58 research outputs found

    The Current Crisis in Emergency Care and the Impact on Disaster Preparedness

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    <p>Abstract</p> <p>Background</p> <p>The Homeland Security Act (HSA) of 2002 provided for the designation of a critical infrastructure protection program. This ultimately led to the designation of emergency services as a targeted critical infrastructure. In the context of an evolving crisis in hospital-based emergency care, the extent to which federal funding has addressed disaster preparedness will be examined.</p> <p>Discussion</p> <p>After 9/11, federal plans, procedures and benchmarks were mandated to assure a unified, comprehensive disaster response, ranging from local to federal activation of resources. Nevertheless, insufficient federal funding has contributed to a long-standing counter-trend which has eroded emergency medical care. The causes are complex and multifactorial, but they have converged to present a severely overburdened system that regularly exceeds emergency capacity and capabilities. This constant acute overcrowding, felt in communities all across the country, indicates a nation at risk. Federal funding has not sufficiently prioritized the improvements necessary for an emergency care infrastructure that is critical for an all hazards response to disaster and terrorist emergencies.</p> <p>Summary</p> <p>Currently, the nation is unable to meet presidential preparedness mandates for emergency and disaster care. Federal funding strategies must therefore be re-prioritized and targeted in a way that reasonably and consistently follows need.</p

    Custom CGH array profiling of copy number variations (CNVs) on chromosome 6p21.32 (HLA locus) in patients with venous malformations associated with multiple sclerosis

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    <p>Abstract</p> <p>Background</p> <p>Multiple sclerosis (MS) is a complex disorder thought to result from an interaction between environmental and genetic predisposing factors which have not yet been characterised, although it is known to be associated with the HLA region on 6p21.32. Recently, a picture of chronic cerebrospinal venous insufficiency (CCSVI), consequent to stenosing venous malformation of the main extra-cranial outflow routes (VM), has been described in patients affected with MS, introducing an additional phenotype with possible pathogenic significance.</p> <p>Methods</p> <p>In order to explore the presence of copy number variations (CNVs) within the HLA locus, a custom CGH array was designed to cover 7 Mb of the HLA locus region (6,899,999 bp; chr6:29,900,001-36,800,000). Genomic DNA of the 15 patients with CCSVI/VM and MS was hybridised in duplicate.</p> <p>Results</p> <p>In total, 322 CNVs, of which 225 were extragenic and 97 intragenic, were identified in 15 patients. 234 known polymorphic CNVs were detected, the majority of these being situated in non-coding or extragenic regions. The overall number of CNVs (both extra- and intragenic) showed a robust and significant correlation with the number of stenosing VMs (Spearman: r = 0.6590, p = 0.0104; linear regression analysis r = 0.6577, p = 0.0106).</p> <p>The region we analysed contains 211 known genes. By using pathway analysis focused on angiogenesis and venous development, MS, and immunity, we tentatively highlight several genes as possible susceptibility factor candidates involved in this peculiar phenotype.</p> <p>Conclusions</p> <p>The CNVs contained in the HLA locus region in patients with the novel phenotype of CCSVI/VM and MS were mapped in detail, demonstrating a significant correlation between the number of known CNVs found in the HLA region and the number of CCSVI-VMs identified in patients. Pathway analysis revealed common routes of interaction of several of the genes involved in angiogenesis and immunity contained within this region. Despite the small sample size in this pilot study, it does suggest that the number of multiple polymorphic CNVs in the HLA locus deserves further study, owing to their possible involvement in susceptibility to this novel MS/VM plus phenotype, and perhaps even other types of the disease.</p

    Epidermal growth factor regulates Mcl-1 expression through the MAPK-Elk-1 signalling pathway contributing to cell survival in breast cancer

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    Myeloid cell leukaemia-1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 family that is elevated in a variety of tumour types including breast cancer. In breast tumours, increased Mcl-1 expression correlates with high tumour grade and poor patient survival. We have previously demonstrated that Her-2 levels correspond to increased Mcl-1 expression in breast tumours. Epidermal growth factor (EGF) receptor signalling is frequently deregulated in breast cancer and leads to increased proliferation and survival. Herein, we determined the critical downstream signals responsible for the EGF mediated increase of Mcl-1 and their role in cell survival. We found that both Mcl-1 mRNA and protein levels are rapidly induced upon stimulation with EGF. Promoter analysis revealed that an Elk-1 transcription factor-binding site is critical for EGF activation of the Mcl-1 promoter. Furthermore, we found that knockdown of Elk-1or inhibition of the Erk signalling pathway was sufficient to block EGF upregulation of Mcl-1 and EGF mediated cell survival. Using chromatin immunoprecipitation and biotin labelled probes of the Mcl-1 promoter, we found that Elk-1 and serum response factor are bound to the promoter after EGF stimulation. To determine whether Mcl-1 confers a survival advantage, we found that knockdown of Mcl-1 expression increased apoptosis whereas overexpression of Mcl-1 inhibited drug induced cell death. In human breast tumours, we found a correlation between phosphorylated Elk-1 and Mcl-1 protein levels. These results indicate that the EGF induced activation of Elk-1 is an important mediator of Mcl-1 expression and cell survival and therefore a potential therapeutic target in breast cancer

    Physiologically Based Pharmacokinetic (PBPK) Models for Lifetime Exposure to PCB 153 in Male and Female Harbor Porpoises (Phocoena phocoena): Model Development and Evaluation

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    Physiologically based pharmacokinetic (PBPK) models were developed for the most persistent polychlorinated biphenyl (PCB 153) in male and female harbor porpoises (Phocoena phocoena) to elucidate processes such as uptake, distribution, and elimination. Due to its limited metabolic capacities, long life span, and top position in marine food chains, this species is highly sensitive to pollution. The models consist of 5 compartments, liver, blubber, kidney, brain, and a compartment which accounts for the rest of the body, all connected through blood. All physiological and biochemical parameters were extracted from the literature, except for the brain/blood partition coefficient and rate of excretion, which were both fitted to data sets used for validation of the models. These data sets were compiled from our own analyses performed with GCMS on tissue samples of harbor porpoises. The intake of PCB 153 was from milk from birth to 4 months, and after weaning fish was the main food source. Overall, these models reveal that concentrations of PCB 153 in males increase with age but suggest that,asthe animalsgrowolder, metabolic transformation can be a possible pathway for elimination as well. In contrast, the model for females confirms that gestation and lactation are key processes for eliminating PCB 153 as body burdens decrease with age. These PBPK models are capable of simulating the bioaccumulation of PCB 153 during the entire life span of approximately 20 years of the harbor porpoises
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