Deletion of the GABAA α2-subunit does not alter self dministration of cocaine or reinstatement of cocaine seeking

Rationale GABAA receptors containing α2-subunits are highly represented in brain areas that are involved in motivation and reward, and have been associated with addiction to several drugs, including cocaine. We have shown previously that a deletion of the α2-subunit results in an absence of sensitisation to cocaine. Objective We investigated the reinforcing properties of cocaine in GABAA α2-subunit knockout (KO) mice using an intravenous self-administration procedure. Methods α2-subunit wildtype (WT), heterozygous (HT) and KO mice were trained to lever press for a 30 % condensed milk solution. After implantation with a jugular catheter, mice were trained to lever press for cocaine (0.5 mg/kg/infusion) during ten daily sessions. Responding was extinguished and the mice tested for cue- and cocaine-primed reinstatement. Separate groups of mice were trained to respond for decreasing doses of cocaine (0.25, 0.125, 0.06 and 0.03 mg/kg). Results No differences were found in acquisition of lever pressing for milk. All genotypes acquired self-administration of cocaine and did not differ in rates of self-administration, dose dependency or reinstatement. However, whilst WT and HT mice showed a dose-dependent increase in lever pressing during the cue presentation, KO mice did not. Conclusions Despite a reported absence of sensitisation, motivation to obtain cocaine remains unchanged in KO and HT mice. Reinstatement of cocaine seeking by cocaine and cocaine-paired cues is also unaffected. We postulate that whilst not directly involved in reward perception, the α2-subunit may be involved in modulating the “energising” aspect of cocaine’s effects on reward-seeking

Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes.

A considerable body of research indicates that mammary gland branching morphogenesis is dependent, in part, on the extracellular matrix (ECM), ECM-receptors, such as integrins and other ECM receptors, and ECM-degrading enzymes, including matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs). There is some evidence that these ECM cues affect one or more of the following processes: cell survival, polarity, proliferation, differentiation, adhesion, and migration. Both three-dimensional culture models and genetic manipulations of the mouse mammary gland have been used to study the signaling pathways that affect these processes. However, the precise mechanisms of ECM-directed mammary morphogenesis are not well understood. Mammary morphogenesis involves epithelial 'invasion' of adipose tissue, a process akin to invasion by breast cancer cells, although the former is a highly regulated developmental process. How these morphogenic pathways are integrated in the normal gland and how they become dysregulated and subverted in the progression of breast cancer also remain largely unanswered questions

Improving the use of research evidence in guideline development: 10. Integrating values and consumer involvement

BACKGROUND: The World Health Organization (WHO), like many other organisations around the world, has recognised the need to use more rigorous processes to ensure that health care recommendations are informed by the best available research evidence. This is the 10(th )of a series of 16 reviews that have been prepared as background for advice from the WHO Advisory Committee on Health Research to WHO on how to achieve this. OBJECTIVES: We reviewed the literature on integrating values and consumers in guideline development. METHODS: We searched PubMed and three databases of methodological studies for existing systematic reviews and relevant methodological research. We reviewed the titles of all citations and retrieved abstracts and full text articles if the citations appeared relevant to the topic. We checked the reference lists of articles relevant to the questions and used snowballing as a technique to obtain additional information. We did not conduct a full systematic review ourselves. Our conclusions based on the available evidence, consideration of what WHO and other organisations are doing and logical arguments. KEY QUESTIONS AND ANSWERS: We did not find a systematic review of methods for integrating values in guidelines, but we found several systematic reviews that dealt with related topics. Whose values should WHO use when making recommendations? • Values, the relative importance or worth of a state or consequences of a decision (outcomes relating to benefits, harms, burden and costs), play a role in every recommendation. Ethical considerations, concepts that determine what is right, also play a role. • The values used in making recommendations should reflect those of the people affected. Judgements should be explicit and should be informed by input from those affected (including citizens, patients, clinicians and policy makers). • When differences in values may lead to different decisions or there is uncertainty about values, this should also be explicit. If differences in values are likely to affect a decision, such that people in different setting would likely make different choices about interventions or actions based on differences in their values, global recommendations should be explicit in terms of which values were applied and allow for adaptation after incorporating local values. How should WHO ensure that appropriate values are integrated in recommendations? • All WHO guideline groups should uniformly apply explicit, transparent and clearly described methods for integrating values. • WHO should consider involving relevant stakeholders if this is feasible and efficient. • WHO should develop a checklist for guidelines panels to help them to ensure that ethical considerations relevant to recommendations are addressed explicitly and transparently. How should users and consumers be involved in generating recommendations? • Including consumers in groups that are making global recommendations presents major challenges with respect to the impossibility of including a representative spectrum of consumers from a variety of cultures and settings. Nonetheless, consideration should be given to including consumers in groups who are able to challenge assumptions that are made about the values used for making recommendations, rather than represent the values of consumers around the world. • WHO should establish a network to facilitate involvement of users. • Draft recommendations should be reviewed by consumers, who should be asked explicitly to consider the values that were used. How should values be presented in recommendations? • Recommendations should include a description of how decisions were made about the relative importance of the consequences (benefits, harms and costs) of a decision. • Values that influence recommendations should be reported along with the research evidence underlying recommendations. • When differences in values would lead to different decisions or there is important uncertainty about values that are critical to a decision, this should be flagged and reflected in the strength of the recommendation. • Adaptable guideline templates that allow for integration of different values should be developed and used when differences in values are likely to be critical to a decision

Uncoupling human and climate drivers of late Holocene vegetation change in southern Brazil

In the highlands of southern Brazil an anthropogenitcally driven expansion of forest occurred at the expense of grasslands between 1410 and 900cal BP, coincident with a period of demographic and cultural change in the region. Previous studies have debated the relative contributions of increasing wetter and warmer climate conditions and human landscape modifcations to forest expansion, but generally lacked high resoltiuon proxies to measure these efects, or have relied on single proxies to reconstruct both climate and vegetation. Here, we develop and test a model of natural ecosystem distribution against vegetation histories, paleoclimate proxies, and the archaeological record to distinguish human from temperature and precipitation impacts on the distribution and expansion of Araucaria forests during the late Holocene. Carbon isotopes from soil profles confrm that in spite of climatic fuctuations, vegetation was stable and forests were spatially limited to south-facing slopes in the absence of human inputs. In contrast, forest management strategies for the past 1400 years expanded this economically important forest beyond its natural geographic boundaries in areas of dense pre-Columbian occupation, suggesting that landscape modifcations were linked to demographic changes, the efects of which are still visible today

Analytic philosophy for biomedical research: the imperative of applying yesterday's timeless messages to today's impasses

The mantra that "the best way to predict the future is to invent it" (attributed to the computer scientist Alan Kay) exemplifies some of the expectations from the technical and innovative sides of biomedical research at present. However, for technical advancements to make real impacts both on patient health and genuine scientific understanding, quite a number of lingering challenges facing the entire spectrum from protein biology all the way to randomized controlled trials should start to be overcome. The proposal in this chapter is that philosophy is essential in this process. By reviewing select examples from the history of science and philosophy, disciplines which were indistinguishable until the mid-nineteenth century, I argue that progress toward the many impasses in biomedicine can be achieved by emphasizing theoretical work (in the true sense of the word 'theory') as a vital foundation for experimental biology. Furthermore, a philosophical biology program that could provide a framework for theoretical investigations is outlined

Discomfort in children undergoing unsedated MRI

Magnetic resonance imaging (MRI) scans for research purposes usually do not directly benefit the children scanned, so that review boards need to assess whether the risk of harm or discomfort is minimal. This study aimed at providing empirical data on discomfort related to unsedated MRI in children aged 5–12 years. Secondary objectives were to determine whether lower age is associated with higher levels of discomfort and to investigate which other characteristics of subjects and/or procedures may be associated with higher levels of discomfort. Self-report scores, observation scores, heart rate standard deviation scores, and incremental salivary cortisol levels were obtained from 54 children aged 5–12 years with non-acute conditions undergoing diagnostic MRI. Of the 54 children, 10 scored relatively high values on the self-report score and on one or two of the other measures, and another 15 scored relatively high on the self-report score alone. Rather than an age effect, associations were found between parents’ trait anxiety and observation score values and between use of contrast fluid (requiring the insertion of a venous cannula) and high incremental salivary cortisol levels. In conclusion, MRI-related discomfort may be regarded as minimal for more than half of children aged 5–12

Interaction Between Convection and Pulsation

This article reviews our current understanding of modelling convection dynamics in stars. Several semi-analytical time-dependent convection models have been proposed for pulsating one-dimensional stellar structures with different formulations for how the convective turbulent velocity field couples with the global stellar oscillations. In this review we put emphasis on two, widely used, time-dependent convection formulations for estimating pulsation properties in one-dimensional stellar models. Applications to pulsating stars are presented with results for oscillation properties, such as the effects of convection dynamics on the oscillation frequencies, or the stability of pulsation modes, in classical pulsators and in stars supporting solar-type oscillations.Comment: Invited review article for Living Reviews in Solar Physics. 88 pages, 14 figure

Association between neighborhood socioeconomic status and screen time among pre-school children: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Sedentary behavior is considered a separate construct from physical activity and engaging in sedentary behaviors results in health effects independent of physical activity levels. A major source of sedentary behavior in children is time spent viewing TV or movies, playing video games, and using computers. To date no study has examined the impact of neighborhood socioeconomic status (SES) on pre-school children's screen time behavior.</p> <p>Methods</p> <p>Proxy reports of weekday and weekend screen time (TV/movies, video games, and computer use) were completed by 1633 parents on their 4-5 year-old children in Edmonton, Alberta between November, 2005 and August, 2007. Postal codes were used to classified neighborhoods into low, medium or high SES. Multiple linear and logistic regression models were conducted to examine relationships between screen time and neighborhood SES.</p> <p>Results</p> <p>Girls living in low SES neighborhoods engaged in significantly more weekly overall screen time and TV/movie minutes compared to girls living in high SES neighborhoods. The same relationship was not observed in boys. Children living in low SES neighborhoods were significantly more likely to be video game users and less likely to be computer users compared to children living in high SES neighborhoods. Also, children living in medium SES neighborhoods were significantly less likely to be computer users compared to children living in high SES neighborhoods.</p> <p>Conclusions</p> <p>Some consideration should be given to providing alternative activity opportunities for children, especially girls who live in lower SES neighborhoods. Also, future research should continue to investigate the independent effects of neighborhood SES on screen time as well as the potential mediating variables for this relationship.</p