Convergence Of Proliferative And Survival Signals On The pRB/E2F Pathway In Haematopoietic Cells

Chronic myeloid leukemia (CML) is a malignant stem cell disease characterised by an expansion of myeloid progenitor cells. These cells express a BCR/ABL fusion protein with constitutively activated tyrosine kinase activity, which causes a deregulation of apoptosis and cell cycle progression. In the pro-B BaF3 cell line, BCR/ABL has been shown to abrogate the EL-3 dependence to proliferate, but the signalling pathways activated by BCR/ABL and IL-3 to promote proliferation and survival are not yet well defined. In this study, BaF3 cells and a BaF3 cell line stably over-expressing BCR/ABL, BaF3-p210, were used to identify the downstream targets of BCR/ABL and IL-3. Both BCR/ABL and IL-3 were shown to induce the expression of cyclin D2 and inhibit the expression of the cell cycle inhibitor, p27 kipl. This regulation was shown to be directly due to BCR/ABL, in haematopoietic cells, by two different approaches. First, using a BaF3 cell line (TonB210.1) where the BCR/ABL expression is inducible by doxycycline and second, by inhibiting the kinase activity of BCR/ABL with the Abl tyrosine kinase inhibitor STI571. In order to establish the functional significance of cyclin D2 and p27 Kipl expression in response to IL-3 and BCR/ABL expression, the effects of ectopic expression of cyclin D2 and p27 Kipl on cell proliferation and survival were studied. The results demonstrate that both cyclin D2 and p27 Kipl have a role in BaF3 cell proliferation and survival, as ectopic expression of cyclin D2 is sufficient to abolish the cell cycle arrest and apoptosis induced by IL-3 withdrawal or BCR/ABL inactivation, while over-expression of p27 Kipl can cause cell cycle arrest and apoptosis in BaF3 cells. Next, the signal pathways triggered by BCR/ABL and IL-3 to regulate cell proliferation and apoptosis via cyclin D2 and p27 Kipl were investigated. The PI 3-Kinase inhibitor LY294002 blocks the ability of BCR/ABL or IL-3 to induce cyclin D2 up-regulation and p27 Kipl down-regulation and inhibits BCR/ABL-induced entry in S phase. Ectopic expression of cyclin D2 was found to overcome the cell cycle arrest induced by inhibition of PI 3-Kinase by LY294002. The results indicate that BCR/ABL and EL-3 target cyclin D2 and p27 Kipl to mediate cell cycle arrest and apoptosis through a pathway involving the phosphatidylinositol-3 kinase (PI 3-K)

A study of thirty-five cases presenting marital problems to the Providence Family Welfare Society

Thesis (M.S.)--Boston University, 1948. This item was digitized by the Internet Archive

Understanding Factors Associated with Clinician Confidence to Identify and Treat PTSD and Complex PTSD

ABSTRACT This dissertation explores mental health clinicians’ experiences and self-identified confidence to identify and treat post-traumatic stress disorder (PTSD) and Complex PTSD. PTSD is a highly prevalent mental health condition that impacts an estimated 24.4 million individuals in the United States (PTSD United, 2019). Complex PTSD has just emerged for the first time with official diagnostic criteria in the publication of the ICD-11 in 2019 for use beginning in January 2022 (WHO, 2019). There is very little existing research that considers the experience or confidence of clinicians who work with clients who have PTSD and Complex PTSD, which is troubling given the prevalence rates of these disorders. Nor does research exist that speaks to what it will mean for clinicians to incorporate the new taxonomy for Complex PTSD or the ways in which Complex PTSD differs in identification or treatment approach in comparison to PTSD. Through the analysis of three principal factors, primary clinical focus on trauma, years of experience, and highest level of training, a foundational understanding of the ways these factors influence clinician confidence is presented in this Volume I report of the Meier’s Therapists’ Experiences Survey (M-TES). This exploratory survey research utilizes descriptive statistics, crosstab calculations, and several post hoc tests to begin to unpack the aggregated responses of 217 outpatient mental health clinicians who participated in the first distribution of the M-TES. This study provides an introductory look at factors associated with clinician confidence to identify PTSD and Complex PTSD and differentiate their treatment approach between the two. Recommendations are suggested for follow-up studies that would enhance knowledge specific to improving clinician confidence in identifying and treating PTSD and Complex PTSD. This research identifies needed areas of support for clinicians to identify PTSD and Complex PTSD and differentiate their treatment approach between the two, which would ultimately enhance and improve the treatment outcomes for individuals seeking mental health care for trauma conditions

Evaluation of a web-based portal to improve resident education by neonatology fellows

Background: Integration of web-based educational tools into medical training has been shown to increase accessibility of resources and optimize teaching. We developed a web-based educational portal (WBEP) to support teaching of pediatric residents about newborn medicine by neonatology fellows. Objectives: 1) To compare residents’ attitudes about their fellow-led education in the NICU pre- and post-WBEP; including assessment of factors that impact their education and usefulness of teaching tools. 2) To compare fellow utilization of various teaching modalities pre- and post-WBEP. Design/methods We queried residents about their attitudes regarding fellow-led education efforts and various teaching modalities in the NICU and logistics potentially impacting effectiveness. Based on these data, we introduced the WBEP – a repository of teaching tools (e.g., mock code cases, board review questions, journal articles, case-based discussion scenarios) for use by fellows to supplement didactic sessions in a faculty-based curriculum. We surveyed residents about the effectiveness of fellow teaching pre- and post-WBEP implementation and the type of fellow-led teaching modalities that were used. Results: After analysis of survey responses, we identified that residents cited fellow level of interest as the most important factor impacting their education. Post-implementation, residents described greater utilization of various teaching modalities by fellows, including an increase in use of mock codes (14% to 76%, p<0.0001) and journal articles (33% to 59%, p=0.02). Conclusions: A web-based resource that supplements traditional curricula led to greater utilization of various teaching modalities by fellows and may encourage fellow involvement in resident teaching

Innate immune activation in neonatal tracheal aspirates suggests endotoxin-driven inflammation

Background:: Tracheal aspirates (TAs) from critically ill neonates accumulate bacterial endotoxin and demonstrate mobilization of endotoxin-binding proteins, but the potential bioactivity of endotoxin in TAs is unknown. We characterized innate immune activation in TAs of mechanically ventilated neonates. Methods: Innate immune activation in TAs of mechanically ventilated neonates was characterized using a targeted 84-gene quantitative real-time (qRT) PCR array. Protein expression of cytokines was confirmed by multiplex assay. Expression and localization of the endotoxin-inducible antimicrobial protein Calgranulin C (S100A12) was assessed by flow cytometry. Endotoxin levels were measured in TA supernatants using the Limulus amoebocyte lysate assay. Results:: Analyses by qRT-PCR demonstrated expression of pattern recognition receptors, Toll-like receptor-nuclear factor κB and inflammasome pathways, cytokines/chemokines and their receptors, and anti-infective proteins in TA cells. Endotoxin positivity increased with postnatal age. As compared with endotoxin-negative TAs, endotoxin-positive TAs demonstrated significantly greater tumor necrosis factor (TNF), interleukin (IL)-6, IL-10, and serpin peptidase inhibitor, clade E, member 1 (SERPINE1) mRNA, and IL-10, TNF, and IL-1β protein. Expression of S100A12 protein was localized to TA neutrophils. Conclusion:: Correlation of endotoxin with TA inflammatory responses suggests endotoxin bioactivity and the possibility that endotoxin antagonists could mitigate pulmonary inflammation and its sequelae in this vulnerable population

Fab@Home Model 2: Towards Ubiquitous Personal Fabrication Devices

The open-architecture, open-source Fab@Home platform has proven to be an important system within the SFF community. In order to facilitate wider spread of the Fab@Home platform and SFF throughout the world, we aimed to improve critical aspects of the system, and business model. By changing the electronics package and streamlining the mechanics, the cost of the system was brought from $2500 to$1600. By changing the business model we hope to transform the SFF market and spur innovation.Mechanical Engineerin

Predictors of insufficient sweat production during confirmatory testing for cystic fibrosis

Michigan's Newborn Screening (NBS) Program began statewide screening for cystic fibrosis (CF) in October 2007. Confirmatory sweat testing is performed in infants having initial immunoreactive trypsinogen concentrations ≥99.8th percentile or ≥96th percentile and at least one CF mutation identified by DNA analysis. Some infants fail to produce a sufficient quantity of sweat (QNS—quantity not sufficient) to test for CF, meaning disease confirmation is delayed and sweat testing is later repeated. In this study, we evaluate predictors of QNS results. Information from the linked birth certificates and NBS diagnostic confirmation data were used. The study population was resident infants born in Michigan in 2008 who underwent a sweat test. Bivariate analyses revealed that preterm birth, low birth weight, CF care center, and race were significantly associated with QNS sweat testing results. Adjusted analyses indicated that preterm infants were 2.4 times more likely to have QNS results (95% CI 0.9, 6.4). When age at time of test, accounting for gestational age (gestational age at delivery plus postdelivery age of life = corrected age), was used in the multivariable model, infants <39 weeks were 7.4 times more likely to have QNS results (95% CI 2.5, 21.8). Waiting to sweat test until an infant is aged 39 weeks or more (corrected age) would likely reduce the rate of QNS results, thereby reducing the burden of repeat sweat testing on families and healthcare providers. Further research is necessary to understand the impact of potential delays in diagnosis/treatment relative to postponing sweat testing. Pediatr Pulmonol. 2011; 46:23–30. © 2010 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78485/1/21318_ftp.pd

NIDCAP improves brain function and structure in preterm infants with severe intrauterine growth restriction

Objective: The effect of NIDCAP (Newborn Individualized Developmental Care and Assessment Program) was examined on the neurobehavioral, electrophysiological and neurostructural development of preterm infants with severe intrauterine growth restriction (IUGR). Study Design: A total of 30 infants, 27–33 weeks gestation, were randomized to control (C; N=17) or NIDCAP/experimental (E; N=13) care. Baseline health and demographics were assessed at intake; electroencephalography (EEG) and magnetic resonance imaging (MRI) at 35 and 42 weeks postmenstrual age; and health, growth and neurobehavior at 42 weeks and 9 months corrected age (9 months). Results: C and E infants were comparable in health and demographics at baseline. At follow-up, E infants were healthier, showed significantly improved brain development and better neurobehavior. Neurobehavior, EEG and MRI discriminated between C and E infants. Neurobehavior at 42 weeks correlated with EEG and MRI at 42 weeks and neurobehavior at 9 months. Conclusion: NIDCAP significantly improved IUGR preterm infants' neurobehavior, electrophysiology and brain structure. Longer-term outcome assessment and larger samples are recommended

Guidelines for implementation of cystic fibrosis newborn screening programs: Cystic Fibrosis Foundation workshop report

Newborn screening for cystic fibrosis offers the opportunity for early intervention and improved outcomes. This summary, resulting from a workshop sponsored by the Cystic Fibrosis Foundation to facilitate implementation of widespread high quality cystic fibrosis newborn screening, outlines the steps necessary for success based on the experience of existing programs. Planning should begin with a workgroup composed of those who will be responsible for the success of the local program, typically including the state newborn screening program director and cystic fibrosis care center directors. The workgroup must develop a screening algorithm based on program resources and goals including mechanisms available for sample collection, regional demographics, the spectrum of cystic fibrosis disease to be detected, and acceptable failure rates of the screen. The workgroup must also ensure that all necessary guidelines and resources for screening, diagnosis, and care be in place prior to cystic fibrosis newborn screening implementation. These include educational materials for parents and primary care providers; systems for screening and for providing diagnostic testing and counseling for screen-positive infants and their families; and protocols for care of this unique population. This summary explores the benefits and risks of various screening algorithms, including complex situations that can occur involving unclear diagnostic results, and provides guidelines and sample materials for state newborn screening programs to develop and implement high quality screening for cystic fibrosis

Diagnosis of Cystic Fibrosis in Screened Populations

Objective Cystic fibrosis (CF) can be difficult to diagnose, even when newborn screening (NBS) tests yield positive results. This challenge is exacerbated by the multitude of NBS protocols, misunderstandings about screening vs diagnostic tests, and the lack of guidelines for presumptive diagnoses. There is also confusion regarding the designation of age at diagnosis. Study design To improve diagnosis and achieve standardization in definitions worldwide, the CF Foundation convened a committee of 32 experts with a mission to develop clear and actionable consensus guidelines on diagnosis of CF with an emphasis on screened populations, especially the newborn population. A comprehensive literature review was performed with emphasis on relevant articles published during the past decade. Results After reviewing the common screening protocols and outcome scenarios, 14 of 27 consensus statements were drafted that apply to screened populations. These were approved by 80% or more of the participants. Conclusions It is recommended that all diagnoses be established by demonstrating dysfunction of the CF transmembrane conductance regulator (CFTR) channel, initially with a sweat chloride test and, when needed, potentially with newer methods assessing membrane transport directly, such as intestinal current measurements. Even in babies with 2 CF-causing mutations detected via NBS, diagnosis must be confirmed by demonstrating CFTR dysfunction. The committee also recommends that the latest classifications identified in the Clinical and Functional Translation of CFTR project [http://www.cftr2.org/index.php] should be used to aid with CF diagnosis. Finally, to avoid delays in treatment, we provide guidelines for presumptive diagnoses and recommend how to determine the age of diagnosis