No description available.

The current study examined the psychological effects of recurring earthquake aftershocks in the city of Christchurch, New Zealand, which began in September 2010. Although it has been identified that exposure to ongoing adverse events such as continuing terrorist attacks generally leads to the development of increasing symptomology over time, differences in perceived controllability and blame between man-made and natural adverse events may contribute to differences in symptom trajectories. Residents of two Christchurch suburbs differentially affected by the earthquakes (N = 128) were assessed on measures of acute stress disorder, generalised anxiety, and depression, at two time points approximately 4-5 months apart, in order to determine whether symptoms intensified or declined over time in the face of ongoing aftershocks. At time 1, clinically significant levels of acute stress were identified in both suburbs, whereas clinical elevations in depression and anxiety were only evident in the most affected suburb. By time 2, both suburbs had fallen below the clinical range on all three symptom types, identifying a pattern of habituation to the aftershocks. Acute stress symptoms at time 2 were the most highly associated with the aftershocks, compared to symptoms of generalised anxiety and depression which were identified by participant reports to be more likely associated with other earthquake-related factors, such as insurance troubles and less frequent socialisation. The finding that exposure to ongoing earthquake aftershocks leads to a decline in symptoms over time may have important implications for the assessment of traumatic stress-related disorders, and provision of services following natural, as compared to man-made, adverse events.

Currently, the intensive chemotherapy remains the first line treatment for B cell acute lymphoblastic leukemia (B-ALL). Although these regimens have significantly improved patient outcomes, their use is associated with debilitating morbidities and fatal relapses, highlighting the great need in new agents that target essential survival signals in leukemia. Thus, the overall goal of my project was to gain insights into the signaling abnormalities that regulate aberrant proliferation and survival of B-ALL cells in an effort to identify novel targets in this malignancy. This study demonstrated that pre-B cell receptor (pre-BCR)-independent spleen tyrosine kinase (SYK) activity was required for the survival and proliferation of a p53-/-PrkdcSCID/SCID mouse model of B-ALL. I extended this discovery to human disease, demonstrating that SYK was activated in primary B-ALL, independent of the pre-BCR expression. The small molecule SYK inhibitor fostamatinib (fosta) significantly attenuated proliferation of 79 primary diagnostic B-ALL samples at clinically achievable concentrations. Importantly, fosta treatment reduced dissemination of engrafting B-ALL cells into the spleen, liver, kidney and central nervous system (CNS) in a NOD.Prkdcscid/scidIl2rgtm1Wjl/SzJ xenotransplant model of B-ALL. Analysis of signaling abnormalities using a high-throughput phospho-flow cytometry platform demonstrated that pediatric and adult B-ALL samples exhibit variable basal activation of BCR, iii PI3K/AKT/mTOR, MAPK and JAK/STAT pathways. Importantly, we identified that fosta-mediated inhibition of SYK, PLC2, CRKL and EIF4E phosphorylation in B-ALL was predictive of its anti-leukemic activity, and was distinct from the cellular actions of other small molecule inhibitors of key nodal signaling pathways. Examination of molecular mechanism of fosta action by gene expression profiling revealed transcriptional effects of fosta treatment that included, most notably, potent inhibition of pathways involved in lymphocyte activation and inflammation. In conclusion, this study demonstrates that SYK signaling is crucial for B-ALL survival and provides detailed characterization of cellular and molecular mechanisms of fosta action in B-ALL. These data argue in favor of testing small molecule SYK inhibitors in pediatric and adult B-ALL.

Acute myeloid leukemia (AML) often remains refractory to current chemotherapy and transplantation approaches despite many advances in our understanding of mechanisms in leukemogenesis. The bone marrow “niche” or microenvironment, however, may be permissive to leukemia development and studying interactions between the microenvironment and leukemia cells may provide new insight for therapeutic advances. Mesenchymal stem cells (MSCs) are central to the development and maintenance of the bone marrow niche and have been shown to have important functional alterations derived from patients with different hematological disorders. The extent to which MSCs derived from AML patients are altered remains unclear. The aim of this study was to detect changes occurring in MSCs obtained from human bone marrow in patients with AML by comparing their function and gene expression pattern with normal age-matched controls. MSCs expanded from patients diagnosed with acute leukemia were observed to have heterogeneous morphological characteristics compared to the healthy controls. Immunohistochemistry and flow data confirmed the typical cell surface immunophenotype of CD90+ CD105+ CD73+ CD34- CD45-, although MSCs from two patients with AML revealed reduced surface expression of CD105 and CD90 antigens respectively. Differentiation assays demonstrated the potential of MSCs from AML patients and healthy donors to differentiate into bone, fat and cartilage. However, the ability of MSCs from AML samples to support hematopoietic function of CD34+ progenitors was found to be impaired while the key hematopoietic genes were found to be differentially expressed on AML-MSCs compared to nMSCs. These studies indicate that there exist differences in the biologic profile of MSCs from AML patients compared to MSCs derived from healthy donors. The results described in the thesis provide a formulation for additional studies that may allow us to identify new targets for improved treatment of AML.

Severe acute malnutrition (SAM) threatens the lives of millions of children globally. In developing countries, 15% of the population is undernourished; and half of the mortality for children younger than 5 years old is associated to undernutrition (UNICEF, 2008), the most vulnerable population to malnutrition. Overall, Haiti reports 19.2% of children are undernourished, 11.4% are underweight, and 10.3% are wasted (Lutter et al., 2011; DHS, 2005, CWW-proposal, 2007). The treatment for the management of SAM has evolved over the decades (Lancet, 2006). The Community Management of Acute Malnutrition (CMAM) is an evidence-based intervention with proven effectiveness for treating children with SAM (Collins, 2007). The CMAM intervention reduces infant mortality related to SAM (Lancet, 2006, Collins, 2007; WHO, 2001; UNICEF, 2009). The CMAM intervention was validated in 2007 through the United Nations agencies for the management of SAM. Nevertheless, it has had limited reach and poor public health impact in some of the developing countries (e.g.; Haiti) where it was implemented. Concern Worldwide is a non-profit humanitarian organization, which pioneered in the creation of the CMAM intervention. Concern introduced the CMAM interventions in Haiti in October 2007 as a pilot program. The program was implemented in close to 20 health institutions in the metropolitan Port-au-Prince. As is the case with any other public health program, there were many challenges to the CMAM intervention implementation in Haiti. Concern’s CMAM intervention was not sustainable after it retracted the technical support in 2012 (UNICEF-Haiti country report, 2014). The purpose of this paper is to first review the Concern Worldwide CMAM program implementation in five communes of Port-au-Prince. Then, a suggested plan is outlined for the revitalization of the intervention’s activities and long-term sustainability once revitalized.

In order to eliminate the unnecessary suffering of children requiring painful procedures to diagnose and treat their illness, management of this pain must be a priority for nurses. The role nurses assume in the current undermanagement of children's pain requires further examination. In the first paper, a comprehensive review of the available literature on pediatric pain management was conducted in order to provide the context in which this issue is situated. The second paper is a qualitative inquiry seeking nurses' accounts of the individual level factors they identify that influence their choices for distraction to manage children's procedural pain. Nurses described the three key determinants of nursing knowledge, experience and relational capacity as influencing their practice. These descriptions provided an extended understanding on nurses' choices for using distraction to manage children's procedure-related pain. Nurses disclosed using distraction for themselves, as well as for the child experiencing a painful procedure.

No description available.

The quality of care for Swedish patients with acute myocardial infarction (AMI) is continuously increasing. Nevertheless, a great potential for improvement still exists. The aim of the present study was to design and implement a systematic quality improvement (QI) collaborative in the area of AMI care, and to validate its usefulness primarily by analyzing its effect on hospital adherence to national guidelines. Also, the impact on patient morbidity and mortality was to be evaluated. The intervention was based on proven QI methodologies, as well as interactive use of a web-based quality registry with enhanced, powerful feedback functions. 19 hospitals in the intervention group were matched to 19 similar control hospitals. In comparison with the control group, the intervention group showed significantly higher post-interventional improvements in 4 out of 5 analyzed quality indicators (significance shown for ACE-inhibitors, Clopidogrel, Heparin/LMWH, Coronary angiography, no significance for Lipid-lowering therapy). From baseline to the post-intervention measurement, the intervention hospitals showed significantly lower all-cause mortality and cardiovascular re-admission rates (events per 100 patient-years; -2,82, 95% CI -5,26 to -0,39; -9,31, 95% CI -15,48 to -3,14, respectively). No significant improvements were seen in the control group. The improved guideline adherence rates in the intervention hospitals were sustained for all indicators but one (ACE-inhibitors), this during a follow-up measurement three months after study support withdrawal. No effects were seen on any indicators other than those primarily targeted. In conclusion, by combining a systematic QI collaborative with the utilization of a national quality registry, significant improvements in quality of care for patients with AMI can be achieved.

Host antigen presenting cells (APC) are known to be critical for the induction of graft versus host disease (GVHD) after allogeneic bone marrow transplantation (BMT) but the relative contribution of specific APC subsets remains unclear. We have studied the role of host B cells in GVHD by using B cell deficient (ìMT) mice as bone marrow transplant recipients in a model of CD4 T cell-dependent GVHD to major histocompatibility antigens. We demonstrated that acute GVHD is initially augmented in ìMT recipients relative to wild-type (WT) recipients (mortality: 85% v 44%, P<0.01) and that this was the result of an increase in donor T cell proliferation, expansion and inflammatory cytokine production early after BMT. Recipient B cells were depleted 28-fold at the time of BMT by total body irradiation (TBI) administered 24 hours earlier and we demonstrated that TBI rapidly induced sustained IL-10 generation from B cells but not dendritic cells (DC) or other cellular populations within the spleen. Finally, recipient mice in which B cells were unable to produce IL-10 due to homologous gene deletion developed more severe acute GVHD than recipient mice in which B cells are WT. Thus the induction of interlukin-10 (IL-10) in host B cells during TBI attenuates experimental acute GVHD.

No description available.