University of Texas Southwestern Medical Center

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    Pediatric Cardiac Surgery in Developing Countries of Africa: Current State and Future Direction
    (2014-04-11) Lee, Kyongjune Benjamin; Mihalic, Angela; Abdelnaby, Abier; Nwariaku, Fiemu; Jones, Eugene
    Surgical services are often the most neglected part of medical care in developing countries of Africa. Cardiac surgical care is even less accessible in comparison due to its need for highly skilled individuals and sophisticated equipment. This lack of proper care places the pediatric population affected by cardiac conditions without much hope for the future. Combining my clinical experience overseas with an extensive literature review, I examined the current state of pediatric cardiac surgery in several developing countries of Africa, and possible future efforts for establishing a viable cardiac surgery centers in low-resource settings. I examined in detail the two most prominent cardiac conditions in the developing world: congenital heart disease and rheumatic heart disease. The review of literature showed that cardiac surgical care is a serious need in many developing countries. It also revealed that with careful long-term international collaboration between institutions, a self-sustainable and economically viable cardiac surgical center with reasonable outcome can be established.
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    Antagonistic Roles of miR-199a-3p/miR-214 and the miR-200 Family in the Regulation of Uterine Contractility During Pregnancy and Labor
    (2014-02-03) Williams, Koriand'r; Hammer, Robert; Mendelson, Carole; Mahendroo, Mala; Olson, Eric
    Progesterone (P4) and estradiol-17β (E2) play critical and opposing roles in regulating myometrial quiescence and contractility during pregnancy and labor (Kamel et al., 2010). While these contrasting hormonal effects are likely mediated via differential regulation of inflammatory and contractile genes, the underlying mechanisms remain incompletely understood. Recently, we discovered that miR-200 family members, miR-200b and miR-429, and their target, transcription factor ZEB1, serve as P4/progesterone receptor (PR)-mediated regulators of uterine quiescence during pregnancy (Renthal et al., 2010). In the present study, we identified a novel role for another miR-200 family member, miR-200a, to enhance local metabolism of P4 in myometrium and, thus, decrease PR function during the progression towards labor (Williams et. al., 2012a). This occurs via miR-200a repression of signal transducer and activator of transcription (STAT)5b, a transcriptional repressor of the P4-metabolizing enzyme 20α-hydroxysteroid dehydrogenase (20α-HSD). We observed that miR-200a expression increased and STAT5b expression coordinately decreased in myometrium of mice as they progressed to labor and in laboring myometrium from pregnant women. These changes were associated with a dramatic increase in expression and activity of 20α-HSD in laboring myometrium from mouse and human. In a progesterone-withdrawal mouse model of preterm labor, preterm labor was associated with increased miR-200a, decreased STAT5b and enhanced 20α-HSD expression. In other studies, we also found that levels of the clustered miRNAs, miR-199a-3p and miR-214, were significantly decreased in laboring myometrium of pregnant mice and humans and in a inflammatory mouse model of preterm labor, while the miR-199a-3p/miR-214 target, cyclooxygenase-2 (COX-2), a critical enzyme in synthesis of pro-inflammatory prostaglandins, was coordinately increased (Williams et al., 2012b). The physiological relevance of the labor-associated increase in miR-199a-3p/214 expression was highlighted by the finding that overexpression of miR-199a-3p and miR-214 in cultured human myometrial cells inhibited COX-2 protein and blocked TNF-α-induced myometrial cell contractility. Notably, estrogen and P4 treatment of ovariectomized mice have opposing effects on uterine miR-199a-3p/214 expression that were mediated by ZEB1. Whereas, P4 stimulated ZEB1 and upregulated miR-199a/214 expression in mouse and human myometrium (Renthal et al., 2010), estrogen had an opposing inhibitory effect. Notably, ZEB1/2 inhibit miR-200 family expression. Together, our findings point to the key pivotal roles of myometrial ZEB1 and its miRNA targets as a hormonally-controlled regulators of inflammatory and contractile gene expression in the pregnant uterus during term and preterm labor.
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    Exploring the Dynamics of Mechanosensitive Channels Utilizing a Post Translational Modification Approach
    (2013-08-07) Parker, Juandell Latrice; Hooper, Lora; Jiang, Qiu-Xing; Shiloh, Michael; Blount, Paul
    It is essential for all living organisms to possess the ability to sense and respond to changes in their environment. The ability to detect external and internal mechanical force is very important as well. The detection of mechanical forces underlies the ability to sense touch, gravity, blood pressure, and changes in osmolarity. The bacterial mechanosensitive channel of large conductance (MscL) and the mechanosensitive channel of small conductance (MscS), from E. coli, have been the most studied mechanosensors to date. These channels coordinate a response to rapid changes in osmolarity to serve as emergency release valves during an osmotic downshock (sudden change to a lower osmotic environment). Crystal structures have been solved for homologues of each of these channels. In addition, patch clamp of giant bacterial spheroplasts has allowed for the study of channel activities in native membranes, and both channels have been functionally reconstituted into membranes and studied by electrophysiological single-channel analyses. However, even though well studied, it is still unclear how specific regions of the protein interact with the membrane, and how these interactions change upon channel gating. Here we hypothesize that during channel gating specific residues of MscL change their local environment. We investigate this hypothesis by using a post-translational modification approach to determine how changing hydrophobicity or charge at specific locations influences gating. Briefly, we used MscL channels with specific residues in the linker between the second transmembrane region (TM2) and the cytoplasmic α-helical bundle changed to cysteine. Changing the individual amino acids to cysteine allows us to use Methanethiosulfonate (MTS) sulfhydryl reagents that can form disulfide bonds with cysteines to change the properties (charge or hydrophobicity) of specific residues. We then use the double knockout strain, ∆MscL/∆MscS, which is osmotically fragile and has a reduced viability when osmotically downshocked. These cells are osmotically downshocked in the presence or absence of different hydrophobic or charged MTS sulfhydryl reagents with different affinities for membrane or membrane/water interface environment, or that possess different charges. The assumption is that the channel changes conformation, and lipid interactions, upon gating. By changing the hydropathy of residues at specific locations, we drag a portion of the protein into a different environment, thus increasing or decreasing the probability of opening. This leads to a channel that opens too frequently or one that fails to open and this can be assessed by measuring changes in cell viability. Here we focused on the specific MscL residues F83-E107 to expand previous work performed on this region of the MscL protein. While the bulk of residues investigated here did not reach a high enough threshold to warrant further investigation, a few of the modifications are of interest. To investigate channels across channel families it would be of interest to use this approach for identification of residues that are important for MscS channel gating. Towards this end, I have generated several cysteine mutations in the transmembrane linker regions for MscS. This will allow similar and more extensive studies to be conducted with MscS to determine if the results observed for MscL are general principles observed in the unrelated MscS channel, or if there are variations between the two mechanosensitive channel families.
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    ADHD Subtypes and the Convergent Validity of the Brief Three-Factor Approach and D-KEFS Color-Word Interference Test
    (2014-05-06) Oasay, Larry; Silver, Cheryl H.
    Deficits in executive functioning (EF) often translate to significant impairment in real-life situations. EF can be assessed by performance-based tests or through the use of behavior ratings; however, most research has found little to no associations between performance-based EF tests and parent ratings. ADHD is a neurodevelopmental disorder characterized by EF deficits, but some studies have found differences on EF measures between subtypes of ADHD. The first aim of this study is to examine the convergent validity between the D-KEFS CWIT, a performance-based EF task, and the recently revised three-factor BRIEF. The second aim of this study is to examine whether there are differences between ADHD-I and ADHD-HI/C subtypes on either of these EF measures. A sample of 49 children with ADHD, aged 6 to 12 years, were administered the D-KEFS CWIT and their parents were given the BRIEF to complete. No significant correlations between Condition 3 of the CWIT and the new Self-Monitor and Inhibit subdomains of the BRIEF were obtained, but the Shift subdomain of the BRIEF significantly correlated with Condition 3. Participants with ADHD-HI/C were rated by parents as having greater executive dysfunction compared to participants with ADHD-I. No significant differences between subtypes were observed on the CWIT after controlling for symptoms of inattention. It would be beneficial to continue developing EF measures with the goal of greater convergent validity between performance-based and informant-report measures. Also, more research should be conducted in identifying differences between ADHD subtypes in their EF profiles as it can potentially aid in improving evaluation and treatment of this disorder.
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    The Impact of Cognitive Processing Therapy On Quality of Life and Healthcare Use in Veterans with Posttraumatic Stress Disorder Due to Military Sexual Trauma
    (2014-01-21) Fekadu, Rahel Abay
    BACKGROUND: Military Sexual Trauma (MST) is a psychological trauma that resulted from a physical assault of a sexual nature, battery of a sexual nature, or sexual harassment (U.S. Code (1720D of Title 38)). Research indicates that MST is associated with increased likelihood of developing Posttraumatic Stress Disorder (PTSD). Veterans who are diagnosed with PTSD due to MST experience a range of comorbid disorders and psychological sequelae including impaired quality of life (Suris et al., 2006), and utilized more primary healthcare services compared to those without PTSD (Frayne, Chiu, Iqbal, Berg, Laungani, Cronkite, Pavao, & Kimerling, 2010). The current study seeks to examine the effectiveness of Cognitive Processing Therapy (CPT), compared to Present Centered Therapy (PCT), on quality of life, health related quality of life and healthcare utilization in veterans who were diagnosed with PTSD due to MST. SUBJECTS: One hundred and ninety veterans with MST were enrolled in to the study and randomized into either CPT or PCT. However, due to fidelity issues data were analyzed for Eighty-six (72 female and 14 male) veterans. METHOD: Data for the proposed study is taken from a larger randomized controlled clinical trial that was conducted at a large Southwestern Veteran Administration Medical Center to evaluate the effectiveness of Cognitive Processing Therapy (CPT) in comparison with Present Centered Therapy (PCT) for PTSD due to MST (Suris et al., 2013). Participants received 12 therapy sessions, bi-weekly, over a six-week period. Data were acquired using face-to-face interviews and written questionnaires at baseline, treatment completion, and at two-month, four-month, and six-month follow-ups. RESULTS: Participants in both treatments did not differ in terms of health related quality of life, quality of life, and healthcare utilization. However, participants in both conditions reported improvement on three of the SF-36 subscales (General Mental Health, Role Limitation Due to Emotional Problems and Vitality), quality of life, and healthcare utilization subscales (Psychotherapy, Outpatient, Hospitalization). DISCUSSION: Although we failed to reject the null hypothesis, the trend indicates that both CPT and PCT are efficacious in terms of improving subjective wellbeing and health related quality of life as well as lowering health care consumption.
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    Bandura’s Social Cognitive Concepts and Physical Activity of People with Multiple Sclerosis: a Hierarchical Regression Analysis
    (2014-01-21) Gaylord, Kathryn Lee
    BACKGROUND: Social Cognitive Theory (SCT), developed by Alfred Bandura, is a theory often employed for health promotion. This theory focuses on a set of determinants, examining how each operates, and translating information about the determinants into health practices. The combination and interaction of the primary determinants of SCT (perceived self-efficacy, outcome expectations, goals, and perceived facilitators and barriers) not only determine, but also influence the health behaviors individuals engage in. Through the use of this theory, determinants to change and adoption of a new behavior can be assessed, and individual treatment plans may be developed to effectively focus on the most influential targets for behavioral change. Multiple Sclerosis, a chronic and debilitating health problem estimated to affect hundreds of thousands of individuals in the United States, often leads to individual suffering and an overall decreased quality of life. Currently, there is no cure for MS, so symptom management and a decrease in debility remain a critical area of focus for health professionals working with MS patients. While there is no cure for this disorder, physical activity has been shown to alleviate multiple symptoms of MS such as mobility impairment, fatigue, pain, and depression, which then improves the quality of one’s life. Furthermore, there is strong empirical evidence to support the use of SCT as an efficacious treatment approach for employing health promotion practices. The purpose of this study is to extend previous findings by examining how various SCT concepts relate to physical health, mental health, stage of change for exercise, and action planning and coping planning for exercise. Additionally, the present study examines how disability affects self-efficacy thereby impacting physical activity. SUBJECTS: A total of 214 individuals (185 females [86%] and 29 males [14%] with self-reported MS recruited from the National Multiple Sclerosis Society and a neurology clinic of a university teaching hospital in the Midwest participated in the current study. The average age among participants was 46.97 years (SD = 9.92). Around 36% of participants were retired due to MS, and approximately 72% of participants reported being treated for secondary health problems (e.g., overweight, high blood pressure, and diabetes). METHOD: Participant demographic data were gathered from self-reports and include age, gender, ethnicity, marital status, years since onset of MS, secondary health issues, education level, vocational status, occupation, area of residence, current and past rehabilitation services received, source of income, total income, access to physical exercise in community, and changes in health practice since onset of MS. SCT concepts were assessed using the following measures: Action Self-Efficacy Scale-Physical Exercise (ASES-PE), Outcome Expectancy Scale-Physical Exercise (OES-PE), Health/Safety Risk Perceptions Scale (HRPS), Health/Safety Expected Benefits Scale (HEBS), Barriers to Health Promoting Activities for Disabled Persons Scale (BHADP), the Action Planning and Coping planning Scale-Physical Exercise (APCPS-PE), the Physical Activity Stages of Change Instrument (PASC). Participant disability and health were assessed using the following measures: Minimal Record of Disability (MRD) and the MOS Short form Health Survey (SF-12v2). The present study used a hierarchical regression analysis to examine associations between various domains and a set of social cognitive concepts (self-efficacy, knowledge of health and risk benefits, and outcome expectancy). RESULTS: There were several significant findings when examining the four domains of action planning and coping planning, stage of change, physical health, and mental health. Results indicated action planning and coping planning was predicted by action self-efficacy (R2 = 45%, ß = .45, p < .001), outcome expectancy (R2 = 45%, ß = .20, p < .01), risk perception (R2 = 45%, ß = .14, p < .05), and perceived barriers (R2 = 16%, ß = -.14, p < .05). Results indicated that stage of change was predicted by action planning and coping planning (R2 = 28%, ß = .26, p < .01). When “physical health” was the outcome variable, it was predicted by age (R2 = 8%, ß = -.20, p < .01), severity of disability (R2 = 14%, ß = -.28, p < .01), action self-efficacy (R2 = 22%, ß = -.16, p < .05), and outcome expectancy (R2 = 22%, ß = .27, p < .01). Lastly, when “mental health” was the outcome variable, it was predicted by age (R2 = 6%, ß = .18, p < .05), perceived barriers (R2 = 11%, ß = -.23, p < .01), outcome expectancy (R2 = 18%, ß = -.25, p < .01), and action self-efficacy (R2 = 18%, ß = .22, p < .05). DISCUSSION: The research findings support the applicability of Bandura’s Social Cognitive Theory as a model for exercise or physical activity for people with MS. This study found unique relationships between physical health and action self-efficacy, and mental health and outcome expectancy (with both relationships having a negative correlation). The current study includes a unique subset of the MS population who are well-educated, affluent, and report greater access to services and who expressed the negative correlate between action self-efficacy and physical health. The aforementioned factors are supposed to support physical health. However, the current group has high action self-efficacy to exercise, and given that they likely have good knowledge about exercise benefits to MS and good environmental support to engage in exercise, their motivation has likely surpassed, and is greater than, their experienced physical health, such as suffering pain and fatigue, which decreases physical health. Furthermore, it may be that the participants in the current study have good knowledge about how physical activity benefits their MS symptoms and progress management; consequently, they have high intention to push themselves to engage in exercise even though they may have experienced pain and fatigue, both of which have affected physical health significantly. Additionally, considering that high outcome expectations of a behavior may lead to stress and anxiety, such stress may decrease mental health, particularly if the positive effects of an activity (such as exercise) are not experienced as soon as and as much as expected. Examining the social cognitive, physical health, and mental health domains provides a well-rounded and empirical basis for employing health promotion efforts in clinical work with persons with MS. Rehabilitation professionals may help persons with MS implement physical activity through the use of SCT, which may improve their mobility impairment, pain, fatigue, and depression. The present study’s findings enable clinicians and rehabilitation professionals to better create and customize treatment to best meet individual patients’ needs and improve their overall quality of life.
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    Understanding the Stressful Challenges of Adolescent Type 1 Diabetes Management in Caucasian and Latino Youth
    (2014-01-21) Lee, Alyssa G.
    BACKGROUND: Type 1 diabetes management poses many challenges and is a potential source of stress among adolescents with diabetes and their families. In primarily Caucasian samples, diabetes management outcomes (e.g., metabolic control) deteriorate across adolescence. A growing literature indicates that Latino youth have poorer diabetes control than do Caucasian youth. The broad objective of the present study was to examine ethnic differences in the experience and effects of stress on type 1 diabetes management during adolescence. SUBJECTS: Participants were Caucasian and Latina mothers and adolescents with type I diabetes (N=118 dyads; 48% Latino; 54% female; 10 to 15 years old; illness duration > 1 year; 25% on insulin pump). Adolescents were between 10 and 15 years of age (M = 12.74, SD = 1.64). METHOD: Demographic information was collected through maternal report, geographic identifiers from available census data, and medical records. Adolescents completed surveys measuring the occurrence of different types of stressful events relevant to a diverse population of Latino and Caucasian youth (i.e., stress dimensions of family conflict, peer hassles, school hassles, and economic stress), treatment adherence, and depressive symptoms. Metabolic control was determined from HbA1c recorded in medical records. Socio-demographic information was collected through a combination of maternal report and census tract data. RESULTS: On average, Latino participants were of a lower socioeconomic status (SES) than Caucasian participants. However, there were not significant ethnic group differences in terms of adolescent age, adolescent gender, illness duration, or insulin pump status. There were also no ethnic differences on adolescent report of different types of stress. In the full sample, heightened levels of each type of stress were associated with indicators of poorer diabetes management and poorer psychosocial adjustment. Hierarchical regression analysis revealed that the stresses of peer hassles, school problems, and family conflict were each associated with poorer outcomes regardless of ethnicity. However, ethnicity moderated associations of economic stress with both adherence and depressive symptoms. Economic stress was associated with poorer adherence and greater depression in Caucasian youth, but was unrelated in Latino youth. DISCUSSION: Latino and Caucasian youth in the sample for this study did not show significant differences in their report of the experience of stress, but Latino youth appeared resilient against the adversity of economic stress. This interaction pattern is consistent with the Latino paradox. Understanding resiliency factors in diverse populations may assist health care professionals in providing effective and culturally sensitive interventions.
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    Symptom Presentation in ADHD and Its Association with Inhibitory Control
    (2014-01-21) Loris, Colin Patrick
    Attention-Deficit/Hyperactivity Disorder (ADHD) has been associated with problems in executive functioning (EF). However, subtype difference in EF may exist between the inattentive type of ADHD and the hyperactive/impulsive and combined types of ADHD. As small number of studies, in fact, have found that inhibitory control is more strongly related to symptoms of inattention than symptoms of hyperactivity/impulsivity, suggesting that children with the inattentive type of ADHD may have more deficits in inhibition. The D-KEFS Color Word Interference Test (CWIT) was administered to 35 children, ages 8-17 years, diagnosed previously with ADHD, to examine possible differences in inhibition between a Predominantly Inattentive group and a Combined group (Predominantly Hyperactive-Impulsive and Combined types). Both ADHD group means on the CWIT were within normal limits. Results from a MANOVA showed no differences between groups on the CWIT, except for the word reading condition (Condition 2). Analysis of the CWIT and symptoms of inattention from the Conners Parent Rating Scale-Revised showed no significant relationship between performance on the CWIT and parent report of inattentive behaviors. Contrary to the hypotheses, this study did not provide evidence that children in the Predominantly Inattentive group display more deficits in inhibition than children in the Combined group, or that deficits in inhibition are related to inattentive behaviors.
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    Developmental Expectations and Adolescent Type 1 Diabetes Management in Latino and Caucasian Families
    (2013-12-30) Sundaram, Saranya Easwar; Wiebe, Deborah
    BACKGROUND: Transfer of responsibility for diabetes management is important across adolescence. It may contribute to poorer adherence and family conflict if unmatched to adolescent development. Research has primarily studied Caucasian samples, which may have different expectations for autonomy compared to Latino samples. This study examined developmental expectations for independence in both general and diabetes-related tasks in age- and sex-matched samples of Caucasian and Latino youth with type 1 diabetes. SUBJECTS: Participants included 118 10- to 15-year-old Caucasian and Latino adolescents with type 1 diabetes [M (SD) = 13.24 (1.69) years; 54% female] and their mothers. METHOD: Participants independently completed questionnaires measuring expectations for independence, diabetes responsibility and conflict, and adherence to diabetes management. In addition, adolescents completed an inventory measuring depressive symptoms, and HbA1c levels were obtained through medical records. RESULTS: Mothers and adolescents held different expectations for the age at which adolescents should make independent decisions about general and diabetes-related activities. In the overall sample, adolescents expected independence at younger ages for prudential activities, but at older ages for diabetes activities than did parents. These mother-adolescent differences occurred in different domains across ethnicity; Caucasians displayed mother-adolescent differences in expectations for diabetes activities, while Latinos displayed differing expectations for prudential activities. In the overall sample, expectations were associated with mother-reported conflict, but were minimally correlated with parental diabetes responsibility. Younger age expectations for prudential items were associated with poorer diabetes outcomes, but age expectations for personal and diabetes items were generally unrelated to diabetes outcomes. In contrast to expectations, associations of developmental expectations with diabetes responsibility, conflict, and outcomes were similar across Caucasian and Latino youth. DISCUSSION: Findings support that there were differing age expectations between parents and adolescents in prudential and diabetes-related activities. Different factors may influence how these expectations were associated with parental responsibility, conflict, and diabetes outcomes.
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    Resilience Profile Among People with Spinal Cord Injury: a Cluster Analysis
    (2013-12-30) White, Brian Dale; Chiu, Chung-Yi
    BACKGROUND: Resilience is considered as an important coping attribute for people adjusting from trauma and loss such as spinal cord injury. Resilience has been found that it has moderate to high correlations with multiple psychosocial characters such as coping strategies, spiritual belief, and life satisfaction as well as mental health. However it is unclear if resilience could have developmental phases when people have adjusted to their trauma and distress over time, or if there are different types of resilience based on a person’s psychosocial characters. Therefore the present study aimed to explore if there are some phases of resilience among people with spinal cord injury (SCI). SUBJECTS: The 93 inpatients with SCI who were undergoing rehabilitation at Baylor Institute of Rehabilitation, Dallas, TX, 58 males (62.4%) and 35 females (37.6%), 77 Caucasians (82.8%) and other races (17.2%; i.e., African American, Hispanic), with mean age of the sample was 44.2 years (SD = 16.2), and the mean months since onset was 16.14 months (SD = 62.12). METHODS: Patients completed the Connor-Davidson Resilience Scale, Personal Health Questionnaire- 9, Satisfaction with Life Scale, Intrinsic Spirituality Scale at any time point since being hospitalized to discharge. Using SPSS 19.0, a hierarchical cluster analysis was performed to preliminarily explore optimal patterns of resilience based on the psychosocial evaluations. Further a two-step cluster was used as a post hoc test of cluster quality and predictor importance. ANOVA and chi-squared test were used to identify any differences of the above psychosocial components of resilience and related demographic characters between the identified patterns of resilience. METHOD: Patients completed the Connor-Davidson Resilience Scale, Personal Health Questionnaire-9, Satisfaction with Life Scale, Intrinsic Spirituality Scale at any time point since being hospitalized to discharge. Using SPSS 19.0, a hierarchical cluster analysis was performed to preliminarily explore optimal patterns of resilience based on the psychosocial evaluations. Further a two-step cluster was used as a post hoc test of cluster quality and predictor importance. ANOVA and chi-squared test were used to identify any differences of the above psychosocial components of resilience and related demographic characters between the identified patterns of resilience. RESULTS: A hierarchical cluster analysis found three clusters with appropriate differentiable dendrogram distance labeled Spontaneous Resilience (SR; n=28, 35.9%), Evolving Resilience (ER; n=28, 35.9%) and Rebounding Resilience (RR; n=22, 28.2%). Further using a two-step cluster analysis as a post hoc testing, the silhouette measure of cohesion and separation indicated that the cluster quality was fair (0.40). The predictor importance for the cluster formation showed spirituality had an importance of 1.00, the most important predictor, with depression and SWL each showing a predictor importance score of 0.46. The ANOVA found significant differences between groups on resilience, F(2,75) = 7.98, p < .001; depression, F(2, 75) = 23.86, p < .000; SWL, F(2,75) = 23.66, p < .000; and spirituality, F(2, 75) = 71.62, p < .000. Chi square test found no significant associations between the two resilience patterns of gender (X2(2, N = 78) = 1.997, p = 0.368), and marital status (X2( 8, N = 78) = 8.287, p = 0.406). Race results were significant (X2(4, N = 78) = 9.559, p = 0.049), but race was unable to be used due to the majority of participants being Caucasians. DISCUSSION: The current study suggested that there are three resilience patterns recognized in this sample of people with SCI. The hierarchical cluster analysis clustered participants into three clusters: Spontaneous Resilience (SR), Evolving Resilience (ER) and Rebounding Resilience (RR), three of which reflect the levels of resilience change over time and differences in depression, SWL and spirituality. Rehabilitation professionals could apply the present findings on understanding the status of patients’ resilience and design according adjustment psycho-educational therapy for growing patients’ optimal resilience.
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    Adherence as a Mediating Variable Between Depression and Health Outcomes in Adolescents with Type 1 Diabetes
    (2013-12-30) Wolfe, Kristin Linette; Wiebe, Deborah
    Adolescence is often a time of diabetes mismanagement and poor metabolic control in adolescents with type 1 diabetes. Symptoms of depression are related to poor metabolic control, but the mechanism that links them is under debate. Because depression tends to be associated with poorer adherence and poor adherence has been shown to be related to poor metabolic control, it is possible that adherence serves as a mediator between the two. The present study tested this mediation pathway in a sample of adolescents with type 1 diabetes. Participants (N=252) were recruited from endocrinology clinics in Utah during their routine diabetes clinic visits. Participants fell between the ages of 10 and 14, were able to read and write in either English or Spanish, had a diagnosis of type 1 diabetes for at least one year, and did not have a condition that would interfere with measurement completion. Participants were drawn from a larger longitudinal observational study. This study analyzed the first three time points of data, which were obtained six months apart. Demographic and illness information was obtained from self-report and participant medical files. Questionnaires were used to assess depression and adherence. Metabolic control was measured through HbA1c levels retrieved from medical records. Data were analyzed to test the mediation hypotheses. Higher levels of depression were correlated with poorer metabolic control in cross-sectional analyses at study entry, and in longitudinal analyses measured one year later. Adherence was found to be a partial mediator in cross-sectional analyses, but did not mediate changes in metabolic control across time.
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    The Response of White Adipose Progenitor Cells to Physiological and Genetic Changes
    (2013-02-21) Zeve, Daniel; Johnson, Jane E; Mangelsdorf, David J; Olson, Eric N; Graff, Jonathan M
    We are in the midst of a dire, unprecedented and global epidemic of obesity and secondary sequelae, most prominently diabetes and hyperlipidemia. Underlying this epidemic are adipocytes and their inherent, dynamic ability to expand and renew. These abilities highlight a newly defined cell population within adipose tissue, the white adipose progenitor cell. These cells have the basic abilities that define a stem/progenitor cell, including the ability to proliferate and differentiate into mature adipocytes, opening up new studies into their involvement in both adipose development and growth. More specifically, interest lies in which physiological and genetic conditions can repress the adipogenic function of these cells, as these findings could lead to possible therapies for obesity and other metabolic diseases. We began our studies by examining the proliferative and adipogenic effect of both high fat diet and exercise on adipose progenitor cells. We found that while high fat diet increased adipose progenitor function, exercise dramatically reduced proliferation of the adipocyte progenitor in addition to diminishing new adipocyte formation during the exercise protocol. One physiological outcome of endurance exercise is the remodeling of skeletal muscle to more of a slow, oxidative fiber type composition. Thus, we hypothesized that type I skeletal muscle may also regulate the adipocyte progenitor. To directly test this hypothesis we analyzed the adipose progenitor cell in two, independent mouse lines that exhibit an increase of Type I fibers. These mice revealed that slow muscle fibers also reduce the activity of the adipocyte progenitor on normal chow and decrease adiposity while on high fat diet. Surprisingly, this effect may be due to non-nutritional factors, as the slow fiber mice exhibit no overt metabolic alterations on normal chow and conditioned media from muscle cell lines reduced pre-adipocyte function. These data suggest Type I fibers directly regulate the adipocyte progenitor cell, which may contribute to the reduced adiposity seen after exercise as well as the reduced adiposity of slow fiber mice in response to high fat diet. We next wanted to examine the genetics that control adipogenesis within the adipose progenitor cells. To do this, we activated Wnt signaling in either adipose progenitor cells or mature adipocytes. Wnt signaling is known to play a role in proliferation and differentiation in multiple stem cell lineages, including intestinal, bone and hematopoietic lineages, and thus we hypothesized that it may also play a role in in vivo adipogenesis and metabolism. Altering canonical Wnt signaling in mature fat tissues in mice had no discernable metabolic effects. In contrast, altering Wnt signaling in fat progenitors led to a depot-specific fate change and a paradoxical murine lipodystrophic syndrome that lacked the expected diabetes and ectopic fatty acid accumulation. Rather, muscle displayed increased glucose uptake and an insulin-independent increase in cell surface glucose transporters along with activation of AMPK and p38 MAPK. Muscle Wnt signaling was unaffected, indicating that these changes resulted from signals derived non-autonomously, which we found to be present in the serum of mutant mice. Thus, this model distinctively dissociates lipodystrophy from dysfunctional metabolism and uncovers a unique and potentially therapeutic method to lower blood glucose and improve metabolism.
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    University of Texas Southwestern Medical Center group therapy outcomes: Social skills training for adults with mental illness
    (2012-12-06) Russo, Amanda; Chiu, Chung-Yi; Casenave, Gerald; Rose, Lindsey
    BACKGROUND: Group therapy is an effective method of treating people with various mental illnesses. Social skills training is often used in a group therapy setting to improve the social functioning of people with mental illness, many of whom have social skills deficits. Currently, there is very little literature on how social skills training reduces symptomology, most of which is limited to children or adolescents and people with autism spectrum disorders. The current study looks to determine what, if any, effect social skills training has on alleviating depression and anxiety symptoms in a mixed mental illness sample. SUBJECTS: 23 subjects were recruited from the University Rehabilitative Services to take part in the study. There were 11 males and 12 females divided into two treatment groups named Connections (CG) and Personal and Social Adjustment Treatment (PSATG). METHOD: A one-way paired samples t-test was used to determine improvement between pre and post BDI-II and BAI scores. RESULTS: BDI-II scores were significantly lowered, indicating improvement in depression symptoms. BAI scores were not statistically significant. DISCUSSION: Social skills training does alleviate depression symptoms in an adult mixed mental illness sample. Future studies need to focus on improving anxiety symptoms as well.
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    Depressive Symptoms and Subclinical Vascular Disease: a Cross-Cultural Comparison
    (2013-07-25) Moore, Patricia Sinclair; Cullum, C. Munro; Weiner, Myron F; Hynan, Linda; King, Kevin S; Rossetti, Heidi; Deschner, Martin
    While rates of depression are similar across ethnic groups, severity of symptoms and disability related to depression are greater in African Americans when compared with other groups (Breslau, Kendler, Su, Gaxiola-Aguilar, & Kessler, 2005). Markers of subclinical cardiovascular disease have been associated with depression, and rates of most cardiovascular risk factors are higher in African Americans than Caucasians (Shaya, Gu, & Saunders, 2007). Whereas rates of atherosclerosis are similar across these groups (Jain et al., 2004), atherosclerosis has been shown to be associated with depression in mostly Caucasian samples (Bus et al., 2011; Gebara & Santos, 2010). A more direct marker of subclinical cerebrovascular impact is cerebral white matter hyperintensity volume (WMHv). Differences in WMHv have been reported across ethnic groups, and WMHv is more closely associated with the cardiovascular risk factors that are higher in African Americans. White matter hyperintensities (WMH) have been independently associated with increased depressive symptoms in late-life depression (Pompili et al., 2007; 2008; Sneed et al., 2011; Tham, Woon, Sum, Lee, & Sim, 2011), although the relationship between vascular disease and depression is poorly understood. This study aimed to examine the relationship between atherosclerosis, WMHv, and depressive symptoms in Caucasians and African Americans over age 50 to determine the association between subclinical vascular disease and depressive symptoms across ethnic groups. To this end, specific measures of subclinical vascular diseases (measures of atherosclerosis, WMHv) were compared to identify the best predictors of depressive symptoms within ethnic groups.
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    Predicting the Rate of Decline in Early Alzheimer Disease: the Role of Neurocognitive Performance Features
    (2013-07-25) Parikh, Mili R; Cullum, C. Munro; Lacritz, Laura H; Hynan, Linda S; Weiner, Myron; Ringe, Wendy
    Alzheimer disease (AD) is a neurodegenerative disorder that characteristically begins with episodic memory impairment followed by other cognitive deficits over time; however, the course of illness varies, with significant variability in terms of the rate of cognitive decline across affected individuals. Several studies have examined demographic, clinical, biological, and neurocognitive performance markers to predict rate of AD progression, but findings are mixed. The current study utilized neurocognitive performance features along with disease-specific and health features to determine the best prediction model for the rate of future cognitive decline in subjects with mild AD. Ninety-six subjects with mild AD at baseline were administered a comprehensive battery of neurocognitive tests and clinical measures. Based on Clinical Dementia Ratings (CDR) of functional and cognitive decline within two years, subjects were determined to be Faster (n = 45) or Slower Progressors (n = 51). Stepwise logistic regressions using neurocognitive performance features, disease-specific, health, and demographic variables were performed in a hierarchical fashion to determine optimal predictors of rate of progression. Several individual neurocognitive measures distinguished Faster from Slower Progressors at baseline, including Trail Making Test - A, Digit Symbol, California Verbal Learning Test (CVLT) Total Learned, CVLT Primacy Recall, and the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Neuropsychological Battery Total Score. No disease-specific, health, or demographic variables predicted rate of progression; however, history of cardiac illness showed a trend. In a stepwise logistic regression of neurocognitive performance features alone, a combination model of three measures (Trail Making Test - A, Semantic Fluency, and CERAD Total) distinguished Faster from Slower Progressors with 76% accuracy. In an omnibus model including neurocognitive, disease-specific, health, and demographic variables, only Trail Making Test - A distinguished groups (68% correct classification). Several neurocognitive performance features may play a role in predicting rate of decline in mild AD. Notably, three relatively brief and commonly used measures were found to predict differences in rate progression with good accuracy. Results from the current research provide important advances in understanding the role of neurocognitive measures in predicting rate of decline in AD.
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    Identification of Cellular Sensors for Unsaturated Fatty Acids
    (2013-03-04) Kim, Hyeonwoo; DeBose-Boyd, Russell; Scherer, Philipp; Goodman, Joel
    In mammalian cells fatty acids (FAs) are required for the synthesis of membrane phospholipid components and energy generation. However, overaccumulation of FA is toxic. Accumulation of FAs prevents their further synthesis by stabilization of Insulin-induced gene 1(Insig-1), an ER membrane protein that inhibits proteolytic activation of sterol regulatory element binding protein-1 (SREBP-1), a transcription factor that activates all genes required for FA synthesis. This regulatory reaction is stimulated by unsaturated but not saturated FAs. Unsaturated FAs stabilize Insig-1 through disrupting the interaction between Insig-1 and UBX domain-containing protein 8 (Ubxd8), which recruits p97, a protein required for degradation of endoplasmic-reticulum (ER) membrane proteins, to Insig-1. Here, we identified Ubxd8, a protein that does not contain any previously recognized domains that bind FAs, as a sensor for unsaturated FAs. In cultured cells, we demonstrated that unsaturated FAs but not saturated FAs stimulated polymerization of Ubxd8 through bimolecular fluorescence complementation (BiFC) assays. In vitro, unsaturated but not saturated FAs also stimulated polymerization of purified recombinant Ubxd8. The effect of different FAs and their derivatives on polymerization of Ubxd8 in vitro correlated with their effect on stabilization of Insig-1 in cultured cells. Ubxd8 contains 3 domains, namely ubiquitin X (UBX), ubiquitin associated (UBA) and ubiquitin associating (UAS) domain. Deletion analysis showed that UAS domain was necessary and sufficient for polymerization of the protein in response to unsaturated FAs. Point mutations in UAS domain that disrupted its interaction with unsaturated FAs in vitro also impaired the ability of full length Ubxd8 to stabilize Insig-1 in response to unsaturated FAs in cultured cells. In addition to Ubxd8, the only other protein expressed in mammalian cells that contains a UAS domain similar to that of Ubxd8 is Fas-associated factor 1 (FAF1). We showed that unsaturated FAs also specifically induced polymerization of FAF1, and this polymerization was mediated by the UAS domain. The identification of UAS domain as a motif polymerizing upon interaction with unsaturated FAs should provide more insights into cellular responses to FAs.
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    Effects of Regional Deletion of Rab3A-interacting Molecule and PTEN on Brain Function
    (2013-04-16) Haws, Michael; Eisch, Amelia J; Powell, Craig M; Huber, Kimberly; Goldberg, Matthew
    This dissertation describes experiments designed to delete/knockdown molecules from targeted neuronal populations to study brain region-specific behavioral functions. To this end, I utilized two different conditional knockdown techniques to study the role of the presynaptic active zone molecule Rab3A-interacting Molecule (RIM1) and the phosphatase and tensin homologue on chromosome 10 (PTEN). The cre-lox system was used to eliminate RIM1 from the hippocampal dentate gyrus and area CA3, while adeno-associated virus expressing PTEN-directed interference RNA was injected into the basolateral amygdala to knockdown PTEN in local pyramidal neurons. In the case of RIM1, I hypothesized that deletion of RIM1 from the dentate gyrus or from area CA3 would replicate a subset of the learning and memory deficits found in RIM1à-/- mice. Though the conditional RIM1 knockout mice were not completely selective for the dentate gyrus or for area CA3, both conditional knockouts induced a different behavioral abnormality present in RIM1à-/- mice. My results help narrow the potential brain regions involved in key RIM1à-/- mice behavioral aberrations. In the case of PTEN, I hypothesized that deletion of PTEN specifically in the basolateral amygdala (BLA) would cause increased anxiety and neuronal hypertrophy. Knockdown of PTEN in the BLA did not induce anxiogenesis though it did increase soma volume, dendritic caliber, spine size, mushroom:thin spine ratio, and the frequency of spontaneous miniature excitatory post-synaptic currents. These findings are in contrast to previous findings of increased spine density with PTEN knockdown. This difference likely represents the more sensitive techniques employed in the present studies to ascertain dendritic spine type and density. Though PTEN knockdown had synaptic effects I did not observe any behavioral effects. However, limitations in viral knockdown of PTEN transcripts or viral infection rate may be responsible for the lack of effect. Indeed, limitations exist for both the transgenic and viral approaches used which proved to be challenging obstacles to designing experiments, interpreting data and coming to more extensive concrete conclusions. Transgene expression is often not as selective as desired. Virus injections may not localize to target region or may not infect enough neurons. Understanding and characterizing these and other limitations is vital.
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    Histology of the Female Reproductive System: An Interactive Educational Module
    (2013-04-11) Gove, Mollie; Calver, Lewis; Diehl, Angela; Hoffman, Barbara
    “Histology of the Female Reproductive System: An Interactive Learning Module” is an interactive animated video project designed to address the need for a complete educational exploration of female reproductive histology for medical students and residents in Obstetrics and Gynecology. The content was developed by Dr. Barbara Hoffman and Dr. Kelley Carrick, and was designed to accompany the existing histology literature in McGraw-Hill’s Williams Gynecology textbook. The project features 18 video animations that present normal and pathological histology features set in an interactive interface. This interface offers primary and secondary menus, as well as an interactive illustration showing the complete female reproductive system. The module was evaluated by current UT Southwestern medical students and residents for its perceived educational value. After using the module, surveys on the efficacy of the project were completed by eleven students. Analysis showed that the project was considered a useful resource for understanding female reproductive histology.
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    Role for NIP45 in Telomere Recruitment to PML Bodies in ALT Cancer Cells
    (2013-05-14) Farley, Demetra Dannielle; Cobb, Melanie; Yu, Hongtao; Corey, David; Scaglioni, Pier
    Telomere length maintenance is critical for continued cell proliferation. The SMC5/6 complex, required for double-strand break (DSB) repair in both yeast and humans, has been implicated in the maintenance of telomere length in certain cancer cells. In the absence of active telomerase, SMC5/6 complex-dependent homologous recombination is utilized to maintain telomere length at PML bodies, a mechanism referred to as alternative lengthening of telomeres (ALT). Sumoylation of several telomere-binding proteins is required for the localization of telomeres to PML bodies in G2 phase cells (APBs). We demonstrate that NIP45, a SUMO-like domain (SLD) containing protein, also affects telomere targeting in ALT cells. Loss of endogenous NIP45 protein results in decreased localization of telomeres to PML bodies in a manner independent of the SMC5/6 complex. NIP45 stimulates telomere binding protein sumoylation, as knockdown of the NIP45 protein negatively affects their sumoylation. Importantly, the NIP45 C-terminal SUMO-like domain (SLD2) is sufficient to rescue both APB formation and telomere-binding-protein sumoylation. NIP45 localizes to PML bodies, but not telomeres, in log phase cells, yet interacts efficiently with TIN2, a sumoylatable telomere binding protein. Additionally, a fragment of NIP45 containing the functional SLD2 domain is sufficient to maintain TIN2 binding. We predict, then, that NIP45 might act to recruit telomeres to the PML bodies via its interaction with TIN2, ultimately allowing for SMC5/6 complex-dependent telomere maintenance in G2 phase cells. In keeping with this hypothesis, loss of endogenous TIN2 protein also negatively affects localization of telomeres to PML bodies, even in the presence of NIP45, supporting a requirement for the TIN2-NIP45 interaction in telomere localization to PML bodies. Through this work, we have defined a role for the NIP45 protein in ALT cancer cell telomere length maintenance, further detailing the mechanism by which telomerase-negative cancer subtypes achieve unlimited replicative potential.
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    Prdm13, a Direct Downstream Target of Ptf1a, Regulates the Balance of Gabaergic Neurons versus Glutamatergic Neurons in the Dorsal Spinal Cord
    (2013-03-12) Chang, Joshua Chia-Hsi; Lu, Q. Richard; Cowan, Christopher W; Wilkie, Thomas; Johnson, Jane E
    A fundamental question in neural development addresses the molecular mechanism for balancing the equilibrium of inhibitory versus excitatory (E/I balance) neurons. The combination of basic helix-loop-helix (bHLH) and homeodomain (HD) transcription factors is essential to generate the E/I balance required for correct functioning of neural networks. During dorsal spinal cord development, the bHLH factor Ascl1 is expressed in progenitors to dI3, dI4, and dI5 (dorsal interneurons 3-5) and is required for the glutamatergic neuronal fate. In contrast, another bHLH factor Ptf1a, is restricted in progenitors to dI4 and is required to specify the GABAergic neuronal fate. Since progenitors to dI4 express both Ascl1 and Ptf1a, some mechanism must exist to repress Ascl1 specification activities in these cells. Given that Ptf1a acts as a transcriptional activator, I hypothesized that Ptf1a induces a transcriptional repressor as one of its downstream targets to mediate the suppression of glutamatergic lineage genes. A chromatin-remodeling transcription factor, Prdm13 (PRDI-BF1 and RIZ homology domain containing 13), was identified as a direct target of Ptf1a. The expression pattern of Prdm13 reflects that of Ptf1a in the spinal cord, cerebellum, diencephalon, and retina, and Ptf1a is the primary factor required for Prdm13 expression. Furthermore, I demonstrate that Prdm13 functions as a transcriptional repressor to actively suppress the excitatory cell fate by binding to specific cis-elements near the glutamatergic lineage regulatory genes, Tlx1 and Tlx3, to silence their expression. Prdm13 acts through multiple protein/DNA complexes, including a novel complex with Ascl1, to repress Ascl1 activation of Tlx3. Prdm13 is also sufficient to induce Pax2 and the GABAergic phenotype. This aspect of Prdm13 function is likely indirect through repression of Tlx1/3 since it is known that Tlx1/3 normally blocks the HD factor Lbx1 that is also involved in GABAergic neuronal specification. Taken together, Prdm13 is a direct target of Ptf1a and is required to suppress the glutamatergic neuronal gene program in GABAergic neurons in the dorsal spinal cord. Therefore, Prdm13 is a novel component of a highly coordinated transcriptional network that provides a missing link in a cell fate decision required for somatosensory processing in the spinal cord.