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981.
Caroline Quach Margaret McArthur Allison McGeer Lynne Li Andrew Simor Marc Dionne Edith L��vesque Lucie Tremblay 《CMAJ》2012,184(4):E232-E239
Background:
The risk of infection following a visit to the emergency department is unknown. We explored this risk among elderly residents of long-term care facilities.Methods:
We compared the rates of new respiratory and gastrointestinal infections among elderly residents aged 65 years and older of 22 long-term care facilities. We used standardized surveillance definitions. For each resident who visited the emergency department during the study period, we randomly selected two residents who did not visit the emergency department and matched them by facility unit, age and sex. We calculated the rates and proportions of new infections, and we used conditional logistic regression to adjust for potential confounding variables.Results:
In total, we included 1269 residents of long-term care facilities, including 424 who visited the emergency department during the study. The baseline characteristics of residents who did or did not visit the emergency department were similar, except for underlying health status (visited the emergency department: mean Charlson Comorbidity Index 6.1, standard deviation [SD] 2.5; did not visit the emergency department: mean Charlson Comorbidity index 5.5, SD 2.7; p < 0.001) and the proportion who had visitors (visited the emergency department: 46.9%; did not visit the emergency department: 39.2%; p = 0.01). Overall, 21 (5.0%) residents who visited the emergency department and 17 (2.0%) who did not visit the emergency department acquired new infections. The incidence of new infections was 8.3/1000 patient-days among those who visited the emergency department and 3.4/1000 patient-days among those who did not visit the emergency department. The adjusted odds ratio for the risk of infection following a visit to the emergency department was 3.9 (95% confidence interval 1.4–10.8).Interpretation:
A visit to the emergency department was associated with more than a threefold increased risk of acute infection among elderly people. Additional precautions should be considered for residents following a visit to the emergency department.Infections associated with health care are an important health risk. A recent survey by the World Health Organization reported that 8.7% of patients in hospital developed such infections.1,2 The third leading cause of death in the United States is health care–associated deaths, with over 100 000 people dying from infections associated with health care each year.3 In Canada, a point-prevalence survey found that 11.6% of adults in hospital experience a health care–associated infection.4Little attention has been paid to infections acquired in other health care settings. Visiting an emergency department has been identified as a risk for disease during outbreaks of measles5,6 and SARS,7,8 but little is known about the potential risk of endemic infection from exposure in this setting. A visit to the emergency department differs from a stay in hospital: exposure and duration of contact with other patients is shorter, but the number and density of patients with acute illness with whom there could be contact is higher.Elderly residents of long-term care facilities are likely to be at the greatest risk of morbidity and mortality from communicable diseases acquired in the emergency department. When residents are transferred to the emergency department for assessment, they are likely to have longer stays and to be cared for in multibed observation areas and corridors.9 If they acquire an infection while in the emergency department, these residents may be the source of an outbreak upon return to their facility; this can lead to increases in workload and costs. A Canadian study estimated the cost of an influenza outbreak to be over $6000 per 30-day period, with an estimated incidence of death of 0.75/100 residents during the same period.10 In this study, we explored the risk of acute respiratory and gastrointestinal infection associated with a visit to the emergency department among elderly residents of long-term care facilities. 相似文献982.
Morgenthau A Livingstone M Adamiak P Schryvers AB 《Biochimie et biologie cellulaire》2012,90(3):417-423
Bacteria that inhabit the mucosal surfaces of the respiratory and genitourinary tracts of mammals encounter an iron-deficient environment because of iron sequestration by the host iron-binding proteins transferrin and lactoferrin. Lactoferrin is also present in high concentrations at sites of inflammation where the cationic, antimicrobial peptide lactoferricin is produced by proteolysis of lactoferrin. Several Gram-negative pathogens express a lactoferrin receptor that enables the bacteria to use lactoferrin as an iron source. The receptor is composed of an integral membrane protein, lactoferrin binding protein A (LbpA), and a membrane-bound lipoprotein, lactoferrin binding protein B (LbpB). LbpA is essential for growth with lactoferrin as the sole iron source, whereas the role of LbpB in iron acquisition is not yet known. In this study, we demonstrate that LbpB from 2 different species is capable of providing protection against the killing activity of a human lactoferrin-derived peptide. We investigated the prevalence of lactoferrin receptors in bacteria and examined their sequence diversity. We propose that the protection against the cationic antimicrobial human lactoferrin-derived peptide is associated with clusters of negatively charged amino acids in the C-terminal lobe of LbpB that is a common feature of this protein. 相似文献
983.
Thiostrepton, a macrocyclic thiopeptide antibiotic, inhibits prokaryotic translation by interfering with the function of elongation factor G (EF-G). Here, we have used 70S ribosome binding and GTP hydrolysis assays to study the effects of thiostrepton on EF-G and a newly described translation factor, elongation factor 4 (EF4). In the presence of thiostrepton, ribosome-dependent GTP hydrolysis is inhibited for both EF-G and EF4, with IC(50) values equivalent to the 70S ribosome concentration (0.15 μM). Further studies indicate the mode of thiostrepton inhibition is to abrogate the stable binding of EF-G and EF4 to the 70S ribosome. In support of this model, an EF-G truncation variant that does not possess domains IV and V was shown to possess ribosome-dependent GTP hydrolysis activity that was not affected by the presence of thiostrepton (>100 μM). Lastly, chemical footprinting was employed to examine the nature of ribosome interaction and tRNA movements associated with EF4. In the presence of non-hydrolyzable GTP, EF4 showed chemical protections similar to EF-G and stabilized a ratcheted state of the 70S ribosome. These data support the model that thiostrepton inhibits stable GTPase binding to 70S ribosomal complexes, and a model for the first step of EF4-catalyzed reverse-translocation is presented. 相似文献
984.
Wang S Astsaturov IA Bingham CA McCarthy KM von Mehren M Xu W Alpaugh RK Tang Y Littlefield BA Hawkins LD Ishizaka ST Weiner LM 《Cancer immunology, immunotherapy : CII》2012,61(1):49-61
Toll-like receptors are potent activators of the innate immune system and generate signals leading to the initiation of the adaptive immune response that can be utilized for therapeutic purposes. We tested the hypothesis that combined treatment with a Toll-like receptor agonist and an antitumor monoclonal antibody is effective and induces host-protective antitumor immunity. C57BL/6 human mutated HER2 (hmHER2) transgenic mice that constitutively express kinase-deficient human HER2 under control of the CMV promoter were established. These mice demonstrate immunological tolerance to D5-HER2, a syngeneic human HER2-expressing melanoma cell line. This human HER2-tolerant model offers the potential to serve as a preclinical model to test both antibody therapy and the immunization potential of human HER2-targeted therapeutics. Here, we show that E6020, a Toll-like receptor-4 (TLR4) agonist effectively boosted the antitumor efficacy of the monoclonal antibody trastuzumab in immunodeficient C57BL/6 SCID mice as well as in C57BL/6 hmHER2 transgenic mice. E6020 and trastuzumab co-treatment resulted in significantly greater inhibition of tumor growth than was observed with either agent individually. Furthermore, mice treated with the combination of trastuzumab and the TLR4 agonist were protected against rechallenge with human HER2-transfected tumor cells in hmHER2 transgenic mouse strains. These findings suggest that combined treatment with trastuzumab and a TLR4 agonist not only promotes direct antitumor effects but also induces a host-protective human HER2-directed adaptive immune response, indicative of a memory response. These data provide an immunological rationale for testing TLR4 agonists in combination with antibody therapy in patients with cancer. 相似文献
985.
Sheibani N Morrison ME Gurel Z Park S Sorenson CM 《American journal of physiology. Renal physiology》2012,302(7):F809-F819
The extracellular matrix (ECM) acts as a scaffold for kidney cellular organization. Local secretion of the ECM allows kidney cells to readily adapt to changes occurring within the kidney. In addition to providing structural support for cells, the ECM also modulates cell survival, migration, proliferation, and differentiation. Although aberrant regulation of ECM proteins can play a causative role in many diseases, it is not known whether ECM production, cell adhesion, and migration are regulated in a similar manner in kidney epithelial and endothelial cells. Here, we demonstrate that lack of BIM expression differentially impacts kidney endothelial and epithelial cell ECM production, migration, and adhesion, further emphasizing the specialized role of these cell types in kidney function. Bim -/- kidney epithelial cells demonstrated decreased migration, increased adhesion, and sustained expression of osteopontin and thrombospondin-1 (TSP1). In contrast, bim -/- kidney endothelial cells demonstrated increased cell migration, and decreased expression of osteopontin and TSP1. We also observed a fivefold increase in VEGF expression in bim -/- kidney endothelial cells consistent with their increased migration and capillary morphogenesis. These cells also had decreased endothelial nitric oxide synthase activity and nitric oxide bioavailability. Thus kidney endothelial and epithelial cells make unique contributions to the regulation of their ECM composition, with specific impact on adhesive and migratory properties that are essential for their proper function. 相似文献
986.
Bowirrat A Chen TJ Oscar-Berman M Madigan M Chen AL Bailey JA Braverman ER Kerner M Giordano J Morse S Downs BW Waite RL Fornari F Armaly Z Blum K 《Molecular neurobiology》2012,45(2):298-313
Executive functions are processes that act in harmony to control behaviors necessary for maintaining focus and achieving outcomes. Executive dysfunction in neuropsychiatric disorders is attributed to structural or functional pathology of brain networks involving prefrontal cortex (PFC) and its connections with other brain regions. The PFC receives innervations from different neurons associated with a number of neurotransmitters, especially dopamine (DA). Here we review findings on the contribution of PFC DA to higher-order cognitive and emotional behaviors. We suggest that examination of multifactorial interactions of an individual's genetic history, along with environmental risk factors, can assist in the characterization of executive functioning for that individual. Based upon the results of genetic studies, we also propose genetic mapping as a probable diagnostic tool serving as a therapeutic adjunct for augmenting executive functioning capabilities. We conclude that preservation of the neurological underpinnings of executive functions requires the integrity of complex neural systems including the influence of specific genes and associated polymorphisms to provide adequate neurotransmission. 相似文献
987.
The spatial dimensionality of the vocal fold vibration is a common challenge in creating parsimonious models of vocal fold vibration. The ideal model is one that is accurate, with the lowest possible computational expense. Inclusion of full 3D flow and structural vibration typically requires massive amounts of computation, whereas reduction of either the flow or the structure to two dimensions eliminates certain aspects of physical reality, thus making the resulting models less accurate. Previous 2D models of the vocal fold structure have utilized a plane strain formulation, which is shown to be an erroneous modeling approach since it ignores influential stress components. We herein present a 2D/3D hybrid vocal fold model that preserves three-dimensional effects of length and longitudinal shear stresses, while taking advantage of a two-dimensional computational domain. The resulting model exhibits static and dynamic responses comparable to a 3D model, and retains the computational advantage of a two-dimensional model. 相似文献
988.
Johnson MA Cartmell J Weisser NE Woods RJ Bundle DR 《The Journal of biological chemistry》2012,287(22):18078-18090
A self-consistent model of β-mannan oligosaccharides bound to a monoclonal antibody, C3.1, that protects mice against Candida albicans has been developed through chemical mapping, NMR spectroscopic, and computational studies. This antibody optimally binds di- and trisaccharide epitopes, whereas larger oligomers bind with affinities that markedly decrease with increasing chain length. The (1→2)-β-linked di-, tri-, and tetramannosides bind in helical conformations similar to the solution global minimum. Antibody recognition of the di- and trisaccharide is primarily dependent on the mannose unit at the reducing end, with the hydrophobic face of this sugar being tightly bound. Recognition of a tetrasaccharide involves a frameshift in the ligand interaction, shown by strong binding of the sugar adjacent to the reducing end. We show that frameshifting may also be deliberately induced by chemical modifications. Molecular recognition patterns similar to that of mAb C3.1, determined by saturation transfer difference-NMR, were also observed in polyclonal sera from rabbits immunized with a trisaccharide glycoconjugate. The latter observation points to the importance of internal residues as immunodominant epitopes in (1→2)-β-mannans and to the viability of a glycoconjugate vaccine composed of a minimal length oligosaccharide hapten. 相似文献
989.
The challenge of stabilization of small molecules and proteins has received considerable interest. The biological activity of small molecules can be lost as a consequence of chemical modifications, while protein activity may be lost due to chemical or structural degradation, such as a change in macromolecular conformation or aggregation. In these cases, stabilization is required to preserve therapeutic and bioactivity efficacy and safety. In addition to use in therapeutic applications, strategies to stabilize small molecules and proteins also have applications in industrial processes, diagnostics, and consumer products like food and cosmetics. Traditionally, therapeutic drug formulation efforts have focused on maintaining stability during product preparation and storage. However, with growing interest in the fields of encapsulation, tissue engineering, and controlled release drug delivery systems, new stabilization challenges are being addressed; the compounds or protein of interest must be stabilized during: (1) fabrication of the protein or small molecule-loaded carrier, (2) device storage, and (3) for the duration of intended release needs in vitro or in vivo. We review common mechanisms of compound degradation for small molecules and proteins during biomaterial preparation (including tissue engineering scaffolds and drug delivery systems), storage, and in vivo implantation. We also review the physical and chemical aspects of polymer-based stabilization approaches, with a particular focus on the stabilizing properties of silk fibroin biomaterials. 相似文献
990.
Recruitment of effector T cells to sites of infection or inflammation is essential for an effective adaptive immune response. The chemokine CCL5 (RANTES) activates its cognate receptor, CCR5, to initiate cellular functions, including chemotaxis. In earlier studies, we reported that CCL5-induced CCR5 signaling activates the mTOR/4E-BP1 pathway to directly modulate mRNA translation. Specifically, CCL5-mediated mTOR activation contributes to T cell chemotaxis by initiating the synthesis of chemotaxis-related proteins. Up-regulation of chemotaxis-related proteins may prime T cells for efficient migration. It is now clear that mTOR is also a central regulator of nutrient sensing and glycolysis. Herein we describe a role for CCL5-mediated glucose uptake and ATP accumulation to meet the energy demands of chemotaxis in activated T cells. We provide evidence that CCL5 is able to induce glucose uptake in an mTOR-dependent manner. CCL5 treatment of ex vivo activated human CD3(+) T cells also induced the activation of the nutrient-sensing kinase AMPK and downstream substrates ACC-1, PFKFB-2, and GSK-3β. Using 2-deoxy-d-glucose, an inhibitor of glucose uptake, and compound C, an inhibitor of AMPK, experimental data are presented that demonstrate that CCL5-mediated T cell chemotaxis is dependent on glucose, as these inhibitors inhibit CCL5-mediated chemotaxis in a dose-dependent manner. Altogether, these findings suggest that both glycolysis and AMPK signaling are required for efficient T cell migration in response to CCL5. These studies extend the role of CCL5 mediated CCR5 signaling beyond lymphocyte chemotaxis and demonstrate a role for chemokines in promoting glucose uptake and ATP production to match energy demands of migration. 相似文献