positives at the desired level. Although a number of model selection methods have been proposed in the literature, including marginal search, exhaustive search, and forward search, their relative performance has only been evaluated through limited simulations due to the lack of an analytical approach to calculating the power of these methods. This article develops a novel statistical approach for power calculation, derives accurate formulas for the power of different model selection strategies, and then uses the formulas to evaluate and compare these strategies in genetic model spaces. In contrast to previous studies, our theoretical framework allows for random genotypes, correlations among test statistics, and a false-positive control based on GWAS practice. After the accuracy of our analytical results is validated through simulations, they are utilized to systematically evaluate and compare the performance of these strategies in a wide class of genetic models. For a specific genetic model, our results clearly reveal how different factors, such as effect size, allele frequency, and interaction, jointly affect the statistical power of each strategy. An example is provided for the application of our approach to empirical research. The statistical approach used in our derivations is general and can be employed to address the model selection problems in other random predictor settings. We have developed an R package markerSearchPower to implement our formulas, which can be downloaded from the Comprehensive R Archive Network (CRAN) or http://bioinformatics.med.yale.edu/group/

Increased Avian Diversity Is Associated with Lower Incidence of Human West Nile Infection: Observation of the Dilution Effect

Recent infectious disease models illustrate a suite of mechanisms that can result in lower incidence of disease in areas of higher disease host diversity–the ‘dilution effect’. These models are particularly applicable to human zoonoses, which are infectious diseases of wildlife that spill over into human populations. As many recent emerging infectious diseases are zoonoses, the mechanisms that underlie the ‘dilution effect’ are potentially widely applicable and could contribute greatly to our understanding of a suite of diseases. The dilution effect has largely been observed in the context of Lyme disease and the predictions of the underlying models have rarely been examined for other infectious diseases on a broad geographic scale. Here, we explored whether the dilution effect can be observed in the relationship between the incidence of human West Nile virus (WNV) infection and bird (host) diversity in the eastern US. We constructed a novel geospatial contrasts analysis that compares the small differences in avian diversity of neighboring US counties (where one county reported human cases of WNV and the other reported no cases) with associated between-county differences in human disease. We also controlled for confounding factors of climate, regional variation in mosquito vector type, urbanization, and human socioeconomic factors that are all likely to affect human disease incidence. We found there is lower incidence of human WNV in eastern US counties that have greater avian (viral host) diversity. This pattern exists when examining diversity-disease relationships both before WNV reached the US (in 1998) and once the epidemic was underway (in 2002). The robust disease-diversity relationships confirm that the dilution effect can be observed in another emerging infectious disease and illustrate an important ecosystem service provided by biodiversity, further supporting the growing view that protecting biodiversity should be considered in public health and safety plans

Hybridization in parasites: consequences for adaptive evolution, pathogenesis and public health in a changing world

[No abstract available

Genetic variation and recombination of RdRp and HSP 70h genes of Citrus tristeza virus isolates from orange trees showing symptoms of citrus sudden death disease

<p>Abstract</p> <p>Background</p> <p>Citrus sudden death (CSD), a disease that rapidly kills orange trees, is an emerging threat to the Brazilian citrus industry. Although the causal agent of CSD has not been definitively determined, based on the disease's distribution and symptomatology it is suspected that the agent may be a new strain of <it>Citrus tristeza virus </it>(CTV). CTV genetic variation was therefore assessed in two Brazilian orange trees displaying CSD symptoms and a third with more conventional CTV symptoms.</p> <p>Results</p> <p>A total of 286 RNA-dependent-RNA polymerase (RdRp) and 284 heat shock protein 70 homolog (HSP70h) gene fragments were determined for CTV variants infecting the three trees. It was discovered that, despite differences in symptomatology, the trees were all apparently coinfected with similar populations of divergent CTV variants. While mixed CTV infections are common, the genetic distance between the most divergent population members observed (24.1% for RdRp and 11.0% for HSP70h) was far greater than that in previously described mixed infections. Recombinants of five distinct RdRp lineages and three distinct HSP70h lineages were easily detectable but respectively accounted for only 5.9 and 11.9% of the RdRp and HSP70h gene fragments analysed and there was no evidence of an association between particular recombinant mosaics and CSD. Also, comparisons of CTV population structures indicated that the two most similar CTV populations were those of one of the trees with CSD and the tree without CSD.</p> <p>Conclusion</p> <p>We suggest that if CTV is the causal agent of CSD, it is most likely a subtle feature of population structures within mixed infections and not merely the presence (or absence) of a single CTV variant within these populations that triggers the disease.</p