Maternal low-protein diet during mouse pre-implantation development induces vascular dysfunction and altered renin-angiotensin-system homeostasis in the offspring

Environmental perturbations during early mammalian development can affect aspects of offspring growth and cardiovascular health. We have demonstrated previously that maternal gestational dietary protein restriction in mice significantly elevated adult offspring systolic blood pressure. Therefore, the present study investigates the key mechanisms of blood pressure regulation in these mice. Following mating, female MF-1 mice were assigned to either a normal-protein diet (NPD; 18% casein) or an isocaloric low-protein diet throughout gestation (LPD; 9% casein), or fed the LPD exclusively during the pre-implantation period (3.5d) before returning to the NPD for the remainder of gestation (Emb-LPD). All offspring received standard chow. At 22 weeks, isolated mesenteric arteries from LPD and Emb-LPD males displayed significantly attenuated vasodilatation to isoprenaline (P=0.04 and P=0.025, respectively), when compared with NPD arteries. At 28 weeks, stereological analysis of glomerular number in female left kidneys revealed no significant difference between the groups. Real-time RT-PCR analysis of type 1a angiotensin II receptor, Na /K ATPase transporter subunits and glucocorticoid receptor expression in male and female left kidneys revealed no significant differences between the groups. LPD females displayed elevated serum angiotensin-converting enzyme (ACE) activity (P=0.044), whilst Emb-LPD males had elevated lung ACE activity (P=0.001), when compared with NPD offspring. These data demonstrate that elevated offspring systolic blood pressure following maternal gestational protein undernutrition is associated with impaired arterial vasodilatation in male offspring, elevated serum and lung ACE activity in female and male offspring, respectively, but kidney glomerular number in females and kidney gene expression in male and female offspring appear unaffected. © 2010 The Authors.

Local economic development initiatives and the transition from training and enterprise councils to new institutional structures in England

Current British government economic development policy emphasises regional and sub-regional scale, multi-agent initiatives that form part of national frameworks to encourage a 'bottom up' approach to economic development. An emphasis on local multi-agent initiatives was also the mission of Training and Enterprise Councils (TECs). Using new survey evidence this article tracks the progress of a number of initiatives established under the TECs, using the TEC Discretionary Fund as an example. It assesses the ability of successor bodies to be more effective in promoting local economic development. Survey evidence is used to confirm that many projects previously set up by the TECs continue to operate successfully under new partnership arrangements. However as new structures have developed, and policy has become more centralized, it is less likely that similar local initiatives will be developed in future. There is evidence to suggest that with the end of the TECs a gap has emerged in the institutional infrastructure for local economic development, particularly with regard to workforce development. Much will depend in future on how the Regional Development Agencies deploy their growing power and resources.

Challenges and emerging solutions in the development of compressed orally disintegrating tablets

Areas covered: The review discusses the main challenges of ODT manufacturing process and the emerging solutions featured at early drug development stages. The research specifically describes the methods reported for taste masking/assessment and solubilisation of unpalatable and poorly soluble drugs, respectively. Furthermore, this review highlights the techniques used for developing modified-release ODTs, an emerging area in the field. In addition, it also discusses the poor flowability and segregation problems of directly compressed powders. Moreover, the review describes the tests reported in the literature for ODT disintegration time assessment since a universal technique is still non-existent. Expert opinion: The approaches used to overcome the manufacturing challenges often have a bearing on the price of the end product. However, despite the technical and regulatory challenges, ODTs can offer many advantages over the conventional dosage forms if accompanied by suitable adjuvant technologies and in vitro analytical tools. © 2014 Informa UK, Ltd. Introduction: Orally disintegrating tablets (ODTs) provide several advantages over conventional tablets such as suitability for patients with swallowing difficulties and faster onset of action. The manufacture of ODTs by compression/tableting offers a practical and cost-effective strategy over the freeze drying (lyophilisation) method. Nonetheless, the FDA recommends a disintegration time of 30 s and a maximum weight of 500 mg for a tablet to be labelled as an ODT. These requirements, alongside other desirable product properties, have created a number of challenges for the formulator to overcome while developing compressed ODTs.

A framework of best practice of continuing professional development for the accounting profession

The International Accounting Education Standards Board (IAESB) places a strong emphasis on individual professionals taking responsibility for their Continuing Professional Development (CPD). On the other hand, the roles performed by professional accountants have evolved out of practical necessity to 'best' suit the diverse needs of business in a global economy. This diversity has meant that professional accountants are seen in highly specialised roles requiring diverse skill sets. In order to enhance the contribution of the accountant as a knowledge professional for business, it follows that CPD that leverages off an individual's experience should be designed to meet the needs of professionals across the different specialised roles within the profession. In doing so the project identifies how CPD should differ across roles and levels of organisational responsibility for accounting professionals. The study also makes a number of policy recommendations to IAESB and IFAC. © 2013 © 2013 Taylor & Francis.

The Approach to Development the Human Resources Intellectual Management System. Management Procedures

The Article suggests an approach to designing the Human Resources Intellectual Management System in order to increase Human Resources reliability, using the management methods known from the Theory of Management.. The Article examines the realization of the Subsystem of implementing management methods by the number of management procedures, executing the corresponding management method.

Paediatric drug development:reformulation, in vitro, genomic and in vivo evaluation

Angiotensin converting enzyme (ACE) inhibitors lisinopril and ramipril were selected from EMA/480197/2010 and the potassium-sparing diuretic spironolactone was selected from the NHS specials list for November 2011 drug tariff with the view to produce oral liquid formulations providing dosage forms targeting paediatrics. Lisinopril, ramipril and spironolactone were chosen for their interaction with transporter proteins in the small intestine. Formulation limitations such as poor solubility or pH sensitivity needed consideration. Lisinopril was formulated without extensive development as drug and excipients were water soluble. Ramipril and spironolactone are both insoluble in water and strategies combating this were employed. Ramipril was successfully solubilised using low concentrations of acetic acid in a co-solvent system and also via complexation with hydroxypropyl-β-cyclodextrin. A ramipril suspension was produced to take formulation development in a third direction. Spironolactone dosages were too high for solubilisation techniques to be effective so suspensions were developed. A buffer controlled pH for the sensitive drug whilst a precisely balanced surfactant and suspending agent mix provided excellent physical stability. Characterisation, stability profiling and permeability assessment were performed following formulation development. The formulation process highlighted current shortcomings in techniques for taste assessment of pharmaceutical preparations resulting in early stage research into a novel in vitro cell based assay. The formulations developed in the initial phase of the research were used as model formulations investigating microarray application in an in vitro-in vivo correlation for carrier mediated drug absorption. Caco-2 cells were assessed following transport studies for changes in genetic expression of the ATP-binding cassette and solute carrier transporter superfamilies. Findings of which were compared to in vitro and in vivo permeability findings. It was not possible to ascertain a correlation between in vivo drug absorption and the expression of individual genes or even gene families, however there was a correlation (R2 = 0.9934) between the total number of genes with significantly changed expression levels and the predicted human absorption.

A quantitative approach for understanding small-scale human mesenchymal stem cell culture - implications for large-scale bioprocess development

Human mesenchymal stem cell (hMSC) therapies have the potential to revolutionise the healthcare industry and replicate the success of the therapeutic protein industry; however, for this to be achieved there is a need to apply key bioprocessing engineering principles and adopt a quantitative approach for large-scale reproducible hMSC bioprocess development. Here we provide a quantitative analysis of the changes in concentration of glucose, lactate and ammonium with time during hMSC monolayer culture over 4 passages, under 100% and 20% dissolved oxgen (dO2), where either a 100%, 50% or 0% growth medium exchange was performed after 72h in culture. Yield coefficients, specific growth rates (h-1) and doubling times (h) were calculated for all cases. The 100% dO2 flasks outperformed the 20% dO2 flasks with respect to cumulative cell number, with the latter consuming more glucose and producing more lactate and ammonium. Furthermore, the 100% and 50% medium exchange conditions resulted in similar cumulative cell numbers, whilst the 0% conditions were significantly lower. Cell immunophenotype and multipotency were not affected by the experimental culture conditions. This study demonstrates the importance of determining optimal culture conditions for hMSC expansion and highlights a potential cost savings from only making a 50% medium exchange, which may prove significant for large-scale bioprocessing. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Serum-free process development:improving the yield and consistency of human mesenchymal stromal cell production

Background aims: The cost-effective production of human mesenchymal stromal cells (hMSCs) for off-the-shelf and patient specific therapies will require an increasing focus on improving product yield and driving manufacturing consistency. Methods: Bone marrow-derived hMSCs (BM-hMSCs) from two donors were expanded for 36 days in monolayer with medium supplemented with either fetal bovine serum (FBS) or PRIME-XV serum-free medium (SFM). Cells were assessed throughout culture for proliferation, mean cell diameter, colony-forming potential, osteogenic potential, gene expression and metabolites. Results: Expansion of BM-hMSCs in PRIME-XV SFM resulted in a significantly higher growth rate (P < 0.001) and increased consistency between donors compared with FBS-based culture. FBS-based culture showed an inter-batch production range of 0.9 and 5 days per dose compared with 0.5 and 0.6 days in SFM for each BM-hMSC donor line. The consistency between donors was also improved by the use of PRIME-XV SFM, with a production range of 0.9 days compared with 19.4 days in FBS-based culture. Mean cell diameter has also been demonstrated as a process metric for BM-hMSC growth rate and senescence through a correlation (R² = 0.8705) across all conditions. PRIME-XV SFM has also shown increased consistency in BM-hMSC characteristics such as per cell metabolite utilization, in vitro colony-forming potential and osteogenic potential despite the higher number of population doublings. Conclusions: We have increased the yield and consistency of BM-hMSC expansion between donors, demonstrating a level of control over the product, which has the potential to increase the cost-effectiveness and reduce the risk in these manufacturing processes.

A study of the regulatory role of retinoic acid receptor gamma in Zebrafish development

Retinoic acid (RA) is thought to signal through retinoic acid receptors (RARs), i.e. RARα, β, and γ to play important roles in embryonic development and tissue regeneration. In this thesis, the zebrafish (Danio rario) was used as a vertebrate model organism to examine the role of RARγ. Treatment of zebrafish embryos with a RARγ specific agonist reduced the axial length of developing embryos, associated with reduced somite number and loss of hoxb13a expression. There were no clear alterations in hoxc11a or myoD expression. Treatment with the RARγ agonist disrupted the formation of anterior structures of the head, the cranial bones and the anterior lateral line ganglia, associated with a loss of sox9 immunopositive cells in the same regions. Pectoral fin outgrowth was blocked by treatment with the RARγ agonist; however, this was not associated with loss of tbx5a immunopositive lateral plate cells and was reversed by wash out of the RARγ agonist or co-treatment with a RARγ antagonist. Regeneration of the transected caudal fin was also blocked by RARγ agonist treatment and restored by agonist washout or antagonist co-treatment; this phenotype was associated with a localised reduction in canonical Wnt signalling. Conversely, elevated canonical Wnt signalling after RARγ treatment was seen in other tissues, including ectopically in the notochord. Furthermore, some phenotypes seen in the RARγ treated embryos were present in mutant zebrafish embryos in which canonical Wnt signalling was constitutively increased. These data suggest that RARγ plays an essential role in maintaining neural crest and mesodermal stem/progenitor cells during normal embryonic development and tissue regeneration when the receptor is in its non-ligated state. In addition, this work has provided evidence that the activation status of RARγ may regulate hoxb13a gene expression and canonical Wnt signalling. Further research is required to confirm such novel regulatory roles.

Does the balanced scorecard make a difference to the strategy development process

A great number of strategy tools are being taught in strategic management modules. These tools are available to managers for use in facilitating strategic decision making and enhancing the strategy development process in their organisations. A number of studies have been published examining which are the most popular tools; however there is little empirical evidence on how their utilisation influences the strategy process. This paper is based on a large scale international survey on the strategy development process, and seeks to examine the impact of a particular strategy tool, the Balanced Scorecard (BSC), upon the strategy process. Recently, it has been suggested that as a strategy tool, the BSC can influence all elements of the strategy process. The results of this study indicate that although there are significant differences in some elements of the strategy process between the organisations that have implemented the BSC and those that have not, the impact is not comprehensive. © 2011 Operational Research Society Ltd. All rights reserved.

The effectiveness of workplace coaching:A meta-analysis of learning and performance outcomes; scale development; theoretical model of individual differences and longitudinal study

The extant literature on workplace coaching is characterised by a lack of theoretical and empirical understanding regarding the effectiveness of coaching as a learning and development tool; the types of outcomes one can expect from coaching; the tools that can be used to measure coaching outcomes; the underlying processes that explain why and how coaching works and the factors that may impact on coaching effectiveness. This thesis sought to address these substantial gaps in the literature with three linked studies. Firstly, a meta-analysis of workplace coaching effectiveness (k = 17), synthesizing the existing research was presented. A framework of coaching outcomes was developed and utilised to code the studies. Analysis indicated that coaching had positive effects on all outcomes. Next, the framework of outcomes was utilised as the deductive start-point to the development of the scale measuring perceived coaching effectiveness. Utilising a multi-stage approach (n = 201), the analysis indicated that perceived coaching effectiveness may be organised into a six factor structure: career clarity; team performance; work well-being; performance; planning and organizing and personal effectiveness and adaptability. The final study was a longitudinal field experiment to test a theoretical model of individual differences and coaching effectiveness developed in this thesis. An organizational sample of 84 employees each participated in a coaching intervention, completed self-report surveys, and had their job performance rated by peers, direct reports and supervisors (a total of 352 employees provided data on participant performance). The results demonstrate that compared to a control group, the coaching intervention generated a number of positive outcomes. The analysis indicated that coachees’ enthusiasm, intellect and orderliness influenced the impact of coaching on outcomes. Mediation analysis suggested that mastery goal orientation, performance goal orientation and approach motivation in the form of behavioural activation system (BAS) drive, were significant mediators between personality and outcomes. Overall, the findings of this thesis make an original contribution to the understanding of the types of outcomes that can be expected from coaching, and the magnitude of impact coaching has on outcomes. The thesis also provides a tool for reliably measuring coaching effectiveness and a theoretical model to understand the influence of coachee individual differences on coaching outcomes.

A lean elvek alkalmazása az egészségügyi folyamatok fejlesztésében = Applying lean principles in healthcare process development

A fejlett társadalmak egészségügyi szolgáltató rendszerei napjainkban kettős kihívással néznek szembe: miközben a társadalom a szolgáltatási színvonal emelkedését, a hibák számának a csökkenését várja el, addig a költségvetési terhek miatt a költségcsökkentés is feltétlenül szükséges. Ez a kihívás nagyságában összevethető azzal, amellyel az USA autóipara nézett szembe az 1970-es évektől. A megoldást az autóipar esetében a konkurens „lean” menedzsment elvek és eszközök megértése és alkalmazása jelentette. A tanulmány arra keresi a választ, hogy vajon lehetséges-e ennek a megoldásnak az alkalmazása az egészségügy esetében is. A cikk az egészségügy problémájának bemutatása után tárgyalja a lean menedzsment kialakulását és hogy milyen módon került köztudatba. A tanulmány második felében a szakirodalomban fellelhető, a témával kapcsolatos tapasztalatokat foglalja össze, majd levonja a következtetéseket. = In developed societies healthcare service systems are facing double challenge; society expects service level to rise and the number of mistakes to drop, but at the same time, because of the overloaded budgets, cutting cost is also absolutely necessary. This challenge compares to the one the US automotive industry was facing in the 1970-s. In case of the automotive industry the solution was the comprehension and application of the principles and the tools of lean management. This study aims to answer the question whether it is possible to apply this solution also in the case of the healthcare system. The article first introduces the problems in the healthcare system, than describes the formation of lean management concept and its wide spread. The second half of the study summarizes the available knowledge in the literature and drives conclusions.

Worker remittances and the global preconditions of ‘smart development’

With the growing environmental crisis affecting our globe, ideas to weigh economic or social progress by the ‘energy input’ necessary to achieve it are increasingly gaining acceptance. This question is intriguing and is being dealt with by a growing number of studies, focusing on the environmental price of human progress. Even more intriguing, however, is the question of which factors of social organization contribute to a responsible use of the resources of our planet to achieve a given social result (‘smart development’). In this essay, we present the first systematic study on how migration – or rather, more concretely, received worker remittances per GDP – helps the nations of our globe to enjoy social and economic progress at a relatively small environmental price. We look at the effects of migration on the balance sheets of societal accounting, based on the ‘ecological price’ of the combined performance of democracy, economic growth, gender equality, human development, research and development, and social cohesion. Feminism in power, economic freedom, population density, the UNDP education index as well as the receipt of worker remittances all significantly contribute towards a ‘smart overall development’, while high military expenditures and a high world economic openness are a bottleneck for ‘smart overall development’.

Development and Application of a Methodology to Identify Projects of Energy Community Interest

Projects of Energy Community Interest” (PECIs) is a label attached to those projects which have the highest positive impact in the largest possible number of Contracting Parties. The assessment of one hundred projects submitted as candidates, and final selection of 35 PECIs was achieved in a collaborative process undertaken by the same Task Force that contributed to the preparation of the Energy Strategy. Chaired by the European Commission, the Task Force was facilitated by the Energy Community Secretariat and benefited from technical assistance of a Consultant sponsored from the Energy Community budget.

Implications of a theoretical framework on stress and burnout for the development of graduate nursing education curricula

This study had two purposes: (a) to develop a theoretical framework integrating and synthesizing findings of prior research regarding stress and burnout among critical care nurses (CCRNs), and (b) to validate the theoretical framework with an empirical study to assure a theory/research based teaching-learning process for graduate courses preparing nursing clinical specialists and administrators.^ The methods used to test the theoretical framework included: (a) adopting instruments with reported validity, (b) conducting a pilot study, (c) revising instruments using results of the pilot study and following concurrence of a panel of experts, and (d) establishing correlations within predetermined parameters. The reliability of the tool was determined through the use of Cronbach's Alpha Coefficient with a resulting range from.68 to.88 for all measures.^ The findings supported all the research hypotheses. Correlations were established at r =.23 for statistically significant alphas at the.01 level and r =.16 for alphas.05. The conclusions indicated three areas of strong correlation among the theoretical variables: (a) work environment stressor antecedents and specific stressor events were correlated significantly with subjective work stress and burnout; (b) subjective work stress (perceived work related stress) was a function of the work environment stressor antecedents and specific stressor events, and (c) emotional exhaustion, the first phase of burnout, was confirmed to be related to stressor antecedents and specific stressor events. This dimension was found to be a function of the work environment stressor antecedents, modified by the individual characteristics of work and non-work related social support, non-work daily stress, and the number of hours worked per week. The implications of the study for nursing graduate curricula, nursing practice and nursing education were discussed. Recommendations for further research were enumerated. ^