Aims/hypothesis
The 5′-AMP-activated protein kinase (AMPK) pathway is intact in type 2 diabetic patients and is seen as a target for diabetes treatment. In this study, we aimed to assess the impact ...of the AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR) on both glucose and fatty acid metabolism in vivo in type 2 diabetic patients.
Methods
Stable isotope methodology and blood and muscle biopsy sampling were applied to assess blood glucose and fatty acid kinetics following continuous i.v. infusion of AICAR (0.75 mg kg
−1
min
−1
) and/or NaCl (0.9%) in ten male type 2 diabetic patients (age 64 ± 2 years; BMI 28 ± 1 kg/m
2
).
Results
Plasma glucose rate of appearance (
R
a
) was reduced following AICAR administration, while plasma glucose rate of disappearance (
R
d
) was similar in the AICAR and control test. Consequently, blood glucose disposal (
R
d
expressed as a percentage of
R
a
) was increased following AICAR infusion (
p
< 0.001). Accordingly, a greater decline in plasma glucose concentration was observed following AICAR infusion (
p
< 0.001). Plasma NEFA
R
a
and
R
d
were both significantly reduced in response to AICAR infusion, and were accompanied by a significant decline in plasma NEFA concentration. Although AMPK phosphorylation in skeletal muscle was not increased, we observed a significant increase in acetyl-CoA carboxylase phosphorylation (
p
< 0.001).
Conclusions/interpretation
The i.v. administration of AICAR reduces hepatic glucose output, thereby lowering blood glucose concentrations in vivo in type 2 diabetic patients. Furthermore, AICAR administration stimulates hepatic fatty acid oxidation and/or inhibits whole body lipolysis, thereby reducing plasma NEFA concentration.
Trial registration:
ISRCTN31384581
Funding:
The study was funded by the Dutch Diabetes Research Foundation. S. L. McGee is a National Health and Medical Research Council (NHMRC) Peter Doherty Fellow (400446).
Bipolar disorder (BD) is a polygenic disorder that shares substantial genetic risk factors with major depressive disorder (MDD). Genetic analyses have reported numerous BD susceptibility genes, while ...some variants, such as single-nucleotide polymorphisms (SNPs) in CACNA1C have been successfully replicated, many others have not and subsequently their effects on the intermediate phenotypes cannot be verified. Here, we studied the MDD-related gene CREB1 in a set of independent BD sample groups of European ancestry (a total of 64,888 subjects) and identified multiple SNPs significantly associated with BD (the most significant being SNP rs6785A, P=6.32 × 10(-5), odds ratio (OR)=1.090). Risk SNPs were then subjected to further analyses in healthy Europeans for intermediate phenotypes of BD, including hippocampal volume, hippocampal function and cognitive performance. Our results showed that the risk SNPs were significantly associated with hippocampal volume and hippocampal function, with the risk alleles showing a decreased hippocampal volume and diminished activation of the left hippocampus, adding further evidence for their involvement in BD susceptibility. We also found the risk SNPs were strongly associated with CREB1 expression in lymphoblastoid cells (P<0.005) and the prefrontal cortex (P<1.0 × 10(-6)). Remarkably, population genetic analysis indicated that CREB1 displayed striking differences in allele frequencies between continental populations, and the risk alleles were completely absent in East Asian populations. We demonstrated that the regional prevalence of the CREB1 risk alleles in Europeans is likely caused by genetic hitchhiking due to natural selection acting on a nearby gene. Our results suggest that differential population histories due to natural selection on regional populations may lead to genetic heterogeneity of susceptibility to complex diseases, such as BD, and explain inconsistencies in detecting the genetic markers of these diseases among different ethnic populations.
The concept of independence has been frequently mentioned in climate science research, but has rarely been defined and discussed in a theoretically robust and quantifiable manner. In this paper we ...argue that any discussion must start from a clear and unambiguous definition of what independence means and how it can be determined. We introduce an approach based on the statistical definition of independence, and illustrate with simple examples how it can be applied to practical questions. Firstly, we apply these ideas to climate models, which are frequently argued to not be independent of each other, raising questions as to the robustness of results from multi-model ensembles. We explore the dependence between models in a multi-model ensemble, and suggest a possible way forward for future weighting strategies. Secondly, we discuss the issue of independence in relation to the synthesis of multiple observationally based constraints on the climate system, using equilibrium climate sensitivity as an example. We show that the same statistical theory applies to this problem, and illustrate this with a test case, indicating how researchers may estimate dependence between multiple constraints.
ABSTRACT
We present a practical, efficient and powerful solution to the problem of parameter estimation in highly non‐linear models. The method is based on the ensemble Kalman filter, and has ...previously been successfully applied to a simple climate model with steady‐state dynamics. We demonstrate, via application to the well‐known Lorenz model, that the method can successfully perform multivariate parameter estimation even in the presence of chaotic dynamics. Traditional variational methods using an adjoint model have limited applicability to problems of this nature, and the alternative of a brute force (or randomized) search in parameter space is prohibitively expensive for high‐dimensional applications. The cost of our method is comparable to that of integrating an ensemble to statistical convergence, and therefore this technique appears to be ideally suited for probabilistic climate prediction.
Comparison of model outputs with observations of the climate system forms an essential component of model assessment and is crucial for building our confidence in model predictions. Methods for ...undertaking this comparison are not always clearly justified and understood. Here we show that the popular approach of comparing the ensemble spread to a so‐called “observationally‐constrained pdf” can be highly misleading. Such a comparison will almost certainly result in disagreement, but in reality tells us little about the performance of the ensemble. We present an alternative approach, and show how it may lead to very different, and rather more encouraging, conclusions. We additionally present some necessary conditions for an ensemble (or more generally, a probabilistic prediction) to be challenged by an observation.
Key Points
We present an alternative paradigm for ensemble evaluation
Previous assessments of CMIP3 ensemble spread may be misleadingly pessimistic
To assess effects of a combined microfinance and training intervention on HIV risk behavior among young female participants in rural South Africa.
: Secondary analysis of quantitative and qualitative ...data from a cluster randomized trial, the Intervention with Microfinance for AIDS and Gender Equity study.
Eight villages were pair-matched and randomly allocated to receive the intervention. At baseline and after 2 years, HIV risk behavior was assessed among female participants aged 14-35 years. Their responses were compared with women of the same age and poverty group from control villages. Intervention effects were calculated using adjusted risk ratios employing village level summaries. Qualitative data collected during the study explored participants' responses to the intervention including HIV risk behavior.
After 2 years of follow-up, when compared with controls, young participants had higher levels of HIV-related communication (adjusted risk ratio 1.46, 95% confidence interval 1.01-2.12), were more likely to have accessed voluntary counseling and testing (adjusted risk ratio 1.64, 95% confidence interval 1.06-2.56), and less likely to have had unprotected sex at last intercourse with a nonspousal partner (adjusted risk ratio 0.76, 95% confidence interval 0.60-0.96). Qualitative data suggest a greater acceptance of intrahousehold communication about HIV and sexuality. Although women noted challenges associated with acceptance of condoms by men, increased confidence and skills associated with participation in the intervention supported their introduction in sexual relationships.
In addition to impacts on economic well being, women's empowerment and intimate partner violence, interventions addressing the economic and social vulnerability of women may contribute to reductions in HIV risk behavior.
Efficient estimation and ensemble generation in climate modelling Annan, J.D; Hargreaves, J.C
Philosophical transactions of the Royal Society of London. Series A: Mathematical, physical, and engineering sciences,
08/2007, Letnik:
365, Številka:
1857
Journal Article
Recenzirano
In this paper, we review progress towards efficiently estimating parameters in climate models. Since the general problem is inherently intractable, a range of approximations and heuristic methods ...have been proposed. Simple Monte Carlo sampling methods, although easy to implement and very flexible, are rather inefficient, making implementation possible only in the very simplest models. More sophisticated methods based on random walks and gradient-descent methods can provide more efficient solutions, but it is often unclear how to extract probabilistic information from such methods and the computational costs are still generally too high for their application to state-of-the-art general circulation models (GCMs). The ensemble Kalman filter is an efficient Monte Carlo approximation which is optimal for linear problems, but we show here how its accuracy can degrade in nonlinear applications. Methods based on particle filtering may provide a solution to this problem but have yet to be studied in any detail in the realm of climate models. Statistical emulators show great promise for future research and their computational speed would eliminate much of the need for efficient sampling techniques. However, emulation of a full GCM has yet to be achieved and the construction of such represents a substantial computational task in itself.
While much descriptive research has documented positive associations between social capital and a range of economic, social and health outcomes, there have been few intervention studies to assess ...whether social capital can be intentionally generated. We conducted an intervention in rural South Africa that combined group-based microfinance with participatory gender and HIV training in an attempt to catalyze changes in solidarity, reciprocity and social group membership as a means to reduce women's vulnerability to intimate partner violence and HIV. A cluster randomized trial was used to assess intervention effects among eight study villages. In this paper, we examined effects on structural and cognitive social capital among 845 participants and age and wealth matched women from households in comparison villages. This was supported by a diverse portfolio of qualitative research.
After two years, adjusted effect estimates indicated higher levels of structural and cognitive social capital in the intervention group than the comparison group, although confidence intervals were wide. Qualitative research illustrated the ways in which economic and social gains enhanced participation in social groups, and the positive and negative dynamics that emerged within the program. There were numerous instances where individuals and village loan centres worked to address community concerns, both working through existing social networks, and through the establishment of new partnerships with local leadership structures, police, the health sector and NGOs. This is among the first experimental trials suggesting that social capital can be exogenously strengthened. The implications for community interventions in public health are further explored.
We present the implementation and results of a model tuning and ensemble forecasting experiment using an ensemble Kalman filter for the simultaneous estimation of 12 parameters in a low resolution ...coupled atmosphere-ocean Earth System Model by tuning it to realistic data sets consisting of Levitus ocean temperature/salinity climatology, and NCEP/NCAR atmospheric temperature/humidity reanalysis data. The resulting ensemble of tuned model states is validated by comparing various diagnostics, such as mass and heat transports, to observational estimates and other model results. We show that this ensemble has a very reasonable climatology, with the 3-D ocean in particular having comparable realism to much more expensive coupled numerical models, at least in respect of these averaged indicators. A simple global warming experiment is performed to investigate the response and predictability of the climate to a change in radiative forcing, due to 100 years of 1% per annum atmospheric CO^sub 2^ increase. The equilibrium surface air temperature rise for this CO^sub 2^ increase is 4.2±0.1°C, which is approached on a time scale of 1,000 years. The simple atmosphere in this version of the model is missing several factors which, if included, would substantially increase the uncertainty of this estimate. However, even within this ensemble, there is substantial regional variability due to the possibility of collapse of the North Atlantic thermohaline circulation (THC), which switches off in more than one third of the ensemble members. For these cases, the regional temperature is not only 3-5°C colder than in the warmed worlds where the THC remains switched on, but is also 1-2°C colder than the current climate. Our results, which illustrate how objective probabilistic projections of future climate change can be efficiently generated, indicate a substantial uncertainty in the long-term future of the THC, and therefore the regional climate of western Europe. However, this uncertainty is only apparent in long-term integrations, with the initial transient response being similar across the entire ensemble. Application of this ensemble Kalman filtering technique to more complete climate models would improve the objectivity of probabilistic forecasts and hence should lead to significantly increased understanding of the uncertainty of our future climate.PUBLICATION ABSTRACT
This paper examines the wind induced forces and moments experienced by a high sided lorry. Full-scale measurements are combined with wind tunnel and CFD simulations in order to gain an insight into ...the flow field around the vehicle. Differences and similarities between the three techniques are noted. It is shown that the rolling moment coefficient obtained from full-scale measurements and CFD simulations agree consistently across a wide range of yaw angles. With respect to the side force coefficient, good agreement between the wind tunnel and full-scale data are achieved. Pressure distributions over selected sections of the lorry reveal that despite good agreement with the overall forces, the localised pressure field can be significantly different.
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