Genetic analysis of white facial and leg markings in the Swiss Franches-Montagnes Horse Breed

White markings and spotting patterns in animal species are thought to be a result of the domestication process. They often serve for the identification of individuals but sometimes are accompanied by complex pathological syndromes. In the Swiss Franches-Montagnes horse population, white markings increased vastly in size and occurrence during the past 30 years, although the breeding goal demands a horse with as little depigmented areas as possible. In order to improve selection and avoid more excessive depigmentation on the population level, we estimated population parameters and breeding values for white head and anterior and posterior leg markings. Heritabilities and genetic correlations for the traits were high (h(2) > 0.5). A strong positive correlation was found between the chestnut allele at the melanocortin-1-receptor gene locus and the extent of white markings. Segregation analysis revealed that our data fit best to a model including a polygenic effect and a biallelic locus with a dominant-recessive mode of inheritance. The recessive allele was found to be the white trait-increasing allele. Multilocus linkage disequilibrium analysis allowed the mapping of the putative major locus to a chromosomal region on ECA3q harboring the KIT gene.

Clinical Use of Quantitative Computed Tomography–Based Finite Element Analysis of the Hip and Spine in the Management of Osteoporosis in Adults: the 2015 ISCD Official Positions—Part II

The International Society for Clinical Densitometry (ISCD) has developed new official positions for the clinical use of quantitative computed tomography (QCT)-based finite element analysis of the spine and hip. The ISCD task force for QCT reviewed the evidence for clinical applications and presented a report with recommendations at the 2015 ISCD Position Development Conference. Here we discuss the agreed upon ISCD official positions with supporting medical evidence, rationale, controversy, and suggestions for further study. Parts I and III address the clinical use of QCT of the hip, and the clinical feasibility of existing techniques for opportunistic screening of osteoporosis using CT scans obtained for other diagnosis such as colonography was addressed.

Anatomic characteristics and clinical implications of angiographic coronary thrombus: insights from a patient-level pooled analysis of SYNTAX, RESOLUTE, and LEADERS Trials.

BACKGROUND The distribution of thrombus-containing lesions (TCLs) in an all-comer population admitted with a heterogeneous clinical presentation (stable, ustable angina, or an acute coronary syndrome) and treated with percutaneous coronary intervention is yet unclear, and the long-term prognostic implications are still disputed. This study sought to assess the distribution and prognostic implications of coronary thrombus, detected by coronary angiography, in a population recruited in all-comer percutaneous coronary intervention trials. METHODS AND RESULTS Patient-level data from 3 contemporary coronary stent trials were pooled by an independent academic research organization (Cardialysis, Rotterdam, the Netherlands). Clinical outcomes in terms of major adverse cardiac events (major adverse cardiac events, a composite of death, myocardial infarction, and repeat revascularization), death, myocardial infarction, and repeated revascularization were compared between patients with and without angiographic TCL. Preprocedural TCL was present in 257 patients (5.8%) and absent in 4193 (94.2%) patients. At 3-year follow-up, there was no difference for major adverse cardiac events (25.3 versus 25.4%; P=0.683); all-cause death (7.4 versus 6.8%; P=0.683); myocardial infarction (5.8 versus 6.0%; P=0.962), and any revascularizations (17.5 versus 17.7%; P=0.822) between patients with and without TCL. The comparison of outcomes in groups weighing the jeopardized myocardial by TCL also did not show a significant difference. TCL were seen more often in the first 2 segments of the right (43.6%) and left anterior descending (36.8%) coronary arteries. The association of TCL and bifurcation lesions was present in 40.1% of the prespecified segments. CONCLUSIONS TCL involved mainly the proximal coronary segments and did not have any effect on clinical outcomes. A more detailed thrombus burden quantification is required to investigate its prognostic implications. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00114972, NCT01443104, NCT00617084.

Post-colonial (American?) English Presence on the North-Western Pacific Island of Kosrae: A cross-linguistic analysis of the overlaps and divergences of Kosraean English compared to standard American English

Kosrae is the most remote island of the Federated States of Micronesia (FSM), with a population of less than 7,000 inhabitants, located in the Pacific Ocean between Hawaii and Guam. FSM is an independent sovereign nation consisting of four states in total: Pohnpei, Chuuk, Yap, and Kosrae. Having passed through the hands of Spain, Germany and Japan, the United States gained administrative control of FSM after WWII, as commissioned by the UN. The FSM became an independent nation in 1986 while still retaining affiliation with the US under a ‘Compact of Free Association’. Now both Kosraean and English are considered to be the two official languages and the variety of Kosraean English which has arisen proves for an interesting comparative study. In order to obtain the relevant data, I spent three months on the island of Kosrae, interviewing 90 local speakers, ranging in age (16-70), occupation, sex and time spent off island. The 45 minute long interviews were informal but supported by participant information to capture relevant data and conversations were guided in a way that aimed to reveal language and cultural attitudes. With reference to these samples, I examine the effects of American English on the language use in Kosrae. This paper aims to present a broad analysis of phonological, morphosyntactic and pragmatic features, such as pro-dropping, discourse markers and other practices in order to demonstrate the similarities and differences between the two varieties, which are coming to shape the variety developing on Kosrae. Having transcribed conversations using the tool Elan, I will put particular focus on [h] deletion and insertion, a rare occurrence found in a variety of post-colonial American English which I believe is of particular interest. I assess the presence of English in Kosrae with reference to sociological influences, past and present. First, I discuss the extralinguistic factors which have shaped the English that is currently used on Kosrae, including migration between US and FSM, and English as a language of administration, social media usage and visual media presence. Secondly, I assess the use of English in this community in light of Schneider’s (2007) ‘Dynamic Model’, with reference to America’s contribution as an ‘exploitation colony’ as defined by Mufwene (2001). Finally, an overview of the salient linguistic characteristics of Kosraean English, based on the data collected will be presented and compared to features associated with standard American English in view of examining overlap and divergence. The overall objective is to present a cross-linguistic description of a hitherto unexamined English emerging in a postcolonial environment with a juxtaposed contact variety. Mufwene, Salikoko S. 2001. The ecology of language evolution. Cambridge: Cambridge University Press. Schneider, E. (2007). Postcolonial Englishes. Cambridge: Cambridge University Press. Segal, H.G. (1989) Kosrae, The Sleeping Lady Awakens. Kosrae: Kosrae Tourist Division, Dept. Of Conservation and Development. Keywords: American English, Global English, Pacific English, Morphosyntactic, Phonological, Variation, Discourse

Temporal analysis of PI-3kinase and MAPK signal transduction during skeletal muscle overload

Skeletal muscles can adapt to increased mechanical forces (or loading) by increasing the size and strength of the muscle. Knowledge of the molecular mechanisms by which muscle responds to increased loading may lead to the discovery of novel treatment strategies for muscle wasting and frailty. The objective of this research was to examine the temporal associations between the activation of specific signaling pathway intermediates and their potential upstream regulator(s) in response to increased muscle loading. Previous work has demonstrated that focal adhesion kinase (FAK) activity is increased in overloaded hypertrophying skeletal muscle. Thus FAK is a candidate for transducing the loading stimulus in skeletal muscle, potentially by activating phosphatidylinositol 3-kinase (PI3K) and members of the mitogen-activated protein kinase (MAPK) family. However, it was unknown if muscle overload would result in activation of PI3K or the MAPKs. Thus, this work seeks to characterized the temporal response of (1) MAPK phosphorylation (including Erk 2, p38 MAPK and JNK), (2) PI3K activity, and (3) FAK tyrosine phosphorylation in response to 24 hours of compensatory overload in the rat soleus and plantaris muscles. In both muscles, overload resulted in transient Increases in the phosphorylation state of Erk2 and JNK, which peaked within the first hour of overload and returned to baseline thereafter. In contrast, p38 MAPK phosphorylation remained elevated throughout the entire 24-hour overload period. Moreover, overload increased PI3K activity only, in the plantaris and only at 12 hours. Moreover, 24 hours of overload induced a significant increase in total protein content in the plantaris but not the soleus. Thus an increase in total muscle protein content within the 24-hour loading period was observed only in muscle exhibiting increased PI3K activity. Surprisingly, FAK tyrosine phosphorylation was not increased during the overload period in either muscle, indicating that PI3K activation and increased MAPK phosphorylation were independent of increased FAK tyrosine phosphorylation. In summary, increased PI3K activity and sustained elevation of p38 MAPK phosphorylation were associated with muscle overload, identifying these pathways as potential mediators of the early hypertrophic response to skeletal muscle overload. This suggests that stimuli or mechanisms that activate these pathways may reduce/minimize muscle wasting and frailty. ^

From Truth to Justice: How Does Amnesty Factor In? A Comparative Analysis of South Africa and Sierra Leone's Truth and Reconciliation Commissions

Truth and Reconciliation Commissions (TRC) have emerged in the last few decades as a mechanism for a state to overcome widespread, grave, human rights violations. There are numerous approaches to a TRC all with an ultimate goal: that formerly warring factions, perpetrators, witnesses, and victims can move forward as a united people. I propose that the provision of amnesty is critical to the success of a TRC. I hypothesize that the form of amnesty chosen (i.e. blanket v. conditional amnesty) determines the revelation of truth and realization of justice, which in turn dictates whether a TRC can achieve reconciliation. To test this hypothesis, I use two case studies: South Africa, which has utilized conditional amnesty, and Sierra Leone which has employed blanket amnesty. I create a model for measuring reconciliation. I can then look at the implications of both types of amnesty and assess which, in the end, is more effective. My overarching conclusion is that the provision of conditional amnesty is more effective than blanket amnesty in achieving reconciliation. Ultimately, I hope that this conclusion can be generalized to other TRCs.

A cross-sectional analysis of physical activity and obesity in inner city Houston Texas Mexican American youth

Obesity prevalence among children and adolescents is rising. It is one of the most attributable causes of hospitalization and death. Overweight and obese children are more likely to suffer from associated conditions such as hypertension, dyslipidemia, chronic inflammation, increased blood clotting tendency, endothelial dysfunction, hyperinsulinemia, and asthma. These children and adolescents are also more likely to be overweight and obese in adulthood. Interestingly, rates of obesity and overweight are not evenly distributed across racial and ethnic groups. Mexican American youth have higher rates of obesity and are at higher risk of becoming obese than non-Hispanic black and non-Hispanic white children. ^ Methods. This cross-sectional study describes the association between rates of obesity and physical activity in a sample of 1313 inner-city Mexican American children and adolescents (5-19 years of age) in Houston, Texas. This study is important because it will contribute to our understanding of childhood and adolescent obesity in this at-risk population. ^ Data from the Mexican American Feasibility Cohort using the Mano a Mano questionnaire are used to describe this population's status of obesity and physical activity. An initial sample taken from 5000 households in inner city Houston Texas was used as the baseline for this prospective cohort. The questionnaire was given in person to the participants to complete (or to parents for younger children) at a home visit by two specially trained bilingual interviewers. Analysis comprised prevalence estimates of obesity represented as percentile rank (<85%= normal weight, >85%= at risk, >95%= obese) by age and gender. The association between light, moderate, strenuous activity, and obesity was also examined using linear regression. ^ Results. Overall, 46% of this Mexican American Feasibility cohort is overweight or obese. The prevalence for children in the 6-11 age range (53.2%) was significantly greater than that reported from NHANES, 1999–2002 data (39.4%). Although the percentage of overweight and obese among the 12-19 year olds was greater than that reported in NHANES (38.5% versus 38.6%) this difference was not statistically significant. ^ A significant association between BMI and sit time and moderate physical activity (both p < 0.05) found in this sample. For males, this association was significant for moderate physical activity (p < 0.01). For the females, this association was significant for BMI and sit time (p < 0.05). These results need to be interpreted in the light of design and measurement limitations. ^ Conclusion. This study supports observations that the inner city Houston Texas Mexican American child and adolescent population is more overweight and obese than nationally reported figures, and that there are positive relationships between BMI, activity levels, and sit time in this population. This study supports the need for public health initiatives within the Houston Hispanic community. ^

A space-time analysis of reported shigellosis and salmonellosis cases in Texas from 2000 to 2004

Background. The purpose of this study was to describe the risk factors and demographics of persons with salmonellosis and shigellosis and to investigate both seasonal and spatial variations in the occurrence of these infections in Texas from 2000 to 2004, utilizing time series analyses and the geographic information system digital mapping methods. ^ Methods. Spatial Analysis: MapInfo software was used to map the distribution of age-adjusted rates of reported shigellosis and salmonellosis in Texas from 2000–2004 by zip codes. Census data on above or below poverty level, household income, highest level of educational attainment, race, ethnicity, and urban/rural community status was obtained from the 2000 Decennial Census for each zip code. The zip codes with the upper 10% and lower 10% were compared using t-tests and logistic regression to determine whether there were any potential risk factors. ^ Temporal analysis. Seasonal patterns in the prevalence of infections in Texas from 2000 to 2003 were determined by performing time-series analysis on the numbers of cases of salmonellosis and shigellosis. A linear regression was also performed to assess for trends in the incidence of each disease, along with auto-correlation and multi-component cosinor analysis. ^ Results. Spatial analysis: Analysis by general linear model showed a significant association between infection rates and age, with young children aged less than 5 and those aged 5–9 years having increased risk of infection for both disease conditions. The data demonstrated that those populations with high percentages of people who attained a higher than high school education were less likely to be represented in zip codes with high rates of shigellosis. However, for salmonellosis, logistic regression models indicated that when compared to populations with high percentages of non-high school graduates, having a high school diploma or equivalent increased the odds of having a high rate of infection. ^ Temporal analysis. For shigellosis, multi-component cosinor analyses were used to determine the approximated cosine curve which represented a statistically significant representation of the time series data for all age groups by sex. The shigellosis results show 2 peaks, with a major peak occurring in June and a secondary peak appearing around October. Salmonellosis results showed a single peak and trough in all age groups with the peak occurring in August and the trough occurring in February. ^ Conclusion. The results from this study can be used by public health agencies to determine the timing of public health awareness programs and interventions in order to prevent salmonellosis and shigellosis from occurring. Because young children depend on adults for their meals, it is important to increase the awareness of day-care workers and new parents about modes of transmission and hygienic methods of food preparation and storage. ^

A qualitative analysis of leadership styles and the selection of quality improvement in primary care practice

In the Practice Change Model, physicians act as key stakeholders, people who have both an investment in the practice and the capacity to influence how the practice performs. This leadership role is critical to the development and change of the practice. Leadership roles and effectiveness are an important factor in quality improvement in primary care practices.^ The study conducted involved a comparative case study analysis to identify leadership roles and the relationship between leadership roles and the number and type of quality improvement strategies adopted during a Practice Change Model-based intervention study. The research utilized secondary data from four primary care practices with various leadership styles. The practices are located in the San Antonio region and serve a large Hispanic population. The data was collected by two ABC Project Facilitators from each practice during a 12-month period including Key Informant Interviews (all staff members), MAP (Multi-method Assessment Process), and Practice Facilitation field notes. This data was used to evaluate leadership styles, management within the practice, and intervention tools that were implemented. The chief steps will be (1) to analyze if the leader-member relations contribute to the type of quality improvement strategy or strategies selected (2) to investigate if leader-position power contributes to the number of strategies selected and the type of strategy selected (3) and to explore whether the task structure varies across the four primary care practices.^ The research found that involving more members of the clinic staff in decision-making, building bridges between organizational staff and clinical staff, and task structure are all associated with the direct influence on the number and type of quality improvement strategies implemented in primary care practice.^ Although this research only investigated leadership styles of four different practices, it will offer future guidance on how to establish the priorities and implementation of quality improvement strategies that will have the greatest impact on patient care improvement. ^

Longitudinal dyadic data analysis of stroke survivors and their spousal caregivers

Approximately 795,000 new and recurrent strokes occur each year. Because of the resulting functional impairment, stroke survivors are often discharged into the care of a family caregiver, most often their spouse. This dissertation explored the effect that mutuality, a measure of the perceived positive aspects of the caregiving relationship, had on the stress and depression of 159 stroke survivors and their spousal caregivers over the first 12 months post discharge from inpatient rehabilitation. Specifically, cross-lagged regression was utilized to investigate the dyadic, longitudinal relationship between caregiver and stroke survivor mutuality and caregiver and stroke survivor stress over time. Longitudinal meditational analysis was employed to examine the mediating effect of mutuality on the dyads’ perception of family function and caregiver and stroke survivor depression over time.^ Caregivers’ mutuality was found to be associated with their own stress over time but not the stress of the stroke survivor. Caregivers who had higher mutuality scores over the 12 months of the study had lower perceived stress. Additionally, a partner effect of stress for the stroke survivor but not the caregiver was found, indicating that stroke survivors’ stress over time was associated with caregivers’ stress but caregivers’ stress over time was not significantly associated with the stress of the stroke survivor.^ This dissertation did not find mutuality to mediate the relationship between caregivers’ and stroke survivors’ perception of family function at baseline and their own or their partners’ depression at 12 months as hypothesized. However, caregivers who perceived healthier family functioning at baseline and stroke survivors who had higher perceived mutuality at 12 months had lower depression at one year post discharge from inpatient rehabilitation. Additionally, caregiver mutuality at 6 months, but not at baseline or 12 months, was found to be inversely related to caregiver depression at 12 months.^ These findings highlight the interpersonal nature of stress in the context of caregiving, especially among spousal relationships. Thus, health professionals should encourage caregivers and stroke survivors to focus on the positive aspects of the caregiving relationship in order to mitigate stress and depression. ^

Mixture modeling for joint analysis of survival, discrete, and continuous data

Mixture modeling is commonly used to model categorical latent variables that represent subpopulations in which population membership is unknown but can be inferred from the data. In relatively recent years, the potential of finite mixture models has been applied in time-to-event data. However, the commonly used survival mixture model assumes that the effects of the covariates involved in failure times differ across latent classes, but the covariate distribution is homogeneous. The aim of this dissertation is to develop a method to examine time-to-event data in the presence of unobserved heterogeneity under a framework of mixture modeling. A joint model is developed to incorporate the latent survival trajectory along with the observed information for the joint analysis of a time-to-event variable, its discrete and continuous covariates, and a latent class variable. It is assumed that the effects of covariates on survival times and the distribution of covariates vary across different latent classes. The unobservable survival trajectories are identified through estimating the probability that a subject belongs to a particular class based on observed information. We applied this method to a Hodgkin lymphoma study with long-term follow-up and observed four distinct latent classes in terms of long-term survival and distributions of prognostic factors. Our results from simulation studies and from the Hodgkin lymphoma study demonstrated the superiority of our joint model compared with the conventional survival model. This flexible inference method provides more accurate estimation and accommodates unobservable heterogeneity among individuals while taking involved interactions between covariates into consideration.^

Analysis of p53 function and regulation

p53 is a tumor suppressor gene that is the most frequent target inactivated in cancers. Overexpression of wild-type p53 in rat embryo fibroblasts suppresses foci formation by other cooperating oncogenes. Introduction of wild-type p53 into cells that lack p53 arrests them at the G1/S boundary and reverses the transformed phenotype of some cells. The function of p53 in normal cells is illustrated by the ability of p53 to arrest cells at G1 phase of the cell cycle upon exposure to DNA-damaging agents including UV-irradiation and biosynthesis inhibitors.^ Since the amino acid sequence of p53 suggested that it may function as a transcription factor, we used GAL4 fusion assays to test that possibility. We found that wild-type p53 could specifically activate transcription when anchored by the GAL4 DNA binding domain. Mutant p53s, which have lost the ability to suppress foci formation by other oncogenes, were not able to activate transcription in this assay. Thus, we established a direct correlation between the tumor suppression and transactivation functions of p53.^ Having learned that p53 was a transcriptional activator, we next sought targets of p53 activation. Because many transcription factors regulate their own expression, we tested whether p53 had this autoregulatory property. Transient expression of wild-type p53 in cells increased the levels of endogenous p53 mRNA. Cotransfection of p53 together with a reporter bearing the p53 promoter confirmed that wild-type p53 specifically activates its own promoter. Deletion analysis from both the 5$\sp\prime$ and 3$\sp\prime$ ends of the promoter minimized the region responsible for p53 autoregulation to 45 bp. Methylation interference identified nucleotides involved in protein-DNA interaction. Mutations within this protected site specifically eliminated the response of the promoter to p53. In addition, multiple copies of this element confer responsiveness to wild-type p53 expression. Thus, we identified a F53 responsive element within the p53 promoter.^ The presence of a consensus NF-$\kappa$B site in the p53 promoter suggested that NF-KB may regulate p53 expression. Gel-shift experiments showed that both the p50 homodimer and the p50/p65 heterodimer bind to the p53 promoter. In addition, the p65 subunit of NF-$\kappa$B activates the p53 promoter in transient transfection experiments. TNF $\alpha$, a natural NF-$\kappa$B inducer, also activates the p53 promoter. Both p65 activation and TNF $\alpha$ induction require an intact NF-$\kappa$B site in the p53 promoter. Since NF-$\kappa$B activation occurs as a response to stress and p53 arrests cells in G1/S, where DNA repair occurs, activation of p53 by NF-$\kappa$B could be a mechanism by which cells recover from stress.^ In conclusion, we provided the first data that wild-type p53 functions as a transcriptional activator, whereas mutant p53 cannot. The correlation between growth suppression and transcriptional activation by p53 implies a pathway of tumor suppression. We have analyzed upstream components of the pathway by the identification of both p53 and NF-$\kappa$B as regulators of the p53 promoter. ^

Functional analysis of p53 phosphorylation and a p53 hot spot mutation

The tumor suppressor p53 is a phosphoprotein which functions as a transcriptional activator. By monitoring the transcriptional activity, we studied how p53 functions is regulated in relation to cell growth and contact inhibition. When cells were arrested at G1 phase of the cell cycle by contact inhibition, we found that p53 transactivation function was suppressed. When contact inhibition was overridden by cyclin E overexpression which stimulates cell cycle progression, p53 function was restored. This observation led to the development of a cell density assay to study the regulation of p53 function during cell cycle for the functional significance of p53 phosphorylation. The murine p53 is phosphorylated at serines 7, 9, 12, 18, 37, 312 and 389. To understand the role of p53 phosphorylation, we generated p53 constructs encoding serine-to-alanine or serine-to-glutamate mutations at these codons. The transcriptional activity were measured in cells capable of contact inhibition. In low-density cycling cells, no difference in transcriptional activity was found between wild type p53 and any of the mutants. In contact-inhibited cells, however, only mutations of p53 at serine 389 resulted in altered responses to cell cycle arrest and to cyclin E overexpression. The mutant with serine-to-glutamate substitution at codon 389 retained its function in contact inhibited cells. Cyclin E overexpression in these cells induced p53 phosphorylation at serine 389. Furthermore, we showed that phosphorylation at serine 389 regulates p53 DNA binding activity. Our findings implicate that phosphorylation is an important mechanism for p53 activation.^ p53 is the most frequently mutated gene in human tumors. To study the mechanism of p53 inactivation by mutations, we carried out detailed analysis of a murine p53 mutation with an arginine-to-tryptophane substitution at codon 245. The corresponding human p53 mutation at amino acid 248 is the most frequently mutated codon in tumors. We showed that this mutant is inactive in suppressing focus formation, binding to DNA and transactivation. Structural analysis revealed that this mutant assumes the wild type protein conformation. These findings define a novel class of p53 mutations and help to understand structure-function relationship of p53. ^