NADPH oxidase-dependent redox signalling in cardiac hypertrophy, remodelling and failure

Markers of increased oxidative stress are known to be elevated following acute myocardial infarction and in the context of chronic left ventricular hypertrophy or heart failure, and their levels may correlate with the degree of contractile dysfunction or cardiac deficit. An obvious pathological mechanism that may account for this correlation is the potential deleterious effects of increased oxidative stress through the induction of cellular dysfunction, energetic deficit or cell death. However, reactive oxygen species have several much more subtle effects in the remodelling or failing heart that involve specific redox-regulated modulation of signalling pathways and gene expression. Such redox-sensitive regulation appears to play important roles in the development of several components of the phenotype of the failing heart, for example cardiomyocyte hypertrophy, interstitial fibrosis and chamber remodelling. In this article, we review the evidence supporting the involvement of reactive oxygen species and redox signalling pathways in the development of cardiac hypertrophy and heart failure, with a particular focus on the NADPH oxidase family of superoxide-generating enzymes which appear to be especially important in redox signalling.

Goal orientation and its relationship to the business family, and family business performance, within the UK’s family owned and managed mid-sized businesses

Mid-Sized Businesses (MSBs) are defined by the Department for Business, Innovation and Skills (BIS) as having a sales turnover of between £25 million and £500 million. A key gap in family firm/business research and literature to date is, understanding the role and importance of non-financial objectives (such as family harmony, tradition and business longevity), and the role the family plays in creating a wide set of business performance objectives (both financial and non-financial) in these businesses. This dissertation contributes to filling this knowledge gap by drawing on Family Systems Theory applied in a business context, and within an overarching Resource Based View (RBV) of the firm.

Strategies for sustaining manufacturing competitiveness:comparative case studies in Australia and Sweden

Purpose - The purpose of this paper is to report an investigation of local sustainable production in Australia and Sweden aimed at exploring the factors contributing to survival and competitiveness of manufacturing companies. Design/methodology/approach - In Australia, six companies were studied in 2010, with comparisons being made with three of them from earlier projects. In Sweden, eight manufacturing companies were studied on two occasions 30 years apart, in 1980 and 2010. To provide a valid comparative perspective a common format for data collection and analysis was used. Findings - There has been a shift in the nature of competition in both Sweden and Australia due to an increasing complexity of the global business environment as well as changes in technology and customer expectations. Despite the differences in country context, the findings suggest that all the manufacturing companies have a good awareness of the elements of the market environment and the relationships with their competitive strategy. However, in general, the Swedish companies have more experience of managing the risks and benefits from operating in the international environment. Research limitations/implications - The results of the research are based on a relatively small sample of case companies in a limited number of industrial sectors. There are methodology implications for future research in the area. Practical implications - The research results have practical implications for the manufacturing industry, especially for companies operating in a competitive international environment. Originality/value - The paper is based on original case research and comparative analysis of data from different geographical contexts. It contributes to both theory and management practice about the strategic resources, decision choices, competitive environments and firm values needed to address external market demands as well as in building internal capabilities.

Survival in the pre-senile dementia frontotemporal lobar degeneration with TDP-43 proteinopathy:effects of genetic, demographic and neuropathological variables

Factors associated with survival were studied in 84 neuropathologically documented cases of the pre-senile dementia frontotemporal dementia lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP). Kaplan-Meier survival analysis estimated mean survival as 7.9 years (range: 1-19 years, SD = 4.64). Familial and sporadic cases exhibited similar survival, including progranulin (GRN) gene mutation cases. No significant differences in survival were associated with sex, disease onset, Braak disease stage, or disease subtype, but higher survival was associated with lower post-mortem brain weight. Survival was significantly reduced in cases with associated motor neuron disease (FTLD-MND) but increased with Alzheimer's disease (AD) or hippocampal sclerosis (HS) co-morbidity. Cox regression analysis suggested that reduced survival was associated with increased densities of neuronal cytoplasmic inclusions (NCI) while increased survival was associated with greater densities of enlarged neurons (EN) in the frontal and temporal lobes. The data suggest that: (1) survival in FTLD-TDP is more prolonged than typical in pre-senile dementia but shorter than some clinical subtypes such as the semantic variant of primary progressive aphasia (svPPA), (2) MND co-morbidity predicts poor survival, and (3) NCI may develop early and EN later in the disease. The data have implications for both neuropathological characterization and subtyping of FTLD-TDP.

The role of law and ethics in developing business management as a profession

Currently, business management is far from being recognised as a profession. This paper suggests that a professional spirit should be developed which could function as a filter of commercial reasoning. Broadly, management will not be organised within the framework of a well-established profession unless formal knowledge, licensing, professional autonomy and professional codes of conduct are developed sufficiently. In developing business management as a profession, law may play a key role. Where the idea is that business management should be more professsionalised, managers must show that they are willing to adopt ethical values, while arriving at business decisions. The paper argues that ethics cannot survive without legal regulation, which, in turn, will not be supported by law unless lawyers can find alternative solutions to the large mechanisms of the official society, secured by the monopolised coercion of the nation state. From a micro perspective of law and business ethics, communities can be developed with their own conventions, rules and standards that are generated and sanctioned within the boundaries of the communities themselves.

Az ellátási láncban elfoglalt pozíció és a szolgálatosodás – üzleti modellek Európában (Supply chain position and servitization – business models in Europe)

A szerzők célja, hogy megvizsgálják, milyen kölcsönhatásban áll az ellátási láncban elfoglalt pozíció, valamint a szolgálatosodás szintje az európai termelővállalatoknál. Vizsgálatuk azt mutatja, hogy a globalizáció és a termelés nemzetközivé válása mindkét tényezőt jelentős mértékben befolyásolja. A termelés globalizációs trendjeinek megfelelően így a kelet-európai (fejlődő), illetve a nyugat-európai (fejlett) országokban eltérő üzleti modellek válnak dominánssá, amelyek különböző ellátásilánc-pozícióval és más-más szintű szolgáltatásnyújtással jellemezhetőek. A domináns üzleti modellek mellett természetesen más üzleti modellek is működőképesnek bizonyulhatnak a két vizsgált régióban. A létesítmények elhelyezésére, valamint az üzleti eredményességre vonatkozó mutatók elemzésbe történő bevonásával cikkük az Európában működő üzleti modellek kialakításának okára, valamint jövőbeli fenntarthatóságára is megpróbál választ adni. __________ The objective of this paper is to examine the relationship between supply chain position and level of servitization in European manufacturing companies. The analysis shows that globalization and internationalization of production has dramatic impact on both phenomena. Due to the globalization trends different business models became dominant in the less developed Eastern-European and the more developed Western European countries, which can be characterized by different supply chain position and servitization level. Certainly other business models can also be successful in the two regions. Involving facility location motivations and business performance indicators the article shed light on the reasons of why these business models came alive and how sustainable they can be.

Business relationships and relationships with stakeholders – Perception of Hungarian executives.

Relationships are crucial concepts in numerous management theoretical frameworks. Both stakeholder theory and IMP’s business network approach put business and non-business relations in the forefront. However, the two theories – stakeholder and business network – are seldom discussed together, and stakeholder theory rarely appears in the IMP literature. In this paper although we want to focus on supply chain relations we strive to conduct our analysis within a more general framework of stakeholder theory. In our research we observed and analyzed the mutual expectations related to various stakeholder groups – business partners (suppliers and buyers) among them.

Defining failure in the nonprofit organization: The case of four human service agencies

Private nonprofit human service organizations provide a spectrum of services that aim to resolve societal problems. Their failure may leave needed and desired services unprovided or not provided sufficiently to meet public demand. However, the concept of organizational failure has not been examined for the nonprofit organization. This research addresses the deficiency in the literatures of organization failure and nonprofit organizations.^ An eight category typology, developed from a review of the current literature and findings from expert interviews, is initially presented to define nonprofit organization failure. A multiple case study design is used to test the typology in four nonprofit human service delivery agencies. The case analysis reduces the typology to five types salient to nonprofit organization failure: input failure, legitimacy failure, adaptive failure, management failure and leadership failure.^ The resulting five category typology is useful to both theory builders and nonprofit practitioners. For theory development, the interaction of the failure types extends the literature and lays a foundation for a theory of nonprofit organization failure that diffuses management and leadership across all of the failure types, highlights management and leadership failure as collective functions shared by paid staff and the volunteer board of directors, and emphasizes the importance of organization legitimacy.^ From a practical perspective, the typology provides a tool for diagnosing failure in the nonprofit organization. Using the management indicators developed for the typology, a checklist of the warning signals of potential failure, emphasizing the key types of management and leadership, offers nonprofit decision makers a priori examination of an organization's propensity for failure. ^

Three essays on entrepreneurial motivation, entry, exit and monetary rewards

This dissertation analyzes rewards and motivations of self-employment. In light of recent research contributions of Barton Hamilton (2000), which find entrepreneurship not as financially rewarding as wage work, my dissertation attempts to both verify and explain this claim. The first essay proposes a theoretical model of evolution of erroneous earnings expectations on part of a nascent entrepreneur. Inability to observe, survey, and take into account all of the returns to entrepreneurship prior to business entry creates a biased set of beliefs on part of the potential entrants. Using Bayesian learning, a nascent entrepreneur starting out with correct perception of profit distribution arrives at erroneous beliefs by incorporating limited information collected from existing businesses. An observed distribution of surviving businesses would exhibit higher earnings because of previous, unobserved, business failure entrepreneur get an overly positive view of her profit potential. Hence, the chapter offers a unique method of modeling overconfidence. The second essay undertakes dynamic empirical comparison of earnings received by business owners and their wage counterparts. Using Survey of Income and Program Participation (SIPP) I examine both short and long run returns to entrepreneurship comparing theses rewards to wage earners returns. I pay particular attention to transitions into and out of business ownership. I estimate entire earnings distribution. To characterize dynamic aspect of changes to individuals’ earnings I split the income distribution into five income quintiles and follow survey participants over the period of seven years. I find that period-to-period transitions to be Markovian. I find business tenure to be short, business ownership is costly in the short and rewarding in the long run. The third essay considered different reporting schemes applied to the self-employed. It is another empirical investigation of entrepreneurial earning uses Panel Study of Income Dynamics (PSID). I find entrepreneurs while reporting lower than wage workers earnings enjoy significant consumption premiums. I observe evidence of income underreporting by entrepreneurs. This finding suggests a need for better earning comparison metrics and proposes to use consumption rather than income metrics for future comparisons.

NOTCH1 Gain of Function in Germ Cells Causes Failure of Spermatogenesis in Male Mice

NOTCH1 is a member of the NOTCH receptor family, a group of single-pass trans-membrane receptors. NOTCH signaling is highly conserved in evolution and mediates communication between adjacent cells. NOTCH receptors have been implicated in cell fate determination, as well as maintenance and differentiation of stem cells. In the mammalian testis expression of NOTCH1 in somatic and germ cells has been demonstrated, however its role in spermatogenesis was not clear. To study the significance of NOTCH1 in germ cells, we applied a cre/loxP approach in mice to induce NOTCH1 gain- or loss-of function specifically in male germ cells. Using a Stra8-icretransgene we produced mice with conditional activation of the NOTCH1 intracellular domain (NICD) in germ cells. Spermatogenesis in these mutants was progressively affected with age, resulting in decreased testis weight and sperm count. Analysis of downstream target genes of NOTCH1 signaling showed an increased expression of Hes5, with a reduction of the spermatogonial differentiation marker, Neurog3 expression in the mutant testis. Apoptosis was significantly increased in mouse germ cells with the corresponding elevation of pro-apoptotic Trp53 and Trp63genes' expression. We also showed that the conditional germ cell-specific ablation of Notch1 had no effect on spermatogenesis or male fertility. Our data suggest the importance of NOTCH signaling regulation in male germ cells for their survival and differentiation.

Engineering Highly-functional, Self-regenerative Skeletal Muscle Tissues with Enhanced Vascularization and Survival in Vivo

Tissue engineering of biomimetic skeletal muscle may lead to development of new therapies for myogenic repair and generation of improved in vitro models for studies of muscle function, regeneration, and disease. For the optimal therapeutic and in vitro results, engineered muscle should recreate the force-generating and regenerative capacities of native muscle, enabled respectively by its two main cellular constituents, the mature myofibers and satellite cells (SCs). Still, after 20 years of research, engineered muscle tissues fall short of mimicking contractile function and self-repair capacity of native skeletal muscle. To overcome this limitation, we set the thesis goals to: 1) generate a highly functional, self-regenerative engineered skeletal muscle and 2) explore mechanisms governing its formation and regeneration in vitro and survival and vascularization in vivo.

By studying myogenic progenitors isolated from neonatal rats, we first discovered advantages of using an adherent cell fraction for engineering of skeletal muscles with robust structure and function and the formation of a SC pool. Specifically, when synergized with dynamic culture conditions, the use of adherent cells yielded muscle constructs capable of replicating the contractile output of native neonatal muscle, generating >40 mN/mm2 of specific force. Moreover, tissue structure and cellular heterogeneity of engineered muscle constructs closely resembled those of native muscle, consisting of aligned, striated myofibers embedded in a matrix of basal lamina proteins and SCs that resided in native-like niches. Importantly, we identified rapid formation of myofibers early during engineered muscle culture as a critical condition leading to SC homing and conversion to a quiescent, non-proliferative state. The SCs retained natural regenerative capacity and activated, proliferated, and differentiated to rebuild damaged myofibers and recover contractile function within 10 days after the muscle was injured by cardiotoxin (CTX). The resulting regenerative response was directly dependent on the abundance of SCs in the engineered muscle that we varied by expanding starting cell population under different levels of basic fibroblast growth factor (bFGF), an inhibitor of myogenic differentiation. Using a dorsal skinfold window chamber model in nude mice, we further demonstrated that within 2 weeks after implantation, initially avascular engineered muscle underwent robust vascularization and perfusion and exhibited improved structure and contractile function beyond what was achievable in vitro.

To enhance translational value of our approach, we transitioned to use of adult rat myogenic cells, but found that despite similar function to that of neonatal constructs, adult-derived muscle lacked regenerative capacity. Using a novel platform for live monitoring of calcium transients during construct culture, we rapidly screened for potential enhancers of regeneration to establish that many known pro-regenerative soluble factors were ineffective in stimulating in vitro engineered muscle recovery from CTX injury. This led us to introduce bone marrow-derived macrophages (BMDMs), an established non-myogenic contributor to muscle repair, to the adult-derived constructs and to demonstrate remarkable recovery of force generation (>80%) and muscle mass (>70%) following CTX injury. Mechanistically, while similar patterns of early SC activation and proliferation upon injury were observed in engineered muscles with and without BMDMs, a significant decrease in injury-induced apoptosis occurred only in the presence of BMDMs. The importance of preventing apoptosis was further demonstrated by showing that application of caspase inhibitor (Q-VD-OPh) yielded myofiber regrowth and functional recovery post-injury. Gene expression analysis suggested muscle-secreted tumor necrosis factor-α (TNFα) as a potential inducer of apoptosis as common for muscle degeneration in diseases and aging in vivo. Finally, we showed that BMDM incorporation in engineered muscle enhanced its growth, angiogenesis, and function following implantation in the dorsal window chambers in nude mice.

In summary, this thesis describes novel strategies to engineer highly contractile and regenerative skeletal muscle tissues starting from neonatal or adult rat myogenic cells. We find that age-dependent differences of myogenic cells distinctly affect the self-repair capacity but not contractile function of engineered muscle. Adult, but not neonatal, myogenic progenitors appear to require co-culture with other cells, such as bone marrow-derived macrophages, to allow robust muscle regeneration in vitro and rapid vascularization in vivo. Regarding the established roles of immune system cells in the repair of various muscle and non-muscle tissues, we expect that our work will stimulate the future applications of immune cells as pro-regenerative or anti-inflammatory constituents of engineered tissue grafts. Furthermore, we expect that rodent studies in this thesis will inspire successful engineering of biomimetic human muscle tissues for use in regenerative therapy and drug discovery applications.

Cost-effectiveness of natriuretic peptide-based screening and collaborative care: a report from the STOP-HF (St Vincent's Screening TO Prevent Heart Failure) study

AIMS: Prevention of cardiovascular disease and heart failure (HF) in a cost-effective manner is a public health goal. This work aims to assess the cost-effectiveness of the St Vincent's Screening TO Prevent Heart Failure (STOP-HF) intervention.

METHODS AND RESULTS: This is a substudy of 1054 participants with cardiovascular risk factors [median age 65.8 years, interquartile range (IQR) 57.8:72.4, with 4.3 years, IQR 3.4:5.2, follow-up]. Annual natriuretic peptide-based screening was performed, with collaborative cardiovascular care between specialist physicians and general practitioners provided to patients with BNP levels >50 pg/mL. Analysis of cost per case prevented and cost-effectiveness per quality-adjusted life year (QALY) gained was performed. The primary clinical endpoint of LV dysfunction (LVD) with or without HF was reduced in intervention patients [odds ratio (OR) 0.60; 95% confidence interval (CI) 0.38-0.94; P = 0.026]. There were 157 deaths and/or emergency hospitalizations for major adverse cardiac events (MACE) in the control group vs. 102 in the intervention group (OR 0.68; 95% CI 0.49-0.93; P = 0.01). The cost per case of LVD/HF prevented was €9683 (sensitivity range -€843 to €20 210), whereas the cost per MACE prevented was €3471 (sensitivity range -€302 to €7245). Cardiovascular hospitalization savings offset increased outpatient and primary care costs. The cost per QALY gain was €1104 and the intervention has an 88% probability of being cost-effective at a willingness to pay threshold of €30 000.

CONCLUSION: Among patients with cardiovascular risk factors, natriuretic peptide-based screening and collaborative care reduced LVD, HF, and MACE, and has a high probability of being cost-effective.

TRIAL REGISTRATION: NCT00921960.

Natriuretic peptide-based screening and collaborative care for heart failure:the STOP-HF randomized trial

IMPORTANCE: Prevention strategies for heart failure are needed.

OBJECTIVE: To determine the efficacy of a screening program using brain-type natriuretic peptide (BNP) and collaborative care in an at-risk population in reducing newly diagnosed heart failure and prevalence of significant left ventricular (LV) systolic and/or diastolic dysfunction.

DESIGN, SETTING, AND PARTICIPANTS: The St Vincent's Screening to Prevent Heart Failure Study, a parallel-group randomized trial involving 1374 participants with cardiovascular risk factors (mean age, 64.8 [SD, 10.2] years) recruited from 39 primary care practices in Ireland between January 2005 and December 2009 and followed up until December 2011 (mean follow-up, 4.2 [SD, 1.2] years).

INTERVENTION: Patients were randomly assigned to receive usual primary care (control condition; n=677) or screening with BNP testing (n=697). Intervention-group participants with BNP levels of 50 pg/mL or higher underwent echocardiography and collaborative care between their primary care physician and specialist cardiovascular service.

MAIN OUTCOMES AND MEASURES: The primary end point was prevalence of asymptomatic LV dysfunction with or without newly diagnosed heart failure. Secondary end points included emergency hospitalization for arrhythmia, transient ischemic attack, stroke, myocardial infarction, peripheral or pulmonary thrombosis/embolus, or heart failure.

RESULTS: A total of 263 patients (41.6%) in the intervention group had at least 1 BNP reading of 50 pg/mL or higher. The intervention group underwent more cardiovascular investigations (control, 496 per 1000 patient-years vs intervention, 850 per 1000 patient-years; incidence rate ratio, 1.71; 95% CI, 1.61-1.83; P<.001) and received more renin-angiotensin-aldosterone system-based therapy at follow-up (control, 49.6%; intervention, 56.5%; P=.01). The primary end point of LV dysfunction with or without heart failure was met in 59 (8.7%) of 677 in the control group and 37 (5.3%) of 697 in the intervention group (odds ratio [OR], 0.55; 95% CI, 0.37-0.82; P = .003). Asymptomatic LV dysfunction was found in 45 (6.6%) of 677 control-group patients and 30 (4.3%) of 697 intervention-group patients (OR, 0.57; 95% CI, 0.37-0.88; P = .01). Heart failure occurred in 14 (2.1%) of 677 control-group patients and 7 (1.0%) of 697 intervention-group patients (OR, 0.48; 95% CI, 0.20-1.20; P = .12). The incidence rates of emergency hospitalization for major cardiovascular events were 40.4 per 1000 patient-years in the control group vs 22.3 per 1000 patient-years in the intervention group (incidence rate ratio, 0.60; 95% CI, 0.45-0.81; P = .002).

CONCLUSION AND RELEVANCE: Among patients at risk of heart failure, BNP-based screening and collaborative care reduced the combined rates of LV systolic dysfunction, diastolic dysfunction, and heart failure.

TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00921960.

Establishing an EGFR mutation screening service for non-small cell lung cancer - sample quality criteria and candidate histological predictors.

INTRODUCTION: EGFR screening requires good quality tissue, sensitivity and turn-around time (TAT). We report our experience of routine screening, describing sample type, TAT, specimen quality (cellularity and DNA yield), histopathological description, mutation result and clinical outcome. METHODS: Non-small cell lung cancer (NSCLC) sections were screened for EGFR mutations (M+) in exons 18-21. Clinical, pathological and screening outcome data were collected for year 1 of testing. Screening outcome alone was collected for year 2. RESULTS: In year 1, 152 samples were tested, most (72%) were diagnostic. TAT was 4.9 days (95%confidence interval (CI)=4.5-5.5). EGFR-M+ prevalence was 11% and higher (20%) among never-smoking women with adenocarcinomas (ADCs), but 30% of mutations occurred in current/ex-smoking men. EGFR-M+ tumours were non-mucinous ADCs and 100% thyroid transcription factor (TTF1+). No mutations were detected in poorly differentiated NSCLC-not otherwise specified (NOS). There was a trend for improved overall survival (OS) among EGFR-M+ versus EGFR-M- patients (median OS=78 versus 17 months). In year 1, test failure rate was 19%, and associated with scant cellularity and low DNA concentrations. However 75% of samples with poor cellularity but representative of tumour were informative and mutation prevalence was 9%. In year 2, 755 samples were tested; mutation prevalence was 13% and test failure only 5.4%. Although samples with low DNA concentration (2.2 ng/μL), the mutation rate was 9.2%. CONCLUSION: Routine epidermal growth factor receptor (EGFR) screening using diagnostic samples is fast and feasible even on samples with poor cellularity and DNA content. Mutations tend to occur in better-differentiated non-mucinous TTF1+ ADCs. Whether these histological criteria may be useful to select patients for EGFR testing merits further investigation.

Advanced Business Simulations-Incorporating business and process execution data

Key Performance Indicators (KPIs) and their predictions are widely used by the enterprises for informed decision making. Nevertheless , a very important factor, which is generally overlooked, is that the top level strategic KPIs are actually driven by the operational level business processes. These two domains are, however, mostly segregated and analysed in silos with different Business Intelligence solutions. In this paper, we are proposing an approach for advanced Business Simulations, which converges the two domains by utilising process execution & business data, and concepts from Business Dynamics (BD) and Business Ontologies, to promote better system understanding and detailed KPI predictions. Our approach incorporates the automated creation of Causal Loop Diagrams, thus empowering the analyst to critically examine the complex dependencies hidden in the massive amounts of available enterprise data. We have further evaluated our proposed approach in the context of a retail use-case that involved verification of the automatically generated causal models by a domain expert.