Utility of the pooling approach as applied to whole genome association scans with high-density Affymetrix microarrays

Background: We report an attempt to extend the previously successful approach of combining SNP (single nucleotide polymorphism) microarrays and DNA pooling (SNP-MaP) employing high-density microarrays. Whereas earlier studies employed a range of Affymetrix SNP microarrays comprising from 10 K to 500 K SNPs, this most recent investigation used the 6.0 chip which displays 906,600 SNP probes and 946,000 probes for the interrogation of CNVs (copy number variations). The genotyping assay using the Affymetrix SNP 6.0 array is highly demanding on sample quality due to the small feature size, low redundancy, and lack of mismatch probes. Findings: In the first study published so far using this microarray on pooled DNA, we found that pooled cheek swab DNA could not accurately predict real allele frequencies of the samples that comprised the pools. In contrast, the allele frequency estimates using blood DNA pools were reasonable, although inferior compared to those obtained with previously employed Affymetrix microarrays. However, it might be possible to improve performance by developing improved analysis methods. Conclusions: Despite the decreasing costs of genome-wide individual genotyping, the pooling approach may have applications in very large-scale case-control association studies. In such cases, our study suggests that high-quality DNA preparations and lower density platforms should be preferred

A targeted decision aid for the elderly to decide whether to undergo colorectal cancer screening: development and results of an uncontrolled trial

Abstract: Background: Competing causes of mortality in the elderly decrease the potential net benefit from colorectal cancer screening and increase the likelihood of potential harms. Individualized decision making has been recommended, so that the elderly can decide whether or not to undergo colorectal cancer (CRC) screening. The objective is to develop and test a decision aid designed to promote individualized colorectal cancer screening decision making for adults age 75 and over. Methods: We used formative research and cognitive testing to develop and refine the decision aid. We then tested the decision aid in an uncontrolled trial. The primary outcome was the proportion of patients who were prepared to make an individualized decision, defined a priori as having adequate knowledge (10/15 questions correct) and clear values (25 or less on values clarity subscale of decisional conflict scale). Secondary outcomes included overall score on the decisional conflict scale, and preferences for undergoing screening. Results: We enrolled 46 adults in the trial. The decision aid increased the proportion of participants with adequate knowledge from 4% to 52% (p < 0.01) and the proportion prepared to make an individualized decision from 4% to 41% (p < 0.01). The proportion that preferred to undergo CRC screening decreased from 67% to 61% (p = 0. 76); 7 participants (15%) changed screening preference (5 against screening, 2 in favor of screening) Conclusion: In an uncontrolled trial, the elderly participants appeared better prepared to make an individualized decision about whether or not to undergo CRC screening after using the decision aid

Childhood bullying, paranoid thinking, and the misappraisal of social threat: trouble at school

Background:Experiences of bullying predict the development of paranoia in school-age adolescents. While many instances of psychotic phenomena are transitory, maintained victimization can lead to increasingly distressing paranoid thinking. Furthermore, paranoid thinkers perceive threat in neutral social stimuli and are vigilant for environmental risk. Aims:The present paper investigated the association between different forms of bullying and paranoid thinking, and the extent to which school-age paranoid thinkers overestimate threat in interpersonal situations. Methods: Two hundred and thirty participants, aged between eleven and fourteen, were recruited from one secondary school in the UK. Participants completed a series of questionnaires hosted on the Bristol Online Survey tool. All data were collected in a classroom setting in quiet and standardized conditions. Results: A significant and positive relationship was found between experiences of bullying and paranoid thinking: greater severity of bullying predicted more distressing paranoid thinking. Further, paranoid thinking mediated the relationship between bullying and overestimation of threat in neutral social stimuli. Conclusion: Exposure to bullying is associated with distressing paranoid thinking and subsequent misappraisal of threat. As paranoid thinkers experience real and overestimated threat, the phenomena may persist

Noninvasive positive pressure ventilation for acute respiratory failure in children: a concise review

Noninvasive positive pressure ventilation (NPPV) refers to the delivery of mechanical respiratory support without the use of endotracheal intubation (ETI). The present review focused on the effectiveness of NPPV in children > 1 month of age with acute respiratory failure (ARF) due to different conditions. ARF is the most common cause of cardiac arrest in children. Therefore, prompt recognition and treatment of pediatric patients with pending respiratory failure can be lifesaving. Mechanical respiratory support is a critical intervention in many cases of ARF. In recent years, NPPV has been proposed as a valuable alternative to invasive mechanical ventilation (IMV) in this acute setting. Recent physiological studies have demonstrated beneficial effects of NPPV in children with ARF. Several pediatric clinical studies, the majority of which were noncontrolled or case series and of small size, have suggested the effectiveness of NPPV in the treatment of ARF due to acute airway (upper or lower) obstruction or certain primary parenchymal lung disease, and in specific circumstances, such as postoperative or postextubation ARF, immunocompromised patients with ARF, or as a means to facilitate extubation. NPPV was well tolerated with rare major complications and was associated with improved gas exchange, decreased work of breathing, and ETI avoidance in 22-100% of patients. High FiO2 needs or high PaCO2 level on admission or within the first hours after starting NPPV appeared to be the best independent predictive factors for the NPPV failure in children with ARF. However, many important issues, such as the identification of the patient, the right time for NPPV application, and the appropriate setting, are still lacking. Further randomized, controlled trials that address these issues in children with ARF are recommended

Evaluating Gene Drive Approaches for Public Benefit

Gene drive approaches—those which bias inheritance of a genetic element in a population of sexually reproducing organisms—have the potential to provide important public benefits. The spread of selected genetic elements in wild populations of organisms may help address certain challenges, such as transmission of vector-borne human and animal diseases and biodiversity loss due to invasive animals. Adapting various naturally occurring gene drive mechanisms to these aims is a long-standing research area, and recent advances in genetics have made engineering gene drive systems significantly more technically feasible. Gene drive approaches would act through changes in natural environments, thus robust methods to evaluate potential research and use are important. Despite the fact that gene drive approaches build on existing paradigms, such as genetic modification of organisms and conventional biological control, there are material challenges to their evaluation. One challenge is the inherent complexity of ecosystems, which makes precise prediction of changes to the environment difficult. For gene drive approaches that are expected to spread spatially and/or persist temporally, responding to this difficulty with the typical stepwise increases in the scale of studies may not be straightforward after studies begin in the natural environment. A related challenge is that study or use of a gene drive approach may have implications for communities beyond the location of introduction, depending on the spatial spread and persistence of the approach and the population biology of the target organism. This poses a particular governance challenge when spread across national borders is plausible. Finally, community engagement is an important element of responsible research and governance, but effective community engagement for gene drive approaches requires addressing complexity and uncertainty and supporting representative participation in decision making. These challenges are not confronted in a void. Existing frameworks, processes, and institutions provide a basis for effective evaluation of gene drive approaches for public benefit. Although engineered gene drive approaches are relatively new, the necessities of making decisions despite uncertainty and governing actions with potential implications for shared environments are well established. There are methodologies to identify potential harms and assess risks when there is limited experience to draw upon, and these methodologies have been applied in similar contexts. There are also laws, policies, treaties, agreements, and institutions in place across many jurisdictions that support national and international decision making regarding genetically modified organisms and the potential applications of gene drive approaches, such as public health and biodiversity conservation. Community engagement is an established component of many decision-making processes, and related experience and conceptual frameworks can inform engagement by researchers. The existence of frameworks, processes, and institutions provides an important foundation for evaluating gene drive approaches, but it is not sufficient by itself. They must be rigorously applied, which requires resources for risk assessment, research, and community engagement and diligent implementation by governance institutions. The continued evolution of the frameworks, processes, and institutions is important to adapt to the growing understanding of gene drive approaches. With appropriate resources and diligence, it will be possible to responsibly evaluate and make decisions on gene drive approaches for public benefit

The effect of birth-weight with genetic susceptibility on depressive symptoms in childhood and adolescence

Low birth-weight has been associated with depression and related outcomes in adults, and with problem behaviours in children. This study aimed to examine the association between low birth-weight for gestation and depressive symptoms in children and adolescents and to examine whether the relationship is moderated by genetic risk for depression. An epidemiological, genetically sensitive design was used including 2,046 twins aged 8–17 years (1,023 families). Data were obtained by parental report and analysed using regression analysis. A small but significant association between birth-weight for gestation and early depressive symptoms was observed. The unit increase in depressive symptoms per unit decrease in birth-weight for gestation was greater for individuals at genetic or familial risk for depression. For low birth-weight children, genetic risk for depression moderated the influence of birth-weight for gestation in predicting early depressive symptoms. Birth-weight for gestation is moderated by genetic and familial risk for depression in influencing early depression symptoms. These observations have clinical implications in that the impact of being small for gestational age on depressive symptoms is greater in children at familial/genetic risk although the association between birth weight and depression does not imply causality

Ecological Thresholds in the Savanna Landscape: Developing a Protocol for Monitoring the Change in Composition and Utilisation of Large Trees

BACKGROUND: Acquiring greater understanding of the factors causing changes in vegetation structure -- particularly with the potential to cause regime shifts -- is important in adaptively managed conservation areas. Large trees (> or =5 m in height) play an important ecosystem function, and are associated with a stable ecological state in the African savanna. There is concern that large tree densities are declining in a number of protected areas, including the Kruger National Park, South Africa. In this paper the results of a field study designed to monitor change in a savanna system are presented and discussed. METHODOLOGY/PRINCIPAL FINDINGS: Developing the first phase of a monitoring protocol to measure the change in tree species composition, density and size distribution, whilst also identifying factors driving change. A central issue is the discrete spatial distribution of large trees in the landscape, making point sampling approaches relatively ineffective. Accordingly, fourteen 10 m wide transects were aligned perpendicular to large rivers (3.0-6.6 km in length) and eight transects were located at fixed-point photographic locations (1.0-1.6 km in length). Using accumulation curves, we established that the majority of tree species were sampled within 3 km. Furthermore, the key ecological drivers (e.g. fire, herbivory, drought and disease) which influence large tree use and impact were also recorded within 3 km. CONCLUSIONS/SIGNIFICANCE: The technique presented provides an effective method for monitoring changes in large tree abundance, size distribution and use by the main ecological drivers across the savanna landscape. However, the monitoring of rare tree species would require individual marking approaches due to their low densities and specific habitat requirements. Repeat sampling intervals would vary depending on the factor of concern and proposed management mitigation. Once a monitoring protocol has been identified and evaluated, the next stage is to integrate that protocol into a decision-making system, which highlights potential leading indicators of change. Frequent monitoring would be required to establish the rate and direction of change. This approach may be useful in generating monitoring protocols for other dynamic systems

Neuroregeneration in neurodegenerative disorders

<p>Abstract</p> <p>Background</p> <p>Neuroregeneration is a relatively recent concept that includes neurogenesis, neuroplasticity, and neurorestoration - implantation of viable cells as a therapeutical approach.</p> <p>Discussion</p> <p>Neurogenesis and neuroplasticity are impaired in brains of patients suffering from Alzheimer's Disease or Parkinson's Disease and correlate with low endogenous protection, as a result of a diminished growth factors expression. However, we hypothesize that the brain possesses, at least in early and medium stages of disease, a "neuroregenerative reserve", that could be exploited by growth factors or stem cells-neurorestoration therapies.</p> <p>Summary</p> <p>In this paper we review the current data regarding all three aspects of neuroregeneration in Alzheimer's Disease and Parkinson's Disease.</p