Master of Science

thesisThe current study was designed to examine biosocial correlates of identity disturbance in a sample of suicidal youth at high risk for borderline personality disorder compared with community controls. We used a multimethod, multi-informant design to examine vulnerability and risk for identity disturbance, including biological assessments, self- and informant-report. Participants' electrodermal responding (EDR), respiratory sinus arrhythmia (RSA), and fundamental frequency were collected during a motherchild discussion task regarding adolescents' personality characteristics. We predicted (1) suicidal adolescents would endorse greater overall identity distress across more domains compared with community controls, and (2) that biological vulnerabilities (e.g., EDR, RSA) and contextual risks (e.g., parent emotional arousal assessed with digital signal processing) would interact to predict higher self-reported identity distress among suicidal adolescents. Results indicate significant differences on identity scales for control and self-injuring adolescents. However, indices of biological and contextual risk did not interact to predict identity problems. Methodological limitations of the current study are discussed, along with implications for future research

Identity-Related Dysfunction: Integrating Clinical and Developmental Perspectives

Recent changes to the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders highlight the importance of identity dysfunction within several psychiatric diagnoses. Despite a long-standing tradition of identity research and theory in the developmental literature, there is limited work establishing intersections between clinical and developmental conceptualizations of identity problems. The relative lack of integration between decades of clinical and developmental work is unfortunate, and likely limits progress in both areas. In this commentary, the authors argue for greater interdisciplinary collaboration and highlight contributions from developmental and clinical theories, which, if integrated, could enhance identity scholarship. The developmental psychopathology perspective is introduced as an ideal framework to promote these goals

Brief Communication: Breeding vectors in the phase space reconstructed from time series data

Bred vectors characterize the nonlinear instability of dynamical systems and so far have been computed only for systems with known evolution equations. In this article, bred vectors are computed from a single time series data using time-delay embedding, with a new technique, nearest-neighbor breeding. Since the dynamical properties of the standard and nearest-neighbor breeding are shown to be similar, this provides a new and novel way to model and predict sudden transitions in systems represented by time series data alone

Effect of Carelink, an Internet-Based Insulin Pump Monitoring System, on Glycemic Control in Children with Type 1 Diabetes Mellitus

Objective : To determine whether use of the internet-based Carelink system improved glycemic control in children on insulin pump therapy. Research Design and Methods - We reviewed records of 146 children treated with insulin pump therapy between the years 2004-2007, and compared glycemic control and diabetes self-care measures associated with Carelink use. Forty percent of the patients resided one hour or more from our clinic. Results: Patients who used the Carelink software and website showed significant improvement in HbA1c levels following use (8.0 ± 0.1 (SE) vs 7.7 ± 0.1 (SE), p=0.002). They uploaded data from their pump and glucometer 2.2 ± 1.8 times per month over 0.8 ± 0.4 (SD) years. Patients who had no access to Carelink software and were followed in a conventional manner showed no change in HbA1c ( 8.0 ± 0.1 (SE) vs 8.1 ± 0.1 (SE), p=0.27) during the study period. These patients did not differ significantly from Carelink users in diabetes self care behaviors. Patients who had Carelink access but did not use it had a higher HbA1c level at the onset and did not change over the study period (HbA1c 8.9 ± 0.2 (SE) vs 8.9 ± 0.3 (SE), p=0.76). These patients differed significantly from Carelink users in self-care behaviors, but not in the frequency of blood glucose monitoring. Patients in a rural location benefited equally as compared to patients who lived within one hour of our clinic. Conclusions: The Carelink software program is a powerful tool that can be used by diabetes care providers and parents to manage insulin pump therapy in children and to improve glycemic control, especially in states with a large rural population

DHODH modulates transcriptional elongation in the neural crest and melanoma

Melanoma is a tumour of transformed melanocytes, which are originally derived from the embryonic neural crest. It is unknown to what extent the programs that regulate neural crest development interact with mutations in the BRAF oncogene, which is the most commonly mutated gene in human melanoma1. We have used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) (which encodes an amino acid substitution mutant of BRAF) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (also known as tp53) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, we performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH), for example leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. Taken together, these studies highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation

Improving quality of breast cancer surgery through development of a national breast cancer surgical outcomes (BRCASO) research database

<p>Abstract</p> <p>Background</p> <p>Common measures of surgical quality are 30-day morbidity and mortality, which poorly describe breast cancer surgical quality with extremely low morbidity and mortality rates. Several national quality programs have collected additional surgical quality measures; however, program participation is voluntary and results may not be generalizable to all surgeons. We developed the Breast Cancer Surgical Outcomes (BRCASO) database to capture meaningful breast cancer surgical quality measures among a non-voluntary sample, and study variation in these measures across providers, facilities, and health plans. This paper describes our study protocol, data collection methods, and summarizes the strengths and limitations of these data.</p> <p>Methods</p> <p>We included 4524 women ≥18 years diagnosed with breast cancer between 2003-2008. All women with initial breast cancer surgery performed by a surgeon employed at the University of Vermont or three Cancer Research Network (CRN) health plans were eligible for inclusion. From the CRN institutions, we collected electronic administrative data including tumor registry information, Current Procedure Terminology codes for breast cancer surgeries, surgeons, surgical facilities, and patient demographics. We supplemented electronic data with medical record abstraction to collect additional pathology and surgery detail. All data were manually abstracted at the University of Vermont.</p> <p>Results</p> <p>The CRN institutions pre-filled 30% (22 out of 72) of elements using electronic data. The remaining elements, including detailed pathology margin status and breast and lymph node surgeries, required chart abstraction. The mean age was 61 years (range 20-98 years); 70% of women were diagnosed with invasive ductal carcinoma, 20% with ductal carcinoma in situ, and 10% with invasive lobular carcinoma.</p> <p>Conclusions</p> <p>The BRCASO database is one of the largest, multi-site research resources of meaningful breast cancer surgical quality data in the United States. Assembling data from electronic administrative databases and manual chart review balanced efficiency with high-quality, unbiased data collection. Using the BRCASO database, we will evaluate surgical quality measures including mastectomy rates, positive margin rates, and partial mastectomy re-excision rates among a diverse, non-voluntary population of patients, providers, and facilities.</p

Platelets generated from human embryonic stem cells are functional in vitro and in the microcirculation of living mice

Platelets play an essential role in hemostasis and atherothrombosis. Owing to their short storage time, there is constant demand for this life-saving blood component. In this study, we report that it is feasible to generate functional megakaryocytes and platelets from human embryonic stem cells (hESCs) on a large scale. Differential-interference contrast and electron microscopy analyses showed that ultrastructural and morphological features of hESC-derived platelets were indistinguishable from those of normal blood platelets. In functional assays, hESC-derived platelets responded to thrombin stimulation, formed microaggregates, and facilitated clot formation/retraction in vitro. Live cell microscopy demonstrated that hESC-platelets formed lamellipodia and filopodia in response to thrombin activation, and tethered to each other as observed in normal blood. Using real-time intravital imaging with high-speed video microscopy, we have also shown that hESC-derived platelets contribute to developing thrombi at sites of laser-induced vascular injury in mice, providing the first evidence for in vivo functionality of hESC-derived platelets. These results represent an important step toward generating an unlimited supply of platelets for transfusion. Since platelets contain no genetic material, they are ideal candidates for early clinical translation involving human pluripotent stem cells