Genetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study.

Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist

Opportunities for primary and secondary prevention of excess gestational weight gain: General Practitioners' perspectives

BackgroundThe impact of excess gestational weight gain (GWG) on maternal and child health outcomes is well documented. Understanding how health care providers view and manage GWG may assist with influencing healthy gestational weight outcomes. This study aimed to assess General Practitioner\u27s (GPs) perspectives regarding the management and assessment of GWG and to understand how GPs can be best supported to provide healthy GWG advice to pregnant women.MethodsDescriptive qualitative research methods utilising semi - structured interview questions to assess GPs perspectives and management of GWG. GPs participating in shared antenatal care in Geelong, Victoria and Sydney, New South Wales were invited to participate in semi - structured, individual interviews via telephone or in person. Interviews were digitally recorded and transcribed verbatim. Data was analysed utilising thematic analysis for common emerging themes.ResultsTwenty eight GPs participated, 14 from each state. Common themes emerged relating to awareness of the implications of excess GWG, advice regarding weight gain, regularity of gestational weighing by GPs, options for GPs to seek support to provide healthy lifestyle behaviour advice and barriers to engaging pregnant women about their weight. GPs perspectives concerning excess GWG were varied. They frequently acknowledged maternal and child health complications resulting from excess GWG yet weighing practices and GWG advice appeared to be inconsistent. The preferred support option to promote healthy weight was referral to allied health practitioners yet GPs noted that cost and limited access were barriers to achieving this.ConclusionsGPs were aware of the importance of healthy GWG yet routine weighing was not standard practice for diverse reasons. Management of GWG and perspectives of the issue varied widely. Time efficient and cost effective interventions may assist GPs in ensuring women are supported in achieving healthy GWG to provide optimal maternal and infant health outcomes.<br /

A double-blind placebo-controlled cross-over clinical trial of DONepezil In Posterior cortical atrophy due to underlying Alzheimer's Disease: DONIPAD study.

BACKGROUND: The study investigated whether donepezil exerts symptomatic benefit in patients with posterior cortical atrophy (PCA), an atypical variant of Alzheimer's disease. METHODS: A single-centre, double-blind, placebo-controlled, cross-over clinical trial was performed to assess the efficacy of donepezil in patients with PCA. Each patient received either donepezil (5 mg once daily in the first 6 weeks and 10 mg once daily in the second 6 weeks) or placebo for 12 weeks. After a 2-week washout period, each patient received the other treatment arm during the following 12 weeks followed by another 2-week washout period. The primary outcome was the Mini-Mental State Examination (MMSE) at 12 weeks. Secondary outcome measures were five neuropsychological tests reflecting parieto-occipital function. Intention-to-treat analysis was used. For each outcome measure, carry-over effects were first assessed. If present, then analysis was restricted to the first 12-week period. Otherwise, the standard approach to the analysis of a 2 × 2 cross-over trial was used. RESULTS: Eighteen patients (13 females) were recruited (mean age 61.6 years). There was a protocol violation in one patient, who subsequently withdrew from the study due to gastrointestinal side effects. There was statistically significant (p 0.05). There were no statistically significant treatment effects on any of the five neuropsychological tests, except for digit span at 12 weeks (higher by 0.5 digits in favour of placebo, 95% CI 0.1 to 0.9). Gastrointestinal side effects occurred most frequently, affecting 13/18 subjects (72%), and were the cause of study discontinuation in one subject. Nightmares and vivid dreams occurred in 8/18 subjects (44%), and were statistically more frequent during treatment with donepezil. CONCLUSIONS: In this small study, there was no statistically significant treatment effect of donepezil on the primary outcome measure (MMSE score at 12 weeks) in PCA patients, who appear to be particularly susceptible to the development of nightmares and vivid dreams when treated. TRIAL REGISTRATION: Trial registration: Current Controlled Trials ISRCTN22636071 . Retrospectively registered 19 May 2010

Analysis of the effects of exposure to acute hypoxia on oxidative lesions and tumour progression in a transgenic mouse breast cancer model

<p>Abstract</p> <p>Background</p> <p>Tumour hypoxia is known to be a poor prognostic indicator, predictive of increased risk of metastatic disease and reduced survival. Genomic instability has been proposed as one of the potential mechanisms for hypoxic tumour progression. Both of these features are commonly found in many cancer types, but their relationship and association with tumour progression has not been examined in the same model.</p> <p>Methods</p> <p>To address this issue, we determined the effects of 6 week <it>in vivo </it>acute hypoxic exposure on the levels of mutagenic lipid peroxidation product, malondialdehyde, and 8-oxo-7,8-dihydro-2'-deoxyguanosine DNA (8-oxo-dG) lesions in the transgenic polyomavirus middle T (PyMT) breast cancer mouse model.</p> <p>Results</p> <p>We observed significantly increased plasma lipid peroxidation and 8-oxo-dG lesion levels in the hypoxia-exposed mice. Consumption of malondialdehyde also induced a significant increase in the PyMT tumour DNA lesion levels, however, these increases did not translate into enhanced tumour progression. We further showed that the <it>in vivo </it>exposure to acute hypoxia induced accumulation of F4/80 positive tumour-associated macrophages (TAMs), demonstrating a relationship between hypoxia and macrophages in an experimental model.</p> <p>Conclusion</p> <p>These data suggest that although exposure to acute hypoxia causes an increase in 8-oxo-dG lesions and TAMs in the PyMT tumours, these increases do not translate into significant changes in tumour progression at the primary or metastatic levels in this strong viral oncogene-driven breast cancer model.</p

Development and validation of the Self-Regulation of Eating Behaviour Questionnaire for adults

Background Eating self-regulatory capacity can help individuals to cope with the obesogenic environment and achieve, as well as maintain, a healthy weight and diet. At present, there is no comprehensive, reliable and valid questionnaire for assessing this capacity and measuring change in response to self-regulation interventions in adults. This paper reports the development of the Self-regulation of Eating Behaviour Questionnaire (SREBQ) for use in UK adults, and presents evidence for its reliability and construct validity. The development of the SREBQ involved generation of an item pool, followed by two pilot studies (Samples 1 and 2) and a test of the questionnaire’s underlying factor structure (Sample 3). The final version of the SREBQ was then assessed for reliability and construct validity (Sample 4). Results Development of the SREBQ resulted in a 5-item questionnaire. The face validity was satisfactory, as assessed by the pilot studies. The factor structure analysis (Sample 3) suggested that it has a single underlying factor, which was confirmed in a second sample (Sample 4). The SREBQ had strong construct validity, showing a positive correlation with general measures of self-regulation. It was also positively correlated with motivation and behavioural automaticity, and negatively correlated with food responsiveness and emotional over-eating (p < 0.001). It showed good discriminant validity, as it was only weakly associated with satiety responsiveness, food fussiness and slowness in eating. Conclusions The SREBQ is a reliable and valid measure for assessment of eating self-regulatory capacity in the general UK adult population

Depicting the tree of life in museums: guiding principles from psychological research

The Tree of Life is revolutionizing our understanding of life on Earth, and, accordingly, evolutionary trees are increasingly important parts of exhibits on biodiversity and evolution. The authors argue that in using these trees to effectively communicate evolutionary principles, museums need to take into account research results from cognitive, developmental, and educational psychology while maintaining a focus on visitor engagement and enjoyment. Six guiding principles for depicting evolutionary trees in museum exhibits distilled from this research literature were used to evaluate five current or recent museum trees. One of the trees was then redesigned in light of the research while preserving the exhibit’s original learning goals. By attending both to traditional factors that influence museum exhibit design and to psychological research on how people understand diagrams in general and Tree of Life graphics in particular, museums can play a key role in fostering 21st century scientific literacy

Use of RDTs to improve malaria diagnosis and fever case management at primary health care facilities in Uganda

<p>Abstract</p> <p>Background</p> <p>Early and accurate diagnosis of malaria followed by prompt treatment reduces the risk of severe disease in malaria endemic regions. Presumptive treatment of malaria is widely practised where microscopy or rapid diagnostic tests (RDTs) are not readily available. With the introduction of artemisinin-based combination therapy (ACT) for treatment of malaria in many low-resource settings, there is need to target treatment to patients with parasitologically confirmed malaria in order to improve quality of care, reduce over consumption of anti-malarials, reduce drug pressure and in turn delay development and spread of drug resistance. This study evaluated the effect of malaria RDTs on health workers' anti-malarial drug (AMD) prescriptions among outpatients at low level health care facilities (LLHCF) within different malaria epidemiological settings in Uganda.</p> <p>Methods</p> <p>All health workers (HWs) in 21 selected intervention (where RDTs were deployed) LLHF were invited for training on the use RDTs. All HWs were trained to use RDTs for parasitological diagnosis of all suspected malaria cases irrespective of age. Five LLHCFs with clinical diagnosis (CD only) were included for comparison. Subsequently AMD prescriptions were compared using both a 'pre - post' and 'intervention - control' analysis designs. In-depth interviews of the HWs were conducted to explore any factors that influence AMD prescription practices.</p> <p>Results</p> <p>A total of 166,131 out-patient attendances (OPD) were evaluated at 21 intervention LLHCFs. Overall use of RDTs resulted in a 38% point reduction in AMD prescriptions. There was a two-fold reduction (RR 0.62, 95% CI 0.55-0.70) in AMD prescription with the greatest reduction in the hypo-endemic setting (RR 0.46 95% CI 0.51-0.53) but no significant change in the urban setting (RR1.01, p-value = 0.820). Over 90% of all eligible OPD patients were offered a test. An average of 30% (range 25%-35%) of the RDT-negative fever patients received AMD prescriptions. When the test result was negative, children under five years of age were two to three times more likely (OR 2.6 p-value <0.001) to receive anti-malarial prescriptions relative to older age group. Of the 63 HWs interviewed 92% believed that a positive RDT result confirmed malaria, while only 49% believed that a negative RDT result excluded malaria infection.</p> <p>Conclusion</p> <p>Use of RDTs resulted in a 2-fold reduction in anti-malarial drug prescription at LLHCFs. The study demonstrated that RDT use is feasible at LLHCFs, and can lead to better targetting of malaria treatment. Nationwide deployment of RDTs in a systematic manner should be prioritised in order to improve fever case management. The process should include plans to educate HWs about the utility of RDTs in order to maximize acceptance and uptake of the diagnostic tools and thereby leading to the benefits of parasitological diagnosis of malaria.</p

Effective Long-Distance Pollen Dispersal in Centaurea jacea

BACKGROUND: Agri-environment schemes play an increasingly important role for the conservation of rare plants in intensively managed agricultural landscapes. However, little is known about their effects on gene flow via pollen dispersal between populations of these species. METHODOLOGY/PRINCIPAL FINDINGS: In a 2-year experiment, we observed effective pollen dispersal from source populations of Centaurea jacea in restored meadows, the most widespread Swiss agri-environment scheme, to potted plants in adjacent intensively managed meadows without other individuals of this species. Potted plants were put in replicated source populations at 25, 50, 100 m and where possible 200 m distance from these source populations. Pollen transfer among isolated plants was prevented by temporary bagging, such that only one isolated plant was accessible for flower visitors at any one time. Because C. jacea is self-incompatible, seed set in single-plant isolates indicated insect mediated effective pollen dispersal from the source population. Seed set was higher in source populations (35.7+/-4.4) than in isolates (4.8+/-1.0). Seed set declined from 18.9% of that in source populations at a distance of 25 m to 7.4% at 200 m. At a distance of 200 m seed set was still significantly higher in selfed plants, indicating long-distance effective pollen dispersal up to 200 m. Analyses of covariance suggested that bees contributed more than flies to this long-distance pollen dispersal. We found evidence that pollen dispersal to single-plant isolates was positively affected by the diversity and flower abundance of neighboring plant species in the intensively managed meadow. Furthermore, the decline of the dispersal was less steep when the source population of C. jacea was large. CONCLUSIONS: We conclude that insect pollinators can effectively transfer pollen from source populations of C. jacea over at least 200 m, even when "recipient populations" consisted of single-plant isolates, suggesting that gene flow by pollen over this distance is very likely. Source population size and flowering environment surrounding recipient plants appear to be important factors affecting pollen dispersal in C. jacea. It is conceivable that most insect-pollinated plants in a network of restored sites within intensively managed grassland can form metapopulations, if distances between sites are of similar magnitude as tested here

Tumor-specific expression of αvβ3 integrin promotes spontaneous metastasis of breast cancer to bone

INTRODUCTION: Studies in xenograft models and experimental models of metastasis have implicated several β3 integrin-expressing cell populations, including endothelium, platelets and osteoclasts, in breast tumor progression. Since orthotopic human xenograft models of breast cancer are poorly metastatic to bone and experimental models bypass the formation of a primary tumor, however, the precise contribution of tumor-specific αvβ3 to the spontaneous metastasis of breast tumors from the mammary gland to bone remains unclear. METHODS: We used a syngeneic orthotopic model of spontaneous breast cancer metastasis to test whether exogenous expression of αvβ3 in a mammary carcinoma line (66cl4) that metastasizes to the lung, but not to bone, was sufficient to promote its spontaneous metastasis to bone from the mammary gland. The tumor burden in the spine and the lung following inoculation of αvβ3-expressing 66cl4 (66cl4beta3) tumor cells or control 66cl4pBabe into the mammary gland was analyzed by real-time quantitative PCR. The ability of these cells to grow and form osteolytic lesions in bone was determined by histology and tartrate-resistant acid phosphatase staining of bone sections following intratibial injection of tumor cells. The adhesive, migratory and invasive properties of 66cl4pBabe and 66cl4beta3 cells were evaluated in standard in vitro assays. RESULTS: The 66cl4beta3 tumors showed a 20-fold increase in metastatic burden in the spine compared with 66cl4pBabe. A similar trend in lung metastasis was observed. αvβ3 did not increase the proliferation of 66cl4 cells in vitro or in the mammary gland in vivo. Similarly, αvβ3 is not required for the proliferation of 66cl4 cells in bone as both 66cl4pBabe and 66cl4beta3 proliferated to the same extent when injected directly into the tibia. 66cl4beta3 tumor growth in the tibia, however, increased osteoclast recruitment and bone resorption compared with 66cl4 tumors. Moreover, αvβ3 increased 66cl4 tumor cell adhesion and αvβ3-dependent haptotactic migration towards bone matrix proteins, as well as their chemotactic response to bone-derived soluble factors in vitro. CONCLUSION: These results demonstrate for the first time that tumor-specific αvβ3 contributes to spontaneous metastasis of breast tumors to bone and suggest a critical role for this receptor in mediating chemotactic and haptotactic migration towards bone factors

Genetic loci for retinal arteriolar microcirculation.

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10(-8). This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10(-12) in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined