Moderate relationships between NAA and cognitive ability in healthy adults:implications for cognitive spectroscopy

Background: Proton Magnetic Resonance Spectroscopy (H-MRS) is a non-invasive imaging technique that enables quantification of neurochemistry in vivo and thereby facilitates investigation of the biochemical underpinnings of human cognitive variability. Studies in the field of cognitive spectroscopy have commonly focused on relationships between measures of N-acetyl aspartate (NAA), a surrogate marker of neuronal health and function, and broad measures of cognitive performance, such as IQ. Methodology/Principal Findings: In this study, we used H-MRS to interrogate single-voxels in occipitoparietal and frontal cortex, in parallel with assessments of psychometric intelligence, in a sample of 40 healthy adult participants. We found correlations between NAA and IQ that were within the range reported in previous studies. However, the magnitude of these effects was significantly modulated by the stringency of data screening and the extent to which outlying values contributed to statistical analyses. Conclusions/Significance: H-MRS offers a sensitive tool for assessing neurochemistry non-invasively, yet the relationships between brain metabolites and broad aspects of human behavior such as IQ are subtle. We highlight the need to develop an increasingly rigorous analytical and interpretive framework for collecting and reporting data obtained from cognitive spectroscopy studies of this kind. © 2014 Patel, Blyth, Griffiths, Kelly and Talcott.

Mechanism of induction of muscle protein degradation by angiotensin II

Angiotensin I and II have been shown to directly induce protein degradation in skeletal muscle through an increased activity and expression of the ubiquitin-proteasome proteolytic pathway. This investigation determines the role of the nuclear transcription factor nuclear factor-κB (NF-κB) in this process. Using murine myotubes as a surrogate model system both angiotensin I and II were found to induce activation of protein kinase C (PKC), with a parabolic dose-response curve similar to the induction of total protein degradation. Activation of PKC was required for the induction of proteasome expression, since calphostin C, a highly specific inhibitor of PKC, attenuated both the increase in total protein degradation and in proteasome expression and functional activity increased by angiotensin II. PKC is known to activate I-κB kinase (IKK), which is responsible for the phosphorylation and subsequent degradation of I-κB. Both angiotensin I and II induced an early decrease in cytoplasmic I-κB levels followed by nuclear accumulation of NF-κB. Using an NF-κB luciferase construct this was shown to increase transcriptional activation of NF-κB regulated genes. Maximal luciferase expression was seen at the same concentrations of angiotensin I/II as those inducing protein degradation. Total protein degradation induced by both angiotensin I and II was attenuated by resveratrol, which prevented nuclear accumulation of NF-κB, confirming that activation of NF-κB was responsible for the increased protein degradation. These results suggest that induction of proteasome expression by angiotensin I/II involves a signalling pathway involving PKC and NF-κB. © 2005 Elsevier Inc. All rights reserved.

Angiotensin II directly inhibits protein synthesis in murine myotubes

Angiotensin II (Ang II) has been implicated in muscle protein loss in cachexia. To determine whether the Ang I/II system directly inhibits protein synthesis in muscle their effect has been monitored in vitro using murine myotubes as a surrogate model system. Ang I inhibited protein synthesis by 40-50% over the concentration range of 0.05-2.5 μM within 30 min of addition, and the inhibition remained relatively constant over 24 h. The effect was attenuated by co-incubation with the angiotensin converting enzyme inhibitor imidaprilat (50 μM) suggesting that inhibition of protein synthesis was due to the formation of Ang II. Ang II also inhibited protein synthesis by 40-50% over the concentration range of 0.1-5 μM, and the inhibition also remained relatively constant between 30 min and 24 h after addition. The effect was attenuated by insulin-like growth factor-1 (IGF-1) (25-100 ng/ml). Thus, Ang I/II have the ability to induce muscle atrophy through inhibition of protein synthesis. © 2005 Elsevier Ireland Ltd. All rights reserved.

Metformin:effects on micro and macrovascular complications in type 2 diabetes

Introduction: The antihyperglycaemic agent metformin is widely used in the treatment of type 2 diabetes. Data from the UK Prospective Diabetes Study and retrospective analyses of large healthcare databases concur that metformin reduces the incidence of myocardial infarction and increases survival in these patients. This apparently vasoprotective effect appears to be independent of the blood glucose-lowering efficacy. Effects of metformin: Metformin has long been known to reduce the development of atherosclerotic lesions in animal models, and clinical studies have shown the drug to reduce surrogate measures such as carotid intima-media thickness. The anti-atherogenic effects of metformin include reductions in insulin resistance, hyperinsulinaemia and obesity. There may be modest favourable effects against dyslipidaemia, reductions in pro-inflammatory cytokines and monocyte adhesion molecules, and improved glycation status, benefiting endothelial function in the macro- and micro-vasculature. Additionally metformin exerts anti-thrombotic effects, contributing to overall reductions in athero-thrombotic risk in type 2 diabetic patients. © 2008 Springer Science+Business Media, LLC.

Correlates of depression in bipolar disorder

We analyse time series from 100 patients with bipolar disorder for correlates of depression symptoms. As the sampling interval is non-uniform, we quantify the extent of missing and irregular data using new measures of compliance and continuity. We find that uniformity of response is negatively correlated with the standard deviation of sleep ratings (ρ = -0.26, p = 0.01). To investigate the correlation structure of the time series themselves, we apply the Edelson-Krolik method for correlation estimation. We examine the correlation between depression symptoms for a subset of patients and find that self-reported measures of sleep and appetite/weight show a lower average correlation than other symptoms. Using surrogate time series as a reference dataset, we find no evidence that depression is correlated between patients, though we note a possible loss of information from sparse sampling. © 2013 The Author(s).

Structural design of contact lens-based drug delivery systems; in vitro and in vivo studies of ocular triggering mechanisms

This study identifies and investigates the potential use of in-eye trigger mechanisms to supplement the widely available information on release of ophthalmic drugs from contact lenses under passive release conditions. Ophthalmic dyes and surrogates have been successfully employed to investigate how these factors can be drawn together to make a successful system. The storage of a drug-containing lens in a pH lower than that of the ocular environment can be used to establish an equilibrium that favours retention of the drug in the lens prior to ocular insertion. Although release under passive conditions does not result in complete dye elution, the use of mechanical agitation techniques which mimic the eyelid blink action in conjunction with ocular tear chemistry promotes further release. In this way differentiation between passive and triggered in vitro release characteristics can be established. Investigation of the role of individual tear proteins revealed significant differences in their ability to alter the equilibrium between matrix-held and eluate-held dye or drug. These individual experiments were then investigated in vivo using ophthalmic dyes. Complete elution was found to be achievable in-eye; this demonstrated the importance of that fraction of the drug retained under passive conditions and the triggering effect of in-eye conditions on the release process. Understanding both the structure-property relationship between drug and material and in-eye trigger mechanisms, using ophthalmic dyes as a surrogate, provides the basis of knowledge necessary to design ocular drug delivery vehicles for in-eye release in a controllable manner.

Improving the economic value of photographic screening for optical coherence tomography-detectable macular oedema:a prospective, multicentre, UK study

Objectives: To determine the best photographic surrogate markers for detecting sight-threatening macular oedema (MO) in people with diabetes attending UK national screening programmes. Design: A multicentre, prospective, observational cohort study of 3170 patients with photographic signs of diabetic retinopathy visible within the macular region [exudates within two disc diameters, microaneurysms/dot haemorrhages (M/DHs) and blot haemorrhages (BHs)] who were recruited from seven study centres. Setting: All patients were recruited and imaged at one of seven study centres in Aberdeen, Birmingham, Dundee, Dunfermline, Edinburgh, Liverpool and Oxford. Participants: Subjects with features of diabetic retinopathy visible within the macular region attending one of seven diabetic retinal screening programmes. Interventions: Alternative referral criteria for suspected MO based on photographic surrogate markers; an optical coherence tomographic examination in addition to the standard digital retinal photograph. Main outcome measures: (1) To determine the best method to detect sight-threatening MO in people with diabetes using photographic surrogate markers. (2) Sensitivity and specificity estimates to assess the costs and consequences of using alternative strategies. (3) Modelled long-term costs and quality-adjusted life-years (QALYs). Results: Prevalence of MO was strongly related to the presence of lesions and was roughly five times higher in subjects with exudates or BHs or more than two M/DHs within one disc diameter. Having worse visual acuity was associated with about a fivefold higher prevalence of MO. Current manual screening grading schemes that ignore visual acuity or the presence of M/DHs could be improved by taking these into account. Health service costs increase substantially with more sensitive/less specific strategies. A fully automated strategy, using the automated detection of patterns of photographic surrogate markers, is superior to all current manual grading schemes for detecting MO in people with diabetes. The addition of optical coherence tomography (OCT) to each strategy, prior to referral, results in a reduction in costs to the health service with no decrement in the number of MO cases detected. Conclusions: Compared with all current manual grading schemes, for the same sensitivity, a fully automated strategy, using the automated detection of patterns of photographic surrogate markers, achieves a higher specificity for detecting MO in people with diabetes, especially if visual acuity is included in the automated strategy. Overall, costs to the health service are likely to increase if more sensitive referral strategies are adopted over more specific screening strategies for MO, for only very small gains in QALYs. The addition of OCT to each screening strategy, prior to referral, results in a reduction in costs to the health service with no decrement in the number of MO cases detected. © Queen's Printer and Controller of HMSO 2013.

Social and environmental accountability in developing countries

The principal aim of this chapter is to undertake a critical review of the social and environmental accountability of global business activities in developing countries. While global business activities have contributed to the economic development of developing countries they have many adverse social and environmental consequences which are often under-studied. I explore the role of accounting in making those consequences visible. The chapter, however, concludes that while social and environmental accounting has the potential to raise the visibility of social and environmental impacts of corporate activities it often fails to do so particularly under the current voluntary disclosure regime where corporations can choose what to report and how to report. This is even more pronounced in the developing countries because of their vulnerabilities arising from various social and environmental problems. The chapter argues for a case of ‘surrogate accountability’ as an alternative to the current corporate driven form of accountability.

Identifying the scope for savings at inpatient episode level:an illustration applying DEA to chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is characterized by a largely irreversible obstruction of the airways, and is one of the leading causes of chronic morbidity and mortality worldwide. This paper illustrates the use of Data Envelopment Analysis (DEA) to assess the potential for cost savings at COPD inpatient episode level. The analysis uses the length of stay of each episode as a surrogate for expenditure on that episode while allowing for the medical condition of the patient and the quality of care received. We find substantial possible reductions in length of stay which would translate to cost savings. The paper also explores differences both between hospitals and between care teams within hospitals so that cost efficient protocols of treatment can be identified and disseminated.

Multiobjective design optimization of IGBT power modules considering power cycling and thermal cycling

Insulated-gate bipolar transistor (IGBT) power modules find widespread use in numerous power conversion applications where their reliability is of significant concern. Standard IGBT modules are fabricated for general-purpose applications while little has been designed for bespoke applications. However, conventional design of IGBTs can be improved by the multiobjective optimization technique. This paper proposes a novel design method to consider die-attachment solder failures induced by short power cycling and baseplate solder fatigue induced by the thermal cycling which are among major failure mechanisms of IGBTs. Thermal resistance is calculated analytically and the plastic work design is obtained with a high-fidelity finite-element model, which has been validated experimentally. The objective of minimizing the plastic work and constrain functions is formulated by the surrogate model. The nondominated sorting genetic algorithm-II is used to search for the Pareto-optimal solutions and the best design. The result of this combination generates an effective approach to optimize the physical structure of power electronic modules, taking account of historical environmental and operational conditions in the field.

Grandfamilies: Grandchildren raised by grandparents. Impact on students and school services

Historically, some grandparents have had to assume the responsibility for raising their grandchildren. More recently, with increasing frequency grandparents are serving as full-time surrogate parents to their grandchildren.^ The term "grandfamily" was coined by this researcher to identify families where children are raised by grandparents. "Supergrands" are the grandparents and "grandkin" are children in these families.^ Supergrands who raise their grandkin tend to have elevated levels of stress that negatively impact their well-being. Grandkin tend to develop problems with attachment and establishing social networks, which can lead to poor psychological adjustment. School personnel believe grandkin evidence behavioral problems and occupy disproportionate amounts of their time each day. However, there is a dearth of data to support this belief.^ This study empirically investigated the impact of grandfamilies on students and school services. The results revealed grandkin experienced significantly greater levels of emotional and behavior problems than similar schoolmates. However, they were not referred for discipline problems in substantially larger numbers.^ These results indicate the practice of education should change to allow for the development and provision of social support procedures in schools. Social support will serve to buffer the stress, manifested in emotional and behavioral problems, encountered by children living with surrogate parents. A case study was presented along with a proposed intervention project that has potential to ameliorate the problems experienced by grandfamilies. ^

A methodology to measure coordination of business processes

Coordination of business processes is the management of dependencies where dependencies constrain how the tasks are performed. It has been traditionally done in an intuitive fashion, without paying much attention to the coordination load. Coordination load is being defined as the ratio between the time spent on coordination activities and the total task time. Previous efforts to understand and analyze coordination have resulted in mostly qualitative approaches to categorize and recommend coordination strategies. This research seeks to answer two questions: (1) How can we analyze process coordination problems to improve overall performance? (2) What guidance can we provide to reduce the coordination load of the process and consequently improve the organization's performance? Thus, this effort developed a quantitative measure for coordination load of business processes and a methodology to apply such measure. ^ This effort used a management simulation game to have a controlled laboratory environment enabling the manipulation of the task factors variability, analyzability, and interdependence to measure their impact on coordination load. The hypothesis was that the more variable, non-analyzable, and interdependent a process, the higher the coordination load, and that a higher coordination load would have a negative impact on performance. Coordination load was measured via the surrogate coordination time, and performance via profit. ^ A 22 x 31 full factorial design, with two replicates, was run to observe the impact on the variables coordination time and profit. Properly validated spreadsheets and questionnaires were used as data collection instruments for each scenario. The experimental results indicate that lower task analyzability (ρ=0.036) and higher task interdependence (ρ=0.000) lead to higher coordination load, and higher levels of task variability (ρ=0.049) lead to lower performance. However, contrary to the hypotheses postulated by this work, coordination load did not prove to be strong predictor of performance (correlation of -0.086). ^ These findings from the laboratory experiment and other lessons learned were incorporated to develop a quantitative measure, a tool (survey) to use to gather data for the variables in the measures, and a methodology to quantify coordination load of production business processes. The practicality of the methodology is demonstrated with an example.^

The development of calibrants through characterization of volatile organic compounds from peroxide based explosives and a non-target chemical calibration compound

Detection canines represent the fastest and most versatile means of illicit material detection. This research endeavor in its most simplistic form is the improvement of detection canines through training, training aids, and calibration. This study focuses on developing a universal calibration compound for which all detection canines, regardless of detection substance, can be tested daily to ensure that they are working with acceptable parameters. Surrogate continuation aids (SCAs) were developed for peroxide based explosives along with the validation of the SCAs already developed within the International Forensic Research Institute (IFRI) prototype surrogate explosives kit. Storage parameters of the SCAs were evaluated to give recommendations to the detection canine community on the best possible training aid storage solution that minimizes the likelihood of contamination. Two commonly used and accepted detection canine imprinting methods were also evaluated for the speed in which the canine is trained and their reliability. As a result of the completion of this study, SCAs have been developed for explosive detection canine use covering: peroxide based explosives, TNT based explosives, nitroglycerin based explosives, tagged explosives, plasticized explosives, and smokeless powders. Through the use of these surrogate continuation aids a more uniform and reliable system of training can be implemented in the field than is currently used today. By examining the storage parameters of the SCAs, an ideal storage system has been developed using three levels of containment for the reduction of possible contamination. The developed calibration compound will ease the growing concerns over the legality and reliability of detection canine use by detailing the daily working parameters of the canine, allowing for Daubert rules of evidence admissibility to be applied. Through canine field testing, it has been shown that the IFRI SCAs outperform other commercially available training aids on the market. Additionally, of the imprinting methods tested, no difference was found in the speed in which the canines are trained or their reliability to detect illicit materials. Therefore, if the recommendations discovered in this study are followed, the detection canine community will greatly benefit through the use of scientifically validated training techniques and training aids.

Monounsaturated fatty acid, carbohydrate intake, and diabetes status are associated with arterial pulse pressure

Background Diabetes is a global epidemic. Cardiovascular disease (CVD) is one of the most prevalent consequences of diabetes. Nutrition is considered a modifiable risk factor for CVD, particularly for individuals with diabetes; albeit, there is little consensus on the role of carbohydrates, proteins and fats for arterial health for persons with or without diabetes. In this study, we examined the association of macronutrients with arterial pulse pressure (APP), a surrogate measure of arterial health by diabetes status and race. Methods Participants were 892 Mexican Americans (MA), 1059 Black, non-Hispanics (BNH) and 2473 White, non-Hispanics (WNH) with and without diabetes of a weighted sample from the National Nutrition and Health Examination Survey (NHANES) 2007-2008. The cross-sectional analysis was performed with IBM-SPSS version 18 with the complex sample analysis module. The two-year sample weight for the sub-sample with laboratory values was applied to reduce bias and approximate a nationally, representative sample. Arterial stiffness was assessed by arterial pulse pressure (APP). Results APP was higher for MA [B = 0.063 (95% CI 0.015 to 0.111), p = 0.013] and BNH [B = 0.044 (95% CI 0.006 to 0.082), p = 0.018] than WNH, controlling for diabetes, age, gender, body mass index (BMI), fiber intake, energy intake (Kcal) and smoking. A two-way interaction of diabetes by carbohydrate intake (grams) was inversely associated with APP [B = -1.18 (95% CI -0.178 to -0.058), p = 0.001], controlling for race, age, gender, BMI, Kcal and smoking. BNH with diabetes who consumed more mono-unsaturated fatty acids (MUFA) than WNH with diabetes had lower APP [B = -0.112 (95%CI-0.179 to -0.045), p = 0.003] adjusting for saturated fatty acids, Kcal, age, gender, BMI and smoking. Conclusion Higher MUFA and carbohydrate intake for persons with diabetes reflecting lower APP may be due to replacement of saturated fats with CHO and MUFA. The associations of APP with diabetes, race and dietary intake need to be confirmed with intervention and prospective studies. Confirmation of these results would suggest that dietary interventions for minorities with diabetes may improve arterial health.

The influence of fathers and other significant male figures on girls' well -being and achievement in early adolescence

Changes in the demographic structure of American families have highlighted the need to reevaluate fatherhood. Research illustrates that paternal involvement positively affects child development, but father absence has increased due to rising rates of divorce, cohabitation, and non-marital childbirth. There is evidence that other male figures can function as effective father surrogates. However, information is limited, particularly with respect to female development. ^ This study examined differences in well-being, achievement, and paternal support among girls in four father categories: (a) Biological Father, (b) Step-Father, (c) Surrogate Father, and (d) No Father. Maternal support, economic hardship, and life stressors were included as potential covariates. Interviews were conducted with an ethnically and economically diverse sample of 694 sixth and eighth grade children. The sample included boys to assess the extent to which the findings were unique to girls. Measures included quantitative and qualitative support from father figures and indices of self-esteem, loneliness, and depression. Standardized test scores and classroom grades were also obtained from school records. ^ Girls with biological fathers had higher achievement test scores than girls in the other father categories, but there were no other differences related to the presence or absence of a father-figure. Biological fathers also provided greater quantitative and qualitative support than step- and surrogate fathers. Surrogate fathers provided a greater amount but lower quality of support than step-fathers. ^ Girls who received lower levels of support from biological fathers reported lower self-esteem and greater loneliness, compared to fatherless girls and those receiving low support from other father figures, suggesting that low support from biological fathers may be especially distressing. On the other hand, girls with low biological father support had higher achievement scores compared to fatherless girls and those who received low support from step- and surrogate fathers. Thus, the mere presence of the biological father appears to facilitate achievement, regardless of the level of support he provides. ^ This study highlights the supportive characteristics of different father figures and their influence on well-being and achievement in females. Future research should focus on the dynamics of surrogate father relationships and the specific characteristics that differentially affect developmental outcomes. ^