The release of genome sequence information is revolutionising the study of helminth parasites by providing important datasets for comparative genomics, allowing the comprehensive analysis of signalling pathways that regulate nematode development. Much of the current knowledge of nematode signalling pathways is based on studies of the free-living model Caenorhabditis elegans. The recent availability of the Trichinella spiralis genome sequence presented an opportunity to study signalling pathways of this, and other, parasitic nematodes, providing a phylum-wide overview of a given signalling pathway. The transforming growth factor-β (TGF-β) ligands are a superfamily of structurally related polypeptides that regulate a wide range of cellular processes in animal tissues. Since the discovery that the TGF-β daf-7 regulates the developmentally-arrested dauer stage in C. elegans, there is the potential for TGF-β signalling to regulate developmental arrest, parasite development and even host-parasite communication in T. spiralis and other nematodes. In the present study, thirteen genes encoding putative TGF-β signalling components, from T. spiralis, have been identified and characterised. Phylogenetic analysis suggests that daf-7 is not conserved beyond C. elegans and that functional extrapolation from C. elegans biology to distantly-related nematodes is difficult. Furthermore, the analysis herein shows a high level of divergence among parasitic nematode TGF-βs. Since the last common ancestor of T. spiralis and C. elegans was the ancestor of the entire nematode phylum, these comparisons allow speculation on the TGF-β signalling networks of the ancestral nematode and provide information on the emergence of TGF-β signalling in animals. ES products from T. spiralis are shown to be capable of interacting directly with mammalian cell receptors and utilise their receptors to control gene expression in vitro. This presents the possibility that these TGF-β ligands may play a part in the formation and maintenance of the host-parasite complex.

Genes, pathways & transcription factors involved in probiotic mediated resolution of gut inflammation in IL10-KO mice an animal model of Inflammatory Bowel Disease. An integrated Gene, Protein and Bioinformatics Approach The IL10-KO mouse is a model of human inflammatory bowel disease (IBD), used to study host microbial interactions and potential therapeutics. Affymetrix microarray and proteomics analysis on colon of WT and IL10-KO mice and cecum of IL10-KO and WT mice orally administered with and without probiotic VSL#3 was performed and identified signalling pathways and transcription factors relevant to gut inflammation and anti-inflammatory probiotics. Results were validated by Real-time PCR, immunocytochemistry, proteomics, histopathology and via pathway signature analysis of publicly available microarray data. Changes in metabolically active bacteria in response to VSL#3 were assessed with DGGE. Inflammation in IL10-KO mice was characterised by up-regulation of immune/inflammatory and down-regulation of lipid/xenobiotic metabolism and PPAR signalling. VSL#3 resolved inflammation in the cecum inducing down-regulation of genes in immune/inflammatory pathways, decrease in the number of CCL5 positive T cells and up-regulation of galectin2, known to trigger apoptosis of T cells. VSL#3 induced up-regulation of PPARα/PPAR signalling and lipid/xenobiotic metabolism, antagonistic to NFB signalling and reduced metabolically active bifidobacteria. Analysis of publicly available data showed results were relevant to human IBD, indicated that antigen processing/presentation is up-regulated early on during development of colitis in IL10-KO mice, identified the potential of PPARα/PPAR signalling to induce down-regulation of CCL5, CD3 & antigen processing/presentation, and the potential of the xenobiotic metabolism to induce down-regulation of cytokine-cytokine interaction & mitosis. As VSL#3 treatment of IL10-KO mice induced up-regulation of PPARα/PPAR signalling and xenobiotic metabolism these results provide a possible mechanistic explanation for the VSL#3 induced down-regulation of CCL5, CD3, antigen processing/presentation, cytokine-cytokine interaction and mitosis in the cecum of VSL#3 treated IL10-KO mice.

This research project was inspired by a survey that was designed to help an organization determine how well it was doing in its efforts to empower associates and achieve a goal of continuous improvement. Initial review of the survey created suspicion that the survey was not built around the appropriate dimensions to accurately measure the level of empowerment in organizations. As such, the survey was psychometrically analyzed to determine the validity of the instrument as a measure of empowerment. Additionally, an extensive review of the literature was performed to determine new dimensions that would most accurately measure empowerment. Eight dimensions (culture, trust, accountability, leadership, ability, commitment, responsibility, and communication) were put forth as the most appropriate to measure empowerment. Subject matter experts with knowledge and experience in the area of organizational empowerment reviewed the new dimensions for accuracy and fit with the original survey items.

SOCIOECONOMIC FACTORS AND THE 2014-16 EBOLA VIRUS DISEASE OUTBREAK IN GUINEA, LIBERIA, AND SIERRA LEONE INTRODUCTION: Ebola virus disease (EVD) is an infectious disease transmitted by close contact with an estimated case fatality rate fluctuating around 50%. The most affected countries by the 2013-16 West African Ebola outbreak were Guinea, Liberia, and Sierra Leone. These countries reported a total of 28616 probable, suspected and confirmed cases. However, we are still learning about the sociodemographic factors that contributed to the outbreak characteristics at the subnational level. METHODS: Data were collected from the World Health Organization, Demographic Health Surveys, and Global Data Lab for 37 districts (8 for Guinea, 15 for Liberia, and 14 for Sierra Leone). The outcome of interest was epidemic size at the district level for Guinea, Liberia, and Sierra Leone (cumulative number of EVD patient confirmed and probable cases). Socio-demographic predictors included household density, sanitation level, mobility, and wealth status. We also controlled for the timing of the start of the outbreak across districts. Pearson’s correlation and multiple linear regression were employed in our analyses. Model building was informed by a review of the relevant literature. Sensitivity analyses were conducted to assess the impact of potential outliers. RESULTS: In the final multivariable regression model, wealth status and household density were positively associated with the epidemic size while sanitation level and the difference in the outbreak start dates were negatively associated with the outcome. These results did not change in the sensitivity analyses. The regression model explained 57% of the variance in epidemic size (Adj R-Sq=0.57), with the largest contribution from the international wealth index (semi-partial R-square=0.22). CONCLUSION: District sociodemographic characteristics such as household density, wealth and sanitation levels contributed to the EVD outbreak in Guinea, Liberia, and Sierra Leone, which is in agreement with recent studies. However, further research should consider other sociodemographic indicators as well as the role of migration and connectivity among regions.

Introduction Coronary artery disease (CAD) is the most common cause of death in Europe and North America and early detection of atherosclerosis is a clinical priority. Diagnosis of CAD remains conventional angiography, although recent technology has introduced non-invasive imaging of coronary arteries using computed tomographic coronary angiography (CTCA), which enables the detection and quantification of coronary artery calcification (CAC). CAC forms within the arterial wall and is usually found in or adjacent to atherosclerotic plaques and is consequently known as sub-clinical atherosclerosis.  The conventional cardiovascular (CV) risk factors used to quantify the estimated 10-year coronary event risk comprise dyslipidaemia, hypertension, diabetes mellitus, obesity, smoking and family history of CAD. Nevertheless, their relationship with significant (>50%) stenosis, their interaction with the CAC score and their predictive ability for CAC presence and extent has not been fully determined in symptomatic patients.   Methods   For Papers 1-4 we took patients from the Euro-CCAD cohort, an international study established in 2009 in Umeå, Sweden. The study data gave us the CAC score and the CV risk factor profile in 6309 patients, together with angiography results for a reduced cohort of 5515 patients. In Papers 1 and 2 we assessed the risk factors for significant stenosis, including CAC as a risk factor. Paper 2 carried out this analysis by geographical region: Europe vs USA and northern vs southern Europe. Paper 3 investigated the CV risk factors for CAC presence, stratified by age and gender, while Paper 4 assessed the CV risk factors for CAC extent, stratified by gender.  In paper 5 we carried out a systematic review and meta-analysis of all studies of the risk factor predictors of CAC presence, extent and progression in symptomatic patients. From a total of 884 studies, we identified 10 which fitted our inclusion criteria, providing us with a total of 15,769 symptomatic patients. All 10 were entered in the systematic review and 7 were also eligible for the meta-analysis.   Results Paper 1:           Among risk factors alone, the most powerful predictors of significant coronary stenosis were male gender followed by diabetes, smoking, hypercholesterolaemia, hypertension, family history of CAD and age; only obesity was not predictive. When including the log transformed CAC score as a risk factor, this proved the most powerful predictor of >50% stenosis, but hypercholesterolaemia and hypertension lost their predictive ability. The conventional risk factors alone were 70% accurate in predicting significant stenosis, the log transformed CAC score alone was 82% accurate but the combination was 84% accurate and improved both sensitivity and specificity.  Paper 2:           Despite some striking differences in profiles between Europe and the USA, the most important risk factors for >50% stenosis in both groups were male gender followed by diabetes. When the log CAC score was included as a risk factor, it became by far the most important predictor of >50% stenosis in both continents, followed by male gender. In the northern vs southern Europe comparison the result was similar, with the log CAC score being the most important predictor of >50% stenosis in both regions, followed by male gender.  Paper 3:           Independent predictors of CAC presence in males and females were age, dyslipidaemia, hypertension, diabetes and smoking, with the addition of family history of CAD in males; obesity was not predictive in either gender. The most important predictors of CAC presence in males were dyslipidaemia and diabetes, while among females the most important predictors of CAC presence were diabetes followed by smoking. When analysed by age groups, in both males and females aged <70 years, diabetes, hypertension and dyslipidaemia were predictive, with diabetes being the strongest; in females aged <70 years, smoking was also predictive. Among those aged ≥70 years, the results are completely different, with only dyslipidaemia being predictive in males but smoking and diabetes were predictive in females.  Paper 4:           In the total cohort, age, male gender, diabetes, obesity, family history of CAD and number of risk factors predicted an increasing CAC score, with the most important being male gender and diabetes. In males, hypertension and dyslipidaemia were also predictive, although diabetes was the most important predictor. Diabetes was similarly the most important risk factor in females, followed by age and number of risk factors. Among patients with CAC, hypertension, dyslipidaemia and diabetes predicted CAC extent in both males and females, with diabetes being the strongest predictor in males followed by dyslipidaemia, while diabetes was also the strongest predictor in females, followed by hypertension. Quantile regression confirmed the consistent predictive ability of diabetes.  Paper 5:           In the systematic review, age was strongly predictive of both CAC presence and extent but not of CAC progression. The results for CAC presence were overwhelmed by data from one study of almost 10,000 patients, which found that white ethnicity, diabetes, hypertension and obesity were predictive of CAC presence but not male gender, dyslipidaemia, family history or smoking. With respect to CAC extent, only male gender and hypertension were clearly predictive, while in the one study of CAC progression, only diabetes and hypertension were predictive. In the meta-analysis, hypertension followed by male gender, diabetes and age were predictive of CAC presence, while for CAC extent mild-moderate CAC was predicted by hypertension alone, whereas severe CAC was predicted by hypertension followed by diabetes.   Conclusion Our investigation of the Euro-CCAD cohort showed that the CAC score is far more predictive of significant stenosis than risk factors alone, followed by male gender and diabetes, and there was little benefit to risk factor assessment over and above the CAC score for >50% stenosis prediction. Regional variations made little difference to this result. Independent predictors of CAC presence were dyslipidaemia and diabetes in males and diabetes followed by smoking in females. The risk factor predictors alter at age 70. The most important risk factor predictors of CAC extent were male gender and diabetes; when analysed by gender, diabetes was the most important in both males and females. Our studies have consistently shown the strong predictive ability of male gender in the total cohort and diabetes in males and females and this is reflected in the meta-analysis, which also found hypertension to be independently predictive. Interestingly, dyslipidaemia does not appear to be a strong risk factor.

Tendon, ligament, and joint capsular injuries represent 45% of the 32 million musculoskeletal injuries each year in the United States. Tendon injuries are especially common, requiring surgical repair for the shoulder’s rotator cuff tendons (51,000 per year), the Achilles tendon (44,000 per year), and the patellar tendon (42,000 per year). Tissue engineering provides an alternative in the treatment of tendon lesions through replacement of an injured tendon segment. The purpose of this study was to develop a tendon construct in vitro for clinical reconstructive surgery. Human tenocytes were isolated from hamstring tendons of patients who had undergone anterior cruciate ligament (ACL) surgeries. These tenocytes were cultured with culture media (α-MEM) supplemented with various concentrations of foetal bovine serum (FBS) (0%, 1%, 5% and 10%) and in the presence of different growth factors such as PDGFBB (0, 5, 10 and 50ng/ml), basic FGF (0, 5, 10 and 50ng/ml), IGF-1 (0, 10 and 50ng/ml) and TGFβ-3 (0, 1 and 10ng/ml). Fractional factorial design was utilized to select the combinations of growth factors that supported the following criteria: (1) the maximal cell proliferation with a minimum differentiation of the tenocytes in the presence of the least concentration of FBS possible and (2) maintaining cell survival and promoting tenocyte differentiation in FBS free culture media. The results have shown that: (i) The tenocyte cell number when cultured for 14 days in media supplemented with 1% FBS, 50ng/ml PDGFBB and 50ng/ml bFGF matched that of the positive control (10% FBS-treated cells). Not only was the collagen synthesis significantly reduced in these growth factor-treated cultures compared to positive control tenocytes, but also a significant inhibition of the mRNA expression of various tenocyte differentiation markers (Scleraxis, Tenomodulin, Collagen type I and Decorin) was evident. IGF-1 did not promote significant cell proliferation under low serum conditions but did induce tenocyte differentiation in vitro. Examination of the cell morphology confirmed that tenocytes were capable of less differentiation when cultured with 1% FBS, 50ng/ml PDGFBB and 50ng/ml bFGF, this culture condition was termed “the expansion phase”; (ii) The cell survival was maintained for up to 14 days in serum free culture media supplemented with 50ng/ml IGF-1 and 10ng/ml TGFβ-3 whilst cell differentiation was enhanced and evident by the increase in collagen synthesis and cell morphology. Furthermore, mRNA expression of the aforementioned cell differentiation markers were also significantly increased, this culture condition was termed “the differentiation phase”; (iii) By combining the culture condition optimized for the expansion and differentiation phase sequentially, it was possible to maintain a long term 2-D tenocyte culture in vitro for up to 28 days. In these cultures, the presence of dense collagen formation was clearly evident whereas in positive control group (10% FBS group) such observation was not noted even after prolonged culturing period of up to 45 days. These results suggested that the sequential treatment of tenocytes with growth factors identified for the expansion and differentiation phases was significantly more superior than the standard 10% FBS treatment; (iv) By combining the expansion and differentiation phases optimized for the 2-D cultures, it was possible to maintain human tenocytes in a 3-D scaffold (Bombix silk) for up to 28 days. The tendon like constructs that were formed, macroscopically and microscopically resembled the human hamstring tendon. This observation was confirmed by using H&E staining, scanning electron microscopy and by detecting collagen type I immunohistochemically; (v) It was possible to further validate these findings using in vivo animal models. This was undertaken by implanting the tenocytes cultured sequentially in the defined culture media described above, into the quadriceps of Balb/c nude male mice for up to 30 days. The nature and specificity of the tendon like structure that was formed after this implantation was investigated by H&E staining and immunohistochemistry. It was revealed that the culture conditions that were optimized during the expansion and differentiation phases were suitable for generating a human tendon reconstruct; a finding which is of significance due to its potential for tendon reconstructive surgery.

In recent years y-y angular correlations have been very useful in confirming the spins of excited nuclear states. Angular correlation techniques have also been employed to study the electric and magnetic character of excited nuclear states. With these things in mind, it was decided to design, construct, and test a precision angular correlation table.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / OBJECTIVE: An estimated 20-30% of patients with primary Clostridium difficile infection (CDI) develop recurrent CDI (rCDI) within 2 weeks of completion of therapy. While the actual mechanism of recurrence remains unknown, a variety of risk factors have been suggested and studied. The aim of this systematic review and meta-analysis was to evaluate current evidence on the risk factors for rCDI. DESIGN: We searched MEDLINE and 5 other databases for subject headings and text related to rCDI. All studies investigating risk factors of rCDI in a multivariate model were eligible. Information on study design, patient population, and assessed risk factors were collected. Data were combined using a random-effects model and pooled relative risk ratios (RRs) were calculated. RESULTS: A total of 33 studies (n=18,530) met the inclusion criteria. The most frequent independent risk factors associated with rCDI were age≥65 years (risk ratio [RR], 1.63; 95% confidence interval [CI], 1.24-2.14; P=.0005), additional antibiotics during follow-up (RR, 1.76; 95% CI, 1.52-2.05; P<.00001), use of proton-pump inhibitors (PPIs) (RR, 1.58; 95% CI, 1.13-2.21; P=.008), and renal insufficiency (RR, 1.59; 95% CI, 1.14-2.23; P=.007). The risk was also greater in patients previously on fluoroquinolones (RR, 1.42; 95% CI, 1.28-1.57; P<.00001). CONCLUSIONS: Multiple risk factors are associated with the development of rCDI. Identification of modifiable risk factors and judicious use of antibiotics and PPI can play an important role in the prevention of rCDI.

The p53 family of transcription factors, which comprises the products of the TP53, TP63 and TP73 genes, is at the hub of different signalling pathways that determine the fate of a cell. In vitro, the p53 family posses a tumour suppressive function. However, in vivo, although p53-deficient mice develop spontaneous tumours, p73 and p63 KO animals show defects in neuronal and epidermal development, respectively. The ASPP family of proteins also consists of three members: ASPP 1, ASPP2 and iASPP. They are evolutionarily conserved binding partners and specific regulators of p53-, p63- and p73- mediated apoptosis in vitro. In contrast to ASPPl and ASPP2, the biological significance of iASPP in vivo and the possible interaction with p53 family members remains unclear, and it is the subject of this study. To investigate the role of iASPP in vivo, a transgenic mouse model was generated in which iASPP expression is controlled by the Cre/loxP recombination system. Deletion of iASPP resulted in the development of a cardiocutaneous disorder which displayed features of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), defects in hair follicle position and impaired epithelial stratification. iASPP loss resulted in a sudden, premature and arrhythmic mode of death of all iASPP mutant mice. iASPP deficiency induced p53-dependent apoptosis in embryonic hearts and dilation of the right ventricle, however, the inactivation of p53 alleles only rescued the fibro-fatty deposits present in iASPP KO hearts. Mechanistically, iASPP locates at the polar ends of cardiomyocytes where it matches the location of other proteins known to be involved in the etiology of ARVC and in maintaining the integrity of intercalated discs. Loss of iASPP also resulted in increased differentiation of primary keratinocytes both in vitro and in vivo. Consistent with this, iASPP bound p63 and inhibited the transcriptional activity of both T Ap63a and T Ap63α and ΔNp63 in vitro, and regulated the expression level ofp63-regulated genes such as envoplakin. These results demonstrate that iASPP prevents cardiocutaneous disorder through its ability to inhibit p53-induced apoptosis and to influence the integrity of intercalated disc. Moreover, iASPP is also an important regulator of p63 and is involved in controlling epithelial stratification in vivo.

Little is currently known about the spatial-temporal dynamics of dengue epidemics in arid areas. This study assesses dengue outbreaks that occurred in two arid cities of Mexico, Hermosillo and Navojoa, located in northern state of Sonora. Laboratory confirmed dengue cases from Hermosillo (N=2730) and Navojoa (N=493) were geocoded by residence and assigned neighborhood-level characteristics from the 2010 Mexican census. Kernel density and Space-time cluster analysis was performed to detect high density areas and space-time clusters of dengue. Ordinary Least Square regression was used to assess the changing socioeconomic characteristics of cases over the course of the outbreaks. Both cities exhibited contiguous patterns of space-time clustering. Initial areas of dissemination were characterized in both cities by high population density, high percentage of occupied houses, and lack of healthcare. Future research and control efforts in these regions should consider these space-time and socioeconomic patterns.