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991.
Shenaz Ramtoola Edward Jude Anthony Robinson Iqbal Malik Gerrard Rayman Cuong Dang Graham David Ross Martin Amar Ali 《Journal of diabetes science and technology》2014,8(4):776-782
Background:Accurate calculation and adjustment of insulin doses is integral to maintaining glycemic control in insulin treated patients. Difficulties with insulin dose calculations may lead to poor adherence to blood glucose monitoring and insulin treatment regimes, resulting in poor metabolic control. The main objective of this study was to evaluate ease of use and user preference of a high specification touch screen blood glucose meter, which has an in-built insulin calculator, compared to patients’ usual method of testing blood glucose and deciding insulin doses.Methods:Patients with diabetes on a multiple daily injection insulin regime used the Test Meter without the insulin calculator and 1 of 3 comparator meters, each for a 7-day period. They then used the Test Meter with the in-built calculator for 10 days. Patients completed an ease of use questionnaire after each 7-day period, a preference questionnaire after the second 7-day period, and a questionnaire comparing the Test Meter with their usual method after the final 10-day period.Results:Of 164 patients who completed the study, 76% stated a preference for the Test Meter as a diabetes management tool compared to their usual method. A small number of patients preferred familiar methods and/or calculating insulin doses themselves. The log book function of meters was important to most patients.Conclusions:The Test Meter system with in-built insulin calculator supports people to better manage their diabetes and increases their confidence. Patients have different needs and preferences which should be acknowledged and supported in a patient centered health service. 相似文献
992.
Safety and efficacy of topical bacteriophage and ethylenediaminetetraacetic acid treatment of Staphylococcus aureus infection in a sheep model of sinusitis 下载免费PDF全文
993.
Hui?Jing Wanming?Tan Yunfeng?Deng Dachuan?Gao Liang?Li Zhiming?Lu Edward?A?Graviss Xin?MaEmail author 《Multidisciplinary respiratory medicine》2014,9(1):48
Background
Nontuberculous mycobacteria (NTM) infection is an emerging, but neglected public health concern in China.Findings
To investigate diagnostic delay of NTM diseases in China, we analyzed 91 patients with pulmonary NTM infection in ShandongProvince. The median diagnostic delay time of the analyzed patients was 84 days, which was significantly associated with rural inhabitance (135 days vs. 73 days of urban inhabitance, p?<?0.01) and lower level of first visiting hospitals/clinics (70 and 82 days of tertiary and secondary hospitals/clinics respectively vs. 120 days of primary hospitals/clinics, p?<?0.05). M. farcinogenes was isolated from a 79-year-old male patient, which is the first report of pulmonary infection in humans.Conclusions
Our results indicate a significant diagnostic delay of NTM diseases in China, especially for rural patients with limited access to higher-level healthcare services.994.
995.
Robert A. Chong Kenneth Wu Donald E. Spratt Yingying Yang Chan Lee Jaladhi Nayak Ming Xu Rana Elkholi Inger Tappin Jessica Li Jerard Hurwitz Brian D. Brown Jerry Edward Chipuk Zhijian J. Chen Roberto Sanchez Gary S. Shaw Lan Huang Zhen-Qiang Pan 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(23):8434-8439
Lysine 48 (K48)-polyubiquitination is the predominant mechanism for mediating selective protein degradation, but the underlying molecular basis of selecting ubiquitin (Ub) K48 for linkage-specific chain synthesis remains elusive. Here, we present biochemical, structural, and cell-based evidence demonstrating a pivotal role for the Ub Y59-E51 loop in supporting K48-polyubiquitination. This loop is established by a hydrogen bond between Ub Y59’s hydroxyl group and the backbone amide of Ub E51, as substantiated by NMR spectroscopic analysis. Loop residues Y59 and R54 are specifically required for the receptor activity enabling K48 to attack the donor Ub-E2 thiol ester in reconstituted ubiquitination catalyzed by Skp1-Cullin1-F-box (SCF)βTrCP E3 ligase and Cdc34 E2-conjugating enzyme. When introduced into mammalian cells, loop-disruptive mutant UbR54A/Y59A diminished the production of K48-polyubiquitin chains. Importantly, conditional replacement of human endogenous Ub by UbR54A/Y59A or UbK48R yielded profound apoptosis at a similar extent, underscoring the global impact of the Ub Y59-E51 loop in cellular K48-polyubiquitination. Finally, disulfide cross-linking revealed interactions between the donor Ub-bound Cdc34 acidic loop and the Ub K48 site, as well as residues within the Y59-E51 loop, suggesting a mechanism in which the Ub Y59-E51 loop helps recruit the E2 acidic loop that aligns the receptor Ub K48 to the donor Ub for catalysis.Central to selective protein turnover by the 26S proteasome is the formation of homotypic lysine 48 (K48)-linked ubiquitin (Ub) chains that tag substrate proteins for degradation (1). Among the most extensively studied systems that produce K48-linked Ub chains is the SCF (Skp1-Cullin1-F-box) E3-directed ubiquitination. SCF is a member of the multisubunit Cullin-RING E3 Ub ligase (CRL) family, the largest of all E3s (2). CRL contains a tandem of a large scaffold protein [Cullin (CUL)] and a RING domain-containing protein (ROC1/Rbx1) that typically associates with an adaptor protein (such as Skp1) in complex with a substrate recognition protein (such as F-box protein). As such, the organization of CRL subunits positions the substrate receptor (such as the F-box protein) within the proximity of ROC1, which recruits an E2-conjugating enzyme that catalyzes the transfer of Ub to a bound substrate. In the SCF reconstitution system, K48-linked polyubiquitin chains on a substrate such as IκBα and β-catenin are produced in a two-step reaction. The E2 UbcH5c deposits the first Ub moiety, forming a substrate–Ub linkage, which is followed by repeated discharge of subsequent Ubs by E2 Cdc34 to form K48-specific Ub chains (3). Human Cdc34 contains a highly conserved charged acidic loop (residues 102–113) that participates in the elongation of K48 chains (4, 5). The current work addresses whether there are determinants on the Ub itself that dictate K48 linkage specificity and, moreover, how Cdc34 might recognize Ub K48. 相似文献
996.
Paul C. Norris David Gosselin Donna Reichart Christopher K. Glass Edward A. Dennis 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(35):12746-12751
Initiation and resolution of inflammation are considered to be tightly connected processes. Lipoxins (LX) are proresolution lipid mediators that inhibit phlogistic neutrophil recruitment and promote wound-healing macrophage recruitment in humans via potent and specific signaling through the LXA4 receptor (ALX). One model of lipoxin biosynthesis involves sequential metabolism of arachidonic acid by two cell types expressing a combined transcellular metabolon. It is currently unclear how lipoxins are efficiently formed from precursors or if they are directly generated after receptor-mediated inflammatory commitment. Here, we provide evidence for a pathway by which lipoxins are generated in macrophages as a consequence of sequential activation of toll-like receptor 4 (TLR4), a receptor for endotoxin, and P2X7, a purinergic receptor for extracellular ATP. Initial activation of TLR4 results in accumulation of the cyclooxygenase-2–derived lipoxin precursor 15-hydroxyeicosatetraenoic acid (15-HETE) in esterified form within membrane phospholipids, which can be enhanced by aspirin (ASA) treatment. Subsequent activation of P2X7 results in efficient hydrolysis of 15-HETE from membrane phospholipids by group IVA cytosolic phospholipase A2, and its conversion to bioactive lipoxins by 5-lipoxygenase. Our results demonstrate how a single immune cell can store a proresolving lipid precursor and then release it for bioactive maturation and secretion, conceptually similar to the production and inflammasome-dependent maturation of the proinflammatory IL-1 family cytokines. These findings provide evidence for receptor-specific and combinatorial control of pro- and anti-inflammatory eicosanoid biosynthesis, and potential avenues to modulate inflammatory indices without inhibiting downstream eicosanoid pathways.A complex network of danger-sensing receptors and bioactive peptide and lipid signals, including cytokines and eicosanoids, regulates innate immunity. Toll-like receptor (TLR) priming is suggested as a precautionary step in building a significant inflammatory response by driving production of IL-1 family protokines, which remain inactive until a second stimulus drives them to bioactive maturation and secretion (1). The second step of this process has been most strongly linked to extracellular ATP and specifically to one of its purinergic receptors, P2X7 (2, 3), particularly in macrophages (4).TLR stimulations also increase prostaglandin synthesis by activating cytosolic phospholipase A2 (cPLA2) through a Ca2+-independent mechanism to release arachidonic acid (AA) from phospholipids, and by increasing expression of cyclooxygenase-2 (COX-2) and microsomal prostaglandin E2 synthase-1. P2X7 stimulation activates cPLA2 through a Ca2+-dependent mechanism that couples AA metabolism with 5-lipoxygenase (5-LOX)-activating protein (FLAP), Ca2+-activated 5-LOX, and constitutive COX-1 to form leukotrienes (LTs) and prostaglandins (PGs). Short-term (∼1 h) TLR priming of Ca2+ ionophore/P2X7-activated immune cells enhances LT synthesis (5, 6), but long-term TLR priming (16–18 h) significantly suppresses LT synthesis by different cell-type–specific mechanisms (7, 8).Whereas PGE2, PGI2, and LTC4 promote local edema from postcapillary venules, and LTB4 amplifies neutrophil recruitment to initiate pathogenic killing, subsequent “class switching” to lipoxin (LX) formation by “reprogrammed” neutrophils inhibits additional neutrophil recruitment during self-resolving inflammatory resolution (9). The direct link between inflammatory commitment and resolution mediated by eicosanoid signaling in macrophages remains unclear from short-term vs. long-term priming, but the complete temporal changes and important interconnections within the entire eicosadome are now demonstrated. 相似文献
997.
Ama Z. S. Rohatiner Matthew L. Smith Orietta Spinelli Alessandro Rambaldi Renato Bassan Eros di Bona Francesco Rodeghiero Roberto Raimondi Magnus Björkholm Steve Johnson Adrian C. Newland Jamie D. Cavenagh Finlay Macdougall Rachel Waters Jude Fitzgibbon Tiziano Barbui Andrew Lister 《British journal of haematology》2014,167(5):724-726
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