Predictors of HIV-1 slow progression among vertically infected children in Botswana

HIV-1 infected children display a highly variable rate of progression to AIDS. Data about reasons underlying the variable progression to AIDS among vertically-infected children is sparse, and the few studies that have examined this important question have almost exclusively been done in the developed world. This is despite the fact that Sub-Saharan Africa is home to over 90% of all HIV infected children around the world.^ The main objective of this study was to examine predictors of HIV-1 slow progression among vertically infected children in Botswana, using a case control design. Cases (slow progressors) and controls (rapid progressors) were drawn from medical records of HIV-1 infected children being followed up for routine care and treatment at the BBCCCOE between February 2003 and February 2011. Univariate and Multivariate Logistic Regression Analyses were performed to identify independent predictors of slow disease progression and control for confounding respectively. ^ The study population comprised of 152 cases and 201 controls with ages ranging from 6 months to 16 years at baseline. Low baseline HIV-1 RNA viral load was the strongest independent predictor of slow progression (adjusted OR = 5.52, 95% CI = 2.75-11.07; P <0.001). Other independent predictors of slow disease progression identified were: lack of history of PMTCT with single dose Nevirapine plus Zidovudine (adjusted OR = 4.45, 95% CI = 1.45-13.69; P = 0.009) and maternal vital status (alive) (adjusted OR = 2.46, 95% CI = 1.51-4.01; P < 0.00 ).^ The results of this study may help clinicians and policy-makers in resource-limited settings to identify, at baseline, which children are at highest risk of rapid progression to AIDS and thus prioritize them for immediate intervention with HAART and other measures that would mitigate disease progression. At the same time HAART may be delayed among children who are at lower risk of disease progression. This would enable the highly affected, yet impoverished, Sub-Saharan African countries to use their scarce resources more efficiently which may in turn ensure that their National Antiretroviral Therapy Programs become more sustainable. Delaying HAART among the low-risk children would also lower the occurrence of adverse drug reactions associated with antiretroviral drugs exposure.^ Keywords. Slow Progressors, Rapid Progressors, HIV-1, Predictors, Children, Vertical Transmission, Sub-Saharan Africa^

Fibulin-2 stabilizes tumor extracellular matrix and drives malignant progression of lung adenocarcinoma

The ECM of epithelial carcinomas undergoes structural remodeling during periods of uncontrolled growth, creating regional heterogeneity and torsional stress. How tumors maintain ECM integrity in the face of dynamic biophysical forces is still largely unclear. This study addresses these deficiencies using mouse models of human lung adenocarcinoma. Spontaneous lung tumors were marked by disorganized basement membranes, dense collagen networks, and increased tissue stiffness. Metastasis-prone lung adenocarcinoma cells secreted fibulin-2 (Fbln2), a matrix glycoprotein involved in ECM supra-molecular assembly. Fibulin-2 depletion in tumor cells decreased the intra-tumoral abundance of matrix metalloproteinases and reduced collagen cross-linking and tumor compressive properties resulting in inhibited tumor growth and metastasis. Fbln2 deposition within intra-tumoral fibrotic bands was a predictor of poor clinical outcome in patients. Collectively, these findings support a feed-forward model in which tumor cells secrete matrix-stabilizing factors required for the assembly of ECM that preferentially favors malignant progression. To our knowledge, this is the first evidence that tumor cells directly regulate the integrity of their surrounding matrix through the secretion of matrix-stabilizing factors such as fibulin-2. These findings open a new avenue of research into matrix assembly molecules as potential therapeutic targets in cancer patients.

Pathway Semantics: An Algebraic Data Driven Algorithm to Generate Hypotheses about Molecular Patterns Underlying Disease Progression

The overarching goal of the Pathway Semantics Algorithm (PSA) is to improve the in silico identification of clinically useful hypotheses about molecular patterns in disease progression. By framing biomedical questions within a variety of matrix representations, PSA has the flexibility to analyze combined quantitative and qualitative data over a wide range of stratifications. The resulting hypothetical answers can then move to in vitro and in vivo verification, research assay optimization, clinical validation, and commercialization. Herein PSA is shown to generate novel hypotheses about the significant biological pathways in two disease domains: shock / trauma and hemophilia A, and validated experimentally in the latter. The PSA matrix algebra approach identified differential molecular patterns in biological networks over time and outcome that would not be easily found through direct assays, literature or database searches. In this dissertation, Chapter 1 provides a broad overview of the background and motivation for the study, followed by Chapter 2 with a literature review of relevant computational methods. Chapters 3 and 4 describe PSA for node and edge analysis respectively, and apply the method to disease progression in shock / trauma. Chapter 5 demonstrates the application of PSA to hemophilia A and the validation with experimental results. The work is summarized in Chapter 6, followed by extensive references and an Appendix with additional material.

Use of Echogenic Immunoliposomes for Delivery of both Drug and Stem Cells for Inhibition of Atheroma Progression

Use of Echogenic Immunoliposomes for Delivery of both Drug and Stem Cells for Inhibition of Atheroma Progression By Ali K. Naji B.S. Advisor: Dr. Melvin E. Klegerman PhD Background and significance: Echogenic liposomes can be used as drug and cell delivery vehicles that reduce atheroma progression. Vascular endothelial growth factor (VEGF) is a signal protein that induces vasculogenesis and angiogenesis. VEGF functionally induces migration and proliferation of endothelial cells and increases intracellular vascular permeability. VEGF activates angiogenic transduction factors through VEGF tyrosine kinase domains in high-affinity receptors of endothelial cells. Bevacizumab is a humanized monoclonal antibody specific for VEGF-A which was developed as an anti-tumor agent. Often, anti-VEGF agents result in regression of existing microvessels, inhibiting tumor growth and possibly causing tumor shrinkage with time. During atheroma progression neovasculation in the arterial adventitia is mediated by VEGF. Therefore, bevacizumab may be effective in inhibiting atheroma progression. Stem cells show an ability to inhibit atheroma progression. We have previously demonstrated that monocyte derived CD-34+ stem cells that can be delivered to atheroma by bifunctional-ELIP ( BF-ELIP) targeted to Intercellular Adhesion Molecule-1 (ICAM-1) and CD-34. Adhesion molecules such as ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1) are expressed by endothelial cells under inflammatory conditions. Ultrasound enhanced liposomal targeting provides a method for stem cell delivery into atheroma and encapsulated drug release. This project is designed to examine the ability of echogenic liposomes to deliver bevacizumab and stem cells to inhibit atheroma progression and neovasculation with and without ultrasound in vitro and optimize the ultrasound parameters for delivery of bevacizumab and stem cells to atheroma. V Hypotheses: Previous studies showed that endothelial cell VEGF expression may relate to atherosclerosis progression and atheroma formation in the cardiovascular system. Bevacizumab-loaded ELIP will inhibit endothelial cell VEGF expression in vitro. Bevacizumab activity can be enhanced by pulsed Doppler ultrasound treatment of BEV-ELIP. I will also test the hypothesis that the transwell culture system can serve as an in vitro model for study of US-enhanced targeted delivery of stem cells to atheroma. Monocyte preparations will serve as a source of CD34+ stem cells. Specific Aims: Induce VEGF expression using PKA and PKC activation factors to endothelial cell cultures and use western blot and ELISA techniques to detect the expressed VEGF.  Characterize the relationship between endothelial cell proliferation and VEGF expression to develop a specific EC culture based system to demonstrate BEV-ELIP activity as an anti-VEGF agent. Design a cell-based assay for in vitro assessment of ultrasound-enhanced bevacizumab release from echogenic liposomes.  Demonstrate ultrasound delivery enhancement of stem cells by applying different types of liposomes on transwell EC culture using fluorescently labeled monocytes and detect the effect on migration and attachment rate of these echogenic liposomes with and without ultrasound in vitro.

Potential roles for bcl-2 in the pathogenesis, progression, and treatment of prostate cancer

The most common molecular alterations observed in prostate cancer are increased bcl-2 protein expression and mutations in p53. Understanding the molecular alterations associated with prostate cancer are critical for successful treatment and designing new therapeutic interventions. Hormone-ablation therapy remains the most effective nonsurgical treatment; however, most patients will relapse with hormone-independent, refractory disease. This study addresses how hormone-ablation therapy may increase bcl-2, develops a transgenic model to elucidate the role of bcl-2 multistep prostate carcinogenesis, and assesses how bcl-2 may confer resistance to cell death induction using adenoviral wild-type p53 gene therapy. ^ Two potential androgen response elements were identified in the bcl-2 promoter. Bcl-2 promoter luciferase constructs were transfected into the hormone- sensitive LNCaP prostate cell line. In the presence of dihydrotestosterone, the activity of one bcl-2 promoter luciferase construct was repressed 40% compared to control cells grown in charcoal-stripped serum. Additionally, it was demonstrated that both bcl-2 mRNA and protein were downregulated in the LNCaP cells grown in the presence DHT. This suggests that DHT represses bcl-2 expression through possible direct and indirect mechanisms and that hormone-ablation therapy may actually increases bcl-2 protein. ^ To determine the role of bcl-2 in prostate cancer progression in vivo, probasin-bcl-2 mice were generated where human bcl-2 was targeted to the prostate. Increased bcl-2 expression rendered the ventral prostate more resistant to apoptosis induction following castration. When the probasin-bcl-2 mice were crossed with TRAMP mice, the latency to tumor formation was decreased. The expression of bcl-2 in the double transgenic mice did not affect the incidence of metastases. The double transgenic model will facilitate the study of in vivo effects of specific genetic lesions during the pathogenesis of prostate cancer. ^ The effects of increased bcl-2 protein on wild-type adenoviral p53-mediated cell death were determined in prostatic cell lines. Increased bcl-2 protected PC3 and DU145 cell lines, which possess mutant p53, from p53-mediated cell death and reductions in cell viability. Bcl-2 did not provide the same protective effect in LNCaP cell line, which expresses wild-type p53. This suggests that the ability of bcl-2 to protect against p53-mediated cell death is dependent upon the endogenous status of p53. ^

Career development and public policy

The rationale for policy interest in career development services, and the way in which this rationale is being strengthened by the current transformations in work and career, are discussed. The potential roles of public policy in relation to career development services are explored, along with ways in which such services can influence the policy-making process. A range of policy issues related to making career development services available to all throughout life are identified: these include the nature of such services, where they are to be located, and who is to pay for them. It is argued that there is a need for stronger structures and processes to bring together career development practitioners with policy- makers and other stakeholder interests in order to address tasks of common concern, at both national and international levels.

Career guidance in Denmark : Social control in a velvet glove

La Orientación Vocacional en Dinamarca está bien organizada y es altamente profesional. Esto refleja una política orientadora centrada en el papel que la orientación juega como instrumento en el ejercicio de un leve control social. Con este telón de fondo, el dilema de la Orientación en Dinamarca reside en el delicado equilibrio existente entre la orientación considerada como una herramienta para el desarrollo personal, y como un instrumento de control social.

Career guidance in Quebec, Canadá

First, the guidance counselor profession in the province of Quebec will be described: the professional association to which it belongs, the required in- struction, the counselors' tasks and the institutions for which they work. There follows the description of the main current tendencies in career guidance devel- opment in this French-speaking area of Canada with about 7.2 million inhabit- ants, approximately one fourth of the total country population. Finally, a brief description of the Center for Research on Education and Labor of the University of Shebrooke as well as of some instruments that one of the teams is constructing will be provided.

International governmental agencies and career guidance

The international Organization for Economic Cooperation and Develop-ment (OECD), like many national and international organizations concerned with economic development believes that career guidance has an important role in promoting the development of a country's human resources. (Mapping the future: Young People and career guidance OECD, 1996). Generally the economic development agencies always recommend that career guidance services should be strengthened. Too frequently, however, they do not recognize the difficulties facing counselor in the schools and do not give clear and specific recommendations, yet they appear to believe that the education or other au thorities who are responsible to guidance will quickly agree and provide more resources for guidance. In addition to economic development agencies, social and educational development agencies also make important recommendations concerning the provision of guidance services. UNESCO, for example, has published two re- cent reports (Policies and Guidelines for Educational and Vocational Guidelines for Equal Access and Opportunity for Girls and Women in Technical and Vocational Education.) It is interesting to compare the OECD and UNESCO rec- ommendations and note that the relative strengths of each set of recommenda- tions, and to imagine how they might be combined in advocating changes in policies and programs.

Theoretical frames for the new tasks in career guidance and counseling

Personal and career development interventions aim to help people find answers to personal and career development issues that stem from the societal context in which they live. Societal definitions of these career issues have a double consequence. On the one hand, these issues differ from one culture to another; and, on the other, they evolve along with the contexts in which they are expressed. Implementation of rigorous career development interventions requires, first, a scientific reconstruction of these societal issues and, second, a clear definition of these interventions' goals and ends. Our current view of the societal issues relating to personal and career development interventions may be phrased thus--"How can we help individuals direct their lives, in the (human) society where they interact?" It may be turned into the following scientific question: "What are the factors and processes of life-long self-construction?" An articulation of three major propositions (sociological, cognitive and dynamic) seems to be needed to answer this question. Such a theoretical frame does not allow for a definition of personal and career development interventions ends. In the world of today, the adoption by everyone of a personal ethic of responsibility towards all life on Earth (H. Jonas) could well be a fundamental end to these interventions.

Career Guidance: Challenges for the New Century under an International Perspective

This paper is dedicated to key issues of the actual challenges in all societies regardless their developmental level and how the international guidance community is coping with these challenges. It deals with the importance of guidance in a changing society, quality assurance, access to services and qualification of guidance practitioners under an international perspective.

The increasing role of career guidance at the turn of the centuries

At the beginning this paper sketches trends of the rapid changes of nearly all life issues, especially in society, work behaviours, labour environment and demands for adjustment under new social values. As main factors which influence worldwide the economic development and the labour market are elaborated the globalization and liberalization process and the labour market aspects of feminization, ageing labour force, migration, unemployment as a global phenomenon and general changes in labour demand by occupations and skill level. A well-developed and highly qualified career guidance service is seen as one of the most effective instruments in solving these problems which are raised by the described developements. The personal and psychological effects of uncertainty and dislocation of people and the new requirements of the expected qualification standard make career guidance an important cornerstone to cope with these social aspects. Thus, the nature and structure of guidance and counselling are described under the new challenges. The international co-operation in the guidance sector has accompanied this process in delivering two important documents. The Mission Statement and the Ethical Standards of IAEVG, adopted by the General Assembly of IAEVG in 1995, show in what direction guidance services have to be developed.

Investigation project: Representations about the professional role of recently graduated from the psychology career, state University of La Plata : Its relation with job insertion and performance

In this paper we present a research that took place between 2010 and 2012 included in an investigation scholarship awarded by the State University of la Plata. It is about the problem with the transition between college and professional work. It is a part of the produced studies on the importance of social representations as factors that impact on the performance of specific activities. In this case it's about finding out the relations given among the representations about graduated professional role of the Psychology career and its job insertion and performance. The theoretical framework corresponds to Social Psychology and Guidance theories. Methodologically this is an exploratory and descriptive study, based on the 'triangulation' conception, of multiple type, that allows combining in the same investigation, different strategies, theoretical perspectives and sources; however qualitative techniques were prioritized to analyze data. Finally there are some considerations about the social representations concerning to the professional performance, mainly in the clinical field associated to education, and also to the problems of both situations over other fields