Delivery of human apolipoprotein (apo) E to liver by an [E1(-), E3(-), polymerase(-), pTP(-)] adenovirus vector containing a liver-specific promoter inhibits atherogenesis in immunocompetent apoE-deficient mice

Recombinant adenovirus (rAd)-mediated apoE gene transfer to the liver of apoE(-/-) mice is anti-atherogenic. However, first generation rAd vectors were associated with immune clearance of transduced hepatocytes, while an improved [E1(-), E3(-) polymerase(-)] adenovirus vector that persisted in the liver, had transient effects due to cellular shutdown of the cytomegalovirus (CMV) promoter (Ad-CMV-apoE). Here, we utilise an improved class of rAd vector with multiple deletions in the E1, E3, polymerase and pTP (pre-terminal protein) genes, which contains a modular synthetic liver-specific promoter (LSP) to drive expression of the human apoE cDNA (Ad-LSP-apoE) for hepatic gene transfer. Approximately 1 year old apoE(-/-) mice were injected intravenously with 4x10(10) virus particles of either Ad-LSP-apoE or Ad-CMV-apoE. Animals were monitored for plasma apoE, total plasma cholesterol and plasma lipoprotein distribution. The effect of Ad-LSP-apoE on atheroma progression was assessed in animals killed at 8 and 28 weeks after the injections. Ad-LSP-apoE vector administration gave sustained, though low, levels of plasma apoE throughout the study period without inducing a humoral immune response, but failed to reduce plasma cholesterol or normalize the adverse lipoprotein profile. Animals killed 8 weeks after the injections, demonstrated no significant retardation of atherosclerosis, whereas aortic lesions in those killed at 28 weeks were significantly reduced by 30% ( P< 0.006) compared to untreated animals. In summary, the combination of a multiply deleted rAd vector with a liver-specific promoter provided sustained low levels of plasma apoE, resulting in significant retardation of aortic atherosclerotic lesions

Retardation of atherosclerosis in immunocompetent apolipoprotein (apo) E-deficient mice followingliver-directed administration of a [E1-, E3-,polymerase-] adenovirus vector containing the elongation factor-1a promoter driving expression of human apoE cDNA

Although gene transfer of human apolipoprotein E (apoE), a 34-kDa circulating glycoprotein, to the liver of apoEdeficient(apoE-/-) mice using recombinant adenoviral vectors (rAd) is antiatherogenic, its full therapeutic potentialhas yet to be realized. First generation vectors led to immune clearance of transduced hepatocytes, while animproved vector with adenovirus regions E1, E3 and DNA polymerase deleted also had transient effects due tocellular shutdown of the cytomegalovirus (CMV) promoter. Here, we have studied an alternative promoter from thecellular elongation factor 1a (EF-1a) gene, injecting 6-8 week old apoE-/- mice intravenously with 2x1010 virusparticles (vp) of the [E1-, E3-, polymerase-] rAd vector Ad-EF1·-apoE. Plasma apoE levels were low (18-55 ng/ml)and failed to reduce plasma cholesterol or normalize the adverse lipoprotein profile. By contrast, thehyperlipidaemic phenotype of apoE-/- mice treated with Ad-CMV-apoE (2x1010 vp) was transiently normalized.Nevertheless, at termination (265 days) the aortic lesion areas in animals given Ad-EF1·-apoE were significantlyreduced by 15% (P<0.05) compared to untreated animals, a decrease approaching that in Ad-CMV-apoE-treatedmice (23%; P<0.02). Importantly, the attenuation of apoE transgene expression noted with the CMV promoter wasabsent with the EF-1a promoter, which gave relatively sustained, albeit low, levels of plasma apoE throughout thestudy period

Dietary patterns, insulin sensitivity and inflammation in older adults.

Background/objectivesSeveral studies have linked dietary patterns to insulin sensitivity and systemic inflammation, which affect risk of multiple chronic diseases. The purpose of this study was to investigate the dietary patterns of a cohort of older adults, and to examine relationships of dietary patterns with markers of insulin sensitivity and systemic inflammation.Subjects/methodsThe Health, Aging and Body Composition (Health ABC) Study is a prospective cohort study of 3075 older adults. In Health ABC, multiple indicators of glucose metabolism and systemic inflammation were assessed. Food intake was estimated with a modified Block food frequency questionnaire. In this study, dietary patterns of 1751 participants with complete data were derived by cluster analysis.ResultsSix clusters were identified, including a 'healthy foods' cluster, characterized by higher intake of low-fat dairy products, fruit, whole grains, poultry, fish and vegetables. In the main analysis, the 'healthy foods' cluster had significantly lower fasting insulin and homeostasis model assessment of insulin resistance values than the 'breakfast cereal' and 'high-fat dairy products' clusters, and lower fasting glucose than the 'high-fat dairy products' cluster (P≤0.05). No differences were found in 2-h glucose. With respect to inflammation, the 'healthy foods' cluster had lower interleukin-6 than the 'sweets and desserts' and 'high-fat dairy products' clusters, and no differences were seen in C-reactive protein or tumor necrosis factor-α.ConclusionsA dietary pattern high in low-fat dairy products, fruit, whole grains, poultry, fish and vegetables may be associated with greater insulin sensitivity and lower systemic inflammation in older adults

Apolipoprotein E delivery by peritoneal implantation of encapsulated recombinant cells improves the hyperlipidaemic profile in apoE-deficient mice

Plasma apolipoprotein E (apoE) is a 34-kDa polymorphic protein which has atheroprotective actions by clearing remnant lipoproteins and sequestering excess cellular cholesterol. Low or dysfunctional apoE is a risk factor for hyperlipidaemia and atherosclerosis, and for restenosis after angioplasty. Here, in short-term studies designed to establish proof-of-principle, we investigate whether encapsulated recombinant Chinese hamster ovary (CHO) cells can secrete wild-type apoE3 protein in vitro and then determine whether peritoneal implantation of the microcapsules into apoE-deficient (apoE(-/-)) mice reduces their hypercholesterolaemia.Recombinant CHO-E3 cells were encapsulated into either alginate poly-L-lysine or alginate polyethyleneimine/polybrene microspheres. After verifying stability and apoE3 secretion, the beads were then implanted into the peritoneal cavity of apoE(-/-) mice; levels of plasma apoE3, cholesterol and lipoproteins were monitored for up to 14 days post-implantation.Encapsulated CHO-E3 cells continued to secrete apoE3 protein throughout a 60-day study period in vitro, though levels declined after 14 days. This cell-derived apoE3 was biologically active. When conditioned medium from encapsulated CHO-E3 cells was incubated with cultured cells pre-labelled with [H-3]-cholesterol, efflux of cholesterol was two to four times greater than with normal medium (at 8 h, for example, 7.4+/-0.3% vs. 2.4+/-0.2% of cellular cholesterol; P<0.001). Moreover, when secreted apoE3 was injected intraperitoneally into apoE(-/-) mice, apoE3 was detected in plasma and the hyperlipidaemia improved. Similarly, when alginate polyethyleneimine/polybrene capsules were implanted into the peritoneum of apoE(-/-) mice, apoE3 was secreted into plasma and at 7 days total cholesterol was reduced, while atheroprotective high-density lipoprotein (HDL) increased. In a second study, apoE was detectable in plasma of five mice treated with alginate poly-L-lysine beads, 4 and 7 days post-implantation, though not at day 14. Furthermore, their hypercholesterolaemia was reduced, while HDL was clearly elevated in all mice at days 4 and 7 (from 18.4+/-6.2% of total lipoproteins to 31.1+/-6.8% at 7 days; P<0.001); however, these had rebounded by day 14, possibly due to the emergence of anti-apoE antibodies.We conclude that microencapsulated apoE-secreting cells have the potential to ameliorate the hyperlipidaemia of apoE deficiency, but that the technology must be improved to become a feasible therapeutic to treat atherosclerosis. (C) 2004 Elsevier B.V. All rights reserved

Concurrent adaptation to opposing visual displacements during an alternating movement.

It has been suggested that, during tasks in which subjects are exposed to a visual rotation of cursor feedback, alternating bimanual adaptation to opposing rotations is as rapid as unimanual adaptation to a single rotation (Bock et al. in Exp Brain Res 162:513–519, 2005). However, that experiment did not test strict alternation of the limbs but short alternate blocks of trials. We have therefore tested adaptation under alternate left/right hand movement with opposing rotations. It was clear that the left and right hand, within the alternating conditions, learnt to adapt to the opposing displacements at a similar rate suggesting that two adaptive states were formed concurrently. We suggest that the separate limbs are used as contextual cues to switch between the relevant adaptive states. However, we found that during online correction the alternating conditions had a significantly slower rate of adaptation in comparison to the unimanual conditions. Control conditions indicate that the results are not directly due the alternation between limbs or to the constant switching of vision between the two eyes. The negative interference may originate from the requirement to dissociate the visual information of these two alternating displacements to allow online control of the two arms

A Bayesian computational model to investigate expert anticipation of a seemingly unpredictable ball bounce

This is the final version. Available on open access from Springer via the DOI in this recordDuring dynamic and time-constrained sporting tasks performers rely on both online perceptual information and prior contextual knowledge to make effective anticipatory judgments. It has been suggested that performers may integrate these sources of information in an approximately Bayesian fashion, by weighting available information sources according to their expected precision. In the present work, we extended Bayesian brain approaches to anticipation by using formal computational models to estimate how performers weighted different information sources when anticipating the bounce direction of a rugby ball. Both recreational (novice) and professional (expert) rugby players (n = 58) were asked to predict the bounce height of an oncoming rugby ball in a temporal occlusion paradigm. A computational model, based on a partially observable Markov decision process, was fitted to observed responses to estimate participants’ weighting of online sensory cues and prior beliefs about ball bounce height. The results showed that experts were more sensitive to online sensory information, but that neither experts nor novices relied heavily on prior beliefs about ball trajectories in this task. Experts, but not novices, were observed to down-weight priors in their anticipatory decisions as later and more precise visual cues emerged, as predicted by Bayesian and active inference accounts of perception

Progress and Challenges in Coupled Hydrodynamic-Ecological Estuarine Modeling

Numerical modeling has emerged over the last several decades as a widely accepted tool for investigations in environmental sciences. In estuarine research, hydrodynamic and ecological models have moved along parallel tracks with regard to complexity, refinement, computational power, and incorporation of uncertainty. Coupled hydrodynamic-ecological models have been used to assess ecosystem processes and interactions, simulate future scenarios, and evaluate remedial actions in response to eutrophication, habitat loss, and freshwater diversion. The need to couple hydrodynamic and ecological models to address research and management questions is clear because dynamic feedbacks between biotic and physical processes are critical interactions within ecosystems. In this review, we present historical and modern perspectives on estuarine hydrodynamic and ecological modeling, consider model limitations, and address aspects of model linkage, skill assessment, and complexity. We discuss the balance between spatial and temporal resolution and present examples using different spatiotemporal scales. Finally, we recommend future lines of inquiry, approaches to balance complexity and uncertainty, and model transparency and utility. It is idealistic to think we can pursue a theory of everything for estuarine models, but recent advances suggest that models for both scientific investigations and management applications will continue to improve in terms of realism, precision, and accuracy

Pesticide Product Use and Risk of Non-Hodgkin Lymphoma in Women

A population-based, incidence case–control study was conducted among women in upstate New York to determine whether pesticide exposure is associated with an increase in risk of non-Hodgkin lymphoma (NHL) among women. The study involved 376 cases of NHL identified through the State Cancer Registry and 463 controls selected from the Medicare beneficiary files and state driver’s license records. Information about history of farm work, history of other jobs associated with pesticide exposure, use of common household pesticide products, and potential confounding variables was obtained by telephone interview. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using an unconditional logistic regression model. The risk of NHL was doubled (OR = 2.12; 95% CI, 1.21–3.71) among women who worked for at least 10 years at a farm where pesticides were reportedly used. When both farming and other types of jobs associated with pesticide exposure were combined, there was a progressive increase in risk of NHL with increasing duration of such work (p = 0.005). Overall cumulative frequency of use of household pesticide products was positively associated with risk of NHL (p = 0.004), which was most pronounced when they were applied by subjects themselves. When exposure was analyzed by type of products used, a significant association was observed for mothballs. The associations with both occupational and household pesticides were particularly elevated if exposure started in 1950–1969 and for high-grade NHL. Although the results of this case–control study suggest that exposure to pesticide products may be associated with an increased risk of NHL among women, methodologic limitations related to selection and recall bias suggest caution in inferring causation

Development of a generic activities model of command and control

This paper reports on five different models of command and control. Four different models are reviewed: a process model, a contextual control model, a decision ladder model and a functional model. Further to this, command and control activities are analysed in three distinct domains: armed forces, emergency services and civilian services. From this analysis, taxonomies of command and control activities are developed that give rise to an activities model of command and control. This model will be used to guide further research into technological support of command and control activities