The entrepreneurial process

This chapter revolves around research-based insights into the entrepreneurial process. By is meant the process of setting up a new business activity resulting in a new market offer. This new offer may be made by a new or an existing firm, although the main focus here is on the start-up of new, independent firms. Further, the new offer may be innovative, bringing to the market something that was not offered before or imita­tive i.e., a new competitor enters the market with products or services very similar to what other firms are already offering. Although the lsatter type of process may be less complex and also have less market impact, it still entails most of the steps that typically have to be taken in order to get a business up and running. If successful, it also shares, at least to some degree, the consequences that signify entrepreneurial processes: - it gives consumers new choice alternatives - it gives incumbent firms reason to shape up - it attracts additional followers to enter the market, further reinforcing the first two effects (Davidsson, 2004). Besides, imitatlve starr-ups outnumber by far innovative ones (Reynolds et al., 2003; Samuelsson and Davidsson, 2009).

The intraocular pressure response to dehydration : a pilot study

This study was designed to determine the Intraocular Pressure (IOP) response to differing levels of dehydration. Seven males participated in a 90 minute treadmill walk (5 km/h and 1 % grade) in both a cool (22 °C) and hot (43 °C) climate. At Baseline and at 30 minute intervals measurements of IOP, by tonometery, and indicators of hydration status (nude weight and plasma osmolality (Posm)) were taken. Body temperature and heart rate were also measured at these time points. Statistically significant interactions (time point (4) by trial (2)) were observed for IOP (F = 10.747, p = 0.009) and body weight loss (F = 50.083, p < 0.001) to decrease, and Posm (F = 34.867, p < 0.001) to increase, by a significantly greater amount during the hot trial compared to the cool. A univariate general linear model showed a significant relationship between IOP and body weight loss (F = 37.63, p < 0.001) and Posm (F = 38.53, p < 0.001). A significant interaction was observed for body temperature (F = 20.908, p < 0.001) and heart rate (F = 25.487, p < 0.001) between the trials and time points, but there was negligible association between these variables and IOP (Pearson correlation coefficient < ±0.5). The present study provides evidence to suggest that IOP is influenced by hydration status.

Weight gain and nutritional intake in obese pregnant women : some clues for intervention

Aim:  Maternal obesity is associated with increased risk of adverse outcomes for mothers and offspring. Strategies to better manage maternal obesity are urgently needed; however, there is little evidence to assist the development of nutrition interventions during antenatal care. The present study aimed to assess maternal weight gain and dietary intakes of overweight and obese women participating in an exercise trial. Results will assist the development of interventions for the management of maternal overweight and obesity. Methods:  Fifty overweight and obese pregnant women receiving antenatal care were recruited and provided dietary and weight data at baseline (12 weeks), 28 weeks, 36 weeks gestation and 6 weeks post-partum. Data collected were compared with current nutritional and weight gain recommendations. Associations used Pearson's correlation coefficient, and ANOVA assessed dietary changes over time, P < 0.05. Results:  Mean prepregnancy body mass index was 34.4 ± 6.6 kg/m2. Gestational weight gain was 10.6 ± 6 kg with a wide range (−4.1 to 23.0 kg). 52% of women gained excessive weight (>11.5 kg for overweight and >9 kg for obese women). Gestational weight gain correlated with post-partum weight retention (P < 0.001). Dietary intakes did not change significantly during pregnancy. No women achieved dietary fat or dietary iron recommendations, only 11% achieved adequate dietary folate, and 38% achieved adequate dietary calcium. Very few women achieved recommended food group servings for pregnancy, with 83% consuming excess servings of non-core foods. Conclusion:  Results provide evidence that early intervention and personalised support for obese pregnant women may help achieve individualised goals for maternal weight gain and dietary adequacy, but this needs to be tested in a clinical setting.

Closed system isolation and scalable expansion of human placental mesenchymal stem cells

Mesenchymal stem cells (MSC) are emerging as a leading cellular therapy for a number of diseases. However, for such treatments to become available as a routine therapeutic option, efficient and cost-effective means for industrial manufacture of MSC are required. At present, clinical grade MSC are manufactured through a process of manual cell culture in specialized cGMP facilities. This process is open, extremely labor intensive, costly, and impractical for anything more than a small number of patients. While it has been shown that MSC can be cultivated in stirred bioreactor systems using microcarriers, providing a route to process scale-up, the degree of numerical expansion achieved has generally been limited. Furthermore, little attention has been given to the issue of primary cell isolation from complex tissues such as placenta. In this article we describe the initial development of a closed process for bulk isolation of MSC from human placenta, and subsequent cultivation on microcarriers in scalable single-use bioreactor systems. Based on our initial data, we estimate that a single placenta may be sufficient to produce over 7,000 doses of therapeutic MSC using a large-scale process.

Stromal upregulation of lateral epithelial adhesions : gene expression analysis of signalling pathways in prostate epithelium

BACKGROUND: Stromal signalling increases the lateral cell adhesions of prostate epithelial cells grown in 3D culture. The aim of this study was to use microarray analysis to identify significant epithelial signalling pathways and genes in this process. METHODS: Microarray analysis was used to identify genes that were differentially expressed when epithelial cells were grown in 3D Matrigel culture with stromal co-culture compared to without stroma. Two culture models were employed: primary epithelial cells (ten samples) and an epithelial cell line (three experiments). A separate microarray analysis was performed on each model system and then compared to identify tissue-relevant genes in a cell line model. RESULTS: TGF beta signalling was significantly ranked for both model systems and in both models the TGF beta signalling gene SOX4 was significantly down regulated. Analysis of all differentially expressed genes to identify genes that were common to both models found several morphology related gene clusters; actin binding (DIAPH2, FHOD3, ABLIM1, TMOD4, MYH10), GTPase activator activity (BCR, MYH10), cytoskeleton (MAP2, MYH10, TMOD4, FHOD3), protein binding (ITGA6, CD44), proteinaceous extracellular matrix (NID2, CILP2), ion channel/ ion transporter activity (CACNA1C, CACNB2, KCNH2, SLC8A1, SLC39A9) and genes associated with developmental pathways (POFUT1, FZD2, HOXA5, IRX2, FGF11, SOX4, SMARCC1). CONCLUSIONS: In 3D prostate cultures, stromal cells increase lateral epithelial cell adhesions. We show that this morphological effect is associated with gene expression changes to TGF beta signalling, cytoskeleton and anion activity.

Stroma regulates increased epithelial lateral cell adhesion in 3D culture : a role for actin/cadherin dynamics

BACKGROUND: Cell shape and tissue architecture are controlled by changes to junctional proteins and the cytoskeleton. How tissues control the dynamics of adhesion and cytoskeletal tension is unclear. We have studied epithelial tissue architecture using 3D culture models and found that adult primary prostate epithelial cells grow into hollow acinus-like spheroids. Importantly, when co-cultured with stroma the epithelia show increased lateral cell adhesions. To investigate this mechanism further we aimed to: identify a cell line model to allow repeatable and robust experiments; determine whether or not epithelial adhesion molecules were affected by stromal culture; and determine which stromal signalling molecules may influence cell adhesion in 3D epithelial cell cultures. METHODOLOGY/PRINCIPAL FINDINGS: The prostate cell line, BPH-1, showed increased lateral cell adhesion in response to stroma, when grown as 3D spheroids. Electron microscopy showed that 9.4% of lateral membranes were within 20 nm of each other and that this increased to 54% in the presence of stroma, after 7 days in culture. Stromal signalling did not influence E-cadherin or desmosome RNA or protein expression, but increased E-cadherin/actin co-localisation on the basolateral membranes, and decreased paracellular permeability. Microarray analysis identified several growth factors and pathways that were differentially expressed in stroma in response to 3D epithelial culture. The upregulated growth factors TGFβ2, CXCL12 and FGF10 were selected for further analysis because of previous associations with morphology. Small molecule inhibition of TGFβ2 signalling but not of CXCL12 and FGF10 signalling led to a decrease in actin and E-cadherin co-localisation and increased paracellular permeability. CONCLUSIONS/SIGNIFICANCE: In 3D culture models, paracrine stromal signals increase epithelial cell adhesion via adhesion/cytoskeleton interactions and TGFβ2-dependent mechanisms may play a key role. These findings indicate a role for stroma in maintaining adult epithelial tissue morphology and integrity.

Polarized fluid movement and not cell death, creates luminal spaces in adult prostate epithelium

There are two predominant theories for lumen formation in tissue morphogenesis: cavitation driven by cell death, and membrane separation driven by epithelial polarity. To define the mechanism of lumen formation in prostate acini, we examined both theories in several cell lines grown in three-dimensional (3D) Matrigel culture. Lumen formation occurred early in culture and preceded the expression of cell death markers for apoptosis (active caspase 3) and autophagy (LC-3). Active caspase 3 was expressed by very few cells and inhibition of apoptosis did not suppress lumen formation. Despite LC-3 expression in all cells within a spheroid, this was not associated with cell death. However, expression of a prostate-secretory protein coincided with lumen formation and subsequent disruption of polarized fluid movement led to significant inhibition of lumen formation. This work indicates that lumen formation is driven by the polarized movement of fluids and proteins in 3D prostate epithelial models and not by cavitation.

Lynch syndrome-associated breast cancers: clinicopathologic characteristics of a case series from the colon cancer family registry

Purpose: The recognition of breast cancer as a spectrum tumor in Lynch syndrome remains controversial. The aim of this study was to explore features of breast cancers arising in Lynch syndrome families. Experimental Design: This observational study involved 107 cases of breast cancer identified from the Colorectal Cancer Family Registry (Colon CFR) from 90 families in which (a) both breast and colon cancer co-occurred, (b) families met either modified Amsterdam criteria, or had at least one early-onset (<50 years) colorectal cancer, and (c) breast tissue was available within the biospecimen repository for mismatch repair (MMR) testing. Eligibility criteria for enrollment in the Colon CFR are available online. Breast cancers were reviewed by one pathologist. Tumor sections were stained for MLH1, PMS2, MSH2, and MSH6, and underwent microsatellite instability testing. Results: Breast cancer arose in 35 mutation carriers, and of these, 18 (51%) showed immunohistochemical absence of MMR protein corresponding to the MMR gene mutation segregating the family. MMR-deficient breast cancers were more likely to be poorly differentiated (P = 0.005) with a high mitotic index (P = 0.002), steroid hormone receptor–negative (estrogen receptor, P = 0.031; progesterone receptor, P = 0.022), and to have peritumoral lymphocytes (P = 0.015), confluent necrosis (P = 0.002), and growth in solid sheets (P < 0.001) similar to their colorectal counterparts. No difference in age of onset was noted between the MMR-deficient and MMR-intact groups. Conclusions: MMR deficiency was identified in 51% of breast cancers arising in known mutation carriers. Breast cancer therefore may represent a valid tissue option for the detection of MMR deficiency in which spectrum tumors are lacking

Licensed to sell : product placement in the James Bond film series

As one of the longest running franchises in cinema history, and with its well-established use of product placements, the James Bond film series provides an ideal framework within which to measure and catalogue the number and types of products used within a particular timeframe. This case study will draw upon extensive content analysis of the James Bond film series in order to chart the evolution of product placement across the franchise's 50 year history.

Timed Up and Go Tests in cardiac rehabilitation : reliability and comparison with the 6-minute walk test

PURPOSE: To test the reliability of Timed Up and Go Tests (TUGTs) in cardiac rehabilitation (CR) and compare TUGTs to the 6-Minute Walk Test (6MWT) for outcome measurement. METHODS: Sixty-one of 154 consecutive community-based CR patients were prospectively recruited. Subjects undertook repeated TUGTs and 6MWTs at the start of CR (start-CR), postdischarge from CR (post-CR), and 6 months postdischarge from CR (6 months post-CR). The main outcome measurements were TUGT time (TUGTT) and 6MWT distance (6MWD). RESULTS: Mean (SD) TUGTT1 and TUGTT2 at the 3 assessments were 6.29 (1.30) and 5.94 (1.20); 5.81 (1.22) and 5.53 (1.09); and 5.39 (1.60) and 5.01 (1.28) seconds, respectively. A reduction in TUGTT occurred between each outcome point (P ≤ .002). Repeated TUGTTs were strongly correlated at each assessment, intraclass correlation (95% CI) = 0.85 (0.76–0.91), 0.84 (0.73–0.91), and 0.90 (0.83–0.94), despite a reduction between TUGTT1 and TUGTT2 of 5%, 5%, and 7%, respectively (P ≤ .006). Relative decreases in TUGTT1 (TUGTT2) occurred from start-CR to post-CR and from start-CR to 6 months post-CR of −7.5% (−6.9%) and −14.2% (−15.5%), respectively, while relative increases in 6MWD1 (6MWD2) occurred, 5.1% (7.2%) and 8.4% (10.2%), respectively (P < .001 in all cases). Pearson correlation coefficients for 6MWD1 to TUGTT1 and TUGTT2 across all times were −0.60 and −0.68 (P < .001) and the intraclass correlations (95% CI) for the speeds derived from averaged 6MWDs and TUGTTs were 0.65 (0.54, 0.73) (P < .001). CONCLUSIONS: Similar relative changes occurred for the TUGT and the 6MWT in CR. A significant correlation between the TUGTT and 6MWD was demonstrated, and we suggest that the TUGT may provide a related or a supplementary measurement of functional capacity in CR.

Estimating the effects of ambient temperature on mortality : methodological challenges and proposed solutions

The health impacts of exposure to ambient temperature have been drawing increasing attention from the environmental health research community, government, society, industries, and the public. Case-crossover and time series models are most commonly used to examine the effects of ambient temperature on mortality. However, some key methodological issues remain to be addressed. For example, few studies have used spatiotemporal models to assess the effects of spatial temperatures on mortality. Few studies have used a case-crossover design to examine the delayed (distributed lag) and non-linear relationship between temperature and mortality. Also, little evidence is available on the effects of temperature changes on mortality, and on differences in heat-related mortality over time. This thesis aimed to address the following research questions: 1. How to combine case-crossover design and distributed lag non-linear models? 2. Is there any significant difference in effect estimates between time series and spatiotemporal models? 3. How to assess the effects of temperature changes between neighbouring days on mortality? 4. Is there any change in temperature effects on mortality over time? To combine the case-crossover design and distributed lag non-linear model, datasets including deaths, and weather conditions (minimum temperature, mean temperature, maximum temperature, and relative humidity), and air pollution were acquired from Tianjin China, for the years 2005 to 2007. I demonstrated how to combine the case-crossover design with a distributed lag non-linear model. This allows the case-crossover design to estimate the non-linear and delayed effects of temperature whilst controlling for seasonality. There was consistent U-shaped relationship between temperature and mortality. Cold effects were delayed by 3 days, and persisted for 10 days. Hot effects were acute and lasted for three days, and were followed by mortality displacement for non-accidental, cardiopulmonary, and cardiovascular deaths. Mean temperature was a better predictor of mortality (based on model fit) than maximum or minimum temperature. It is still unclear whether spatiotemporal models using spatial temperature exposure produce better estimates of mortality risk compared with time series models that use a single site’s temperature or averaged temperature from a network of sites. Daily mortality data were obtained from 163 locations across Brisbane city, Australia from 2000 to 2004. Ordinary kriging was used to interpolate spatial temperatures across the city based on 19 monitoring sites. A spatiotemporal model was used to examine the impact of spatial temperature on mortality. A time series model was used to assess the effects of single site’s temperature, and averaged temperature from 3 monitoring sites on mortality. Squared Pearson scaled residuals were used to check the model fit. The results of this study show that even though spatiotemporal models gave a better model fit than time series models, spatiotemporal and time series models gave similar effect estimates. Time series analyses using temperature recorded from a single monitoring site or average temperature of multiple sites were equally good at estimating the association between temperature and mortality as compared with a spatiotemporal model. A time series Poisson regression model was used to estimate the association between temperature change and mortality in summer in Brisbane, Australia during 1996–2004 and Los Angeles, United States during 1987–2000. Temperature change was calculated by the current day's mean temperature minus the previous day's mean. In Brisbane, a drop of more than 3 �C in temperature between days was associated with relative risks (RRs) of 1.16 (95% confidence interval (CI): 1.02, 1.31) for non-external mortality (NEM), 1.19 (95% CI: 1.00, 1.41) for NEM in females, and 1.44 (95% CI: 1.10, 1.89) for NEM aged 65.74 years. An increase of more than 3 �C was associated with RRs of 1.35 (95% CI: 1.03, 1.77) for cardiovascular mortality and 1.67 (95% CI: 1.15, 2.43) for people aged < 65 years. In Los Angeles, only a drop of more than 3 �C was significantly associated with RRs of 1.13 (95% CI: 1.05, 1.22) for total NEM, 1.25 (95% CI: 1.13, 1.39) for cardiovascular mortality, and 1.25 (95% CI: 1.14, 1.39) for people aged . 75 years. In both cities, there were joint effects of temperature change and mean temperature on NEM. A change in temperature of more than 3 �C, whether positive or negative, has an adverse impact on mortality even after controlling for mean temperature. I examined the variation in the effects of high temperatures on elderly mortality (age . 75 years) by year, city and region for 83 large US cities between 1987 and 2000. High temperature days were defined as two or more consecutive days with temperatures above the 90th percentile for each city during each warm season (May 1 to September 30). The mortality risk for high temperatures was decomposed into: a "main effect" due to high temperatures using a distributed lag non-linear function, and an "added effect" due to consecutive high temperature days. I pooled yearly effects across regions and overall effects at both regional and national levels. The effects of high temperature (both main and added effects) on elderly mortality varied greatly by year, city and region. The years with higher heat-related mortality were often followed by those with relatively lower mortality. Understanding this variability in the effects of high temperatures is important for the development of heat-warning systems. In conclusion, this thesis makes contribution in several aspects. Case-crossover design was combined with distribute lag non-linear model to assess the effects of temperature on mortality in Tianjin. This makes the case-crossover design flexibly estimate the non-linear and delayed effects of temperature. Both extreme cold and high temperatures increased the risk of mortality in Tianjin. Time series model using single site’s temperature or averaged temperature from some sites can be used to examine the effects of temperature on mortality. Temperature change (no matter significant temperature drop or great temperature increase) increases the risk of mortality. The high temperature effect on mortality is highly variable from year to year.

A hybrid association rule mining approach for characterizing network traffic behaviour

Understanding network traffic behaviour is crucial for managing and securing computer networks. One important technique is to mine frequent patterns or association rules from analysed traffic data. On the one hand, association rule mining usually generates a huge number of patterns and rules, many of them meaningless or user-unwanted; on the other hand, association rule mining can miss some necessary knowledge if it does not consider the hierarchy relationships in the network traffic data. Aiming to address such issues, this paper proposes a hybrid association rule mining method for characterizing network traffic behaviour. Rather than frequent patterns, the proposed method generates non-similar closed frequent patterns from network traffic data, which can significantly reduce the number of patterns. This method also proposes to derive new attributes from the original data to discover novel knowledge according to hierarchy relationships in network traffic data and user interests. Experiments performed on real network traffic data show that the proposed method is promising and can be used in real applications. Copyright2013 John Wiley & Sons, Ltd.

Development and validation of a new self-report instrument for measuring sedentary behaviors and light-intensity physical activity in adults

Background Low levels of physical activity and high levels of sedentary behavior (SB) are major public health concerns. This study was designed to develop and validate the 7-day Sedentary (S) and Light Intensity Physical Activity (LIPA) Log (7-day SLIPA Log), a self-report measure of specific daily behaviors. Method To develop the log, 62 specific SB and LIPA behaviors were chosen from the Compendium of Physical Activities. Face-to-face interviews were conducted with 32 sedentary volunteers to identify domains and behaviors of SB and LIPA. To validate the log, a further 22 sedentary adults were recruited to wear the GT3X for 7 consecutive days and nights. Results Pearson correlations (r) between the 7-day SLIPA Log and GT3X were significant for sedentary (r =.86, p < 0.001), for LIPA (r =.80, p < 0.001). Lying and sitting postures were positively correlated with GT3X output (r =.60 and r =.64, p < 0.001, respectively). No significant correlation was found for standing posture (r =.14, p = 0.53).The kappa values between the 7-day SLIPA Log and GT3X variables ranged from 0.09–0.61, indicating poor to good agreement. Conclusion The 7-day SLIPA Log is a valid self-report measure of SB and LIPA in specific behavioral domains.

Circulating microRNAs involved in multiple sclerosis

Multiple sclerosis (MS) is an immune-mediated, demyelinating and neurodegenerative disease of the central nervous system. After traumatic brain injury, it is the leading cause of neurology disability in young adults. Considerable advances have been made in identifying genes involved in MS but the genetic and phenotypic complexity associated with this disease significantly hinders any progress. A novel class of small RNA molecules, microRNAs (miRNAs) has acquired much attention because they regulate the expression of up to 30% of protein-coding genes and may play a pivotal role in the development of many, if not all, complex diseases. Seven published studies investigated miRNAs from peripheral blood mononuclear cells, CD4+, CD8+ T cell, B lymphocytes, peripheral blood leukocytes, whole blood and brain astrocytes with MS risk. The absence of MS studies investigating plasma miRNA prompted the current investigation of identifying a circulating miRNA signature in MS. We conducted a microarray analysis of over 900 known miRNA transcripts from plasma samples collected from four MS individuals and four sex-aged and ethnicity matched healthy controls. We identified six plasma miRNA (miR-614, miR-572, miR-648, miR-1826, miR-422a and miR-22) that were significantly up-regulated and one plasma miRNA (miR-1979) that was significantly down-regulated in MS individuals. Both miR-422a and miR-22 have previously been implicated in MS. The present study is the first to show a circulating miRNA signature involved in MS that could serve as a potential prognostic and diagnostic biomarker for MS.