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881.
Zoungas S Chalmers J Ninomiya T Li Q Cooper ME Colagiuri S Fulcher G de Galan BE Harrap S Hamet P Heller S MacMahon S Marre M Poulter N Travert F Patel A Neal B Woodward M;ADVANCE Collaborative Group 《Diabetologia》2012,55(3):636-643
Aims/hypothesis
There is conflicting evidence regarding appropriate glycaemic targets for patients with type 2 diabetes. Here, we investigate the relationship between HbA1c and the risks of vascular complications and death in such patients.Methods
Eleven thousand one hundred and forty patients were randomised to intensive or standard glucose control in the Action in Diabetes and Vascular disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Glycaemic exposure was assessed as the mean of HbA1c measurements during follow-up and prior to the first event. Adjusted risks for each HbA1c decile were estimated using Cox models. Possible differences in the association between HbA1c and risks at different levels of HbA1c were explored using linear spline models.Results
There was a non-linear relationship between mean HbA1c during follow-up and the risks of macrovascular events, microvascular events and death. Within the range of HbA1c studied (5.5?C10.5%), there was evidence of ??thresholds??, such that below HbA1c levels of 7.0% for macrovascular events and death, and 6.5% for microvascular events, there was no significant change in risks (all p?>?0.8). Above these thresholds, the risks increased significantly: every 1% higher HbA1c level was associated with a 38% higher risk of a macrovascular event, a 40% higher risk of a microvascular event and a 38% higher risk of death (all p?0.0001).Conclusions/interpretation
In patients with type 2 diabetes, HbA1c levels were associated with lower risks of macrovascular events and death down to a threshold of 7.0% and microvascular events down to a threshold of 6.5%. There was no evidence of lower risks below these levels but neither was there clear evidence of harm.Trial Registration:
ClinicalTrial.gov NCT00145925Funding:
Servier and the National Health and Medical Research Council of Australia (project grant ID 211086 and programme grant IDs 358395 and 571281) 相似文献882.
Q Liu M Dalman Y Chen M Akhter S Brahmandam Y Patel J Lowe M Thakkar AV Gregory D Phelps C Riley RL Londraville 《General and comparative endocrinology》2012,178(3):562-572
Using morpholino antisense oligonucleotide (MO) technology, we blocked leptin A or leptin receptor expression in embryonic zebrafish, and analyzed consequences of leptin A knock-down on fish development. Embryos injected with leptin A or leptin receptor MOs (leptin A or leptin receptor morphants) had smaller bodies and eyes, undeveloped inner ear, enlarged pericardial cavity, curved body and/or tail and larger yolk compared to control embryos of the same stages. The defects persisted in 6-9days old larvae. We found that blocking leptin A function had little effect on the development of early brain (1day old), but differentiation of both the morphant dorsal brain and retinal cells was severely disrupted in older (2days old) embryos. Despite the enlarged pericardial cavity, differentiation of cardiac cells appeared to be similar to control embryos. Formation of the morphants' inner ear is also severely disrupted, which corroborates existing reports of leptin receptor expression in inner ear of both zebrafish and mammals. Co-injection of leptin A MO and recombinant leptin results in partial rescue of the wild-type phenotype. Our results suggest that leptin A plays distinct roles in zebrafish development. 相似文献
883.
884.
You H Tsutsui S Hameed S Kannanayakal TJ Chen L Xia P Engbers JD Lipton SA Stys PK Zamponi GW 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(5):1737-1742
N-methyl-d-aspartate receptors (NMDARs) mediate critical CNS functions, whereas excessive activity contributes to neuronal damage. At physiological glycine concentrations, NMDAR currents recorded from cultured rodent hippocampal neurons exhibited strong desensitization in the continued presence of NMDA, thus protecting neurons from calcium overload. Reducing copper availability by specific chelators (bathocuproine disulfonate, cuprizone) induced nondesensitizing NMDAR currents even at physiologically low glycine concentrations. This effect was mimicked by, and was not additive with, genetic ablation of cellular prion protein (PrP(C)), a key copper-binding protein in the CNS. Acute ablation of PrP(C) by enzymatically cleaving its cell-surface GPI anchor yielded similar effects. Biochemical studies and electrophysiological measurements revealed that PrP(C) interacts with the NMDAR complex in a copper-dependent manner to allosterically reduce glycine affinity for the receptor. Synthetic human Aβ(1-42) (10 nM-5 μM) produced an identical effect that could be mitigated by addition of excess copper ions or NMDAR blockers. Taken together, Aβ(1-42), copper chelators, or PrP(C) inactivation all enhance the activity of glycine at the NMDAR, giving rise to pathologically large nondesensitizing steady-state NMDAR currents and neurotoxicity. We propose a physiological role for PrP(C), one that limits excessive NMDAR activity that might otherwise promote neuronal damage. In addition, we provide a unifying molecular mechanism whereby toxic species of Aβ(1-42) might mediate neuronal and synaptic injury, at least in part, by disrupting the normal copper-mediated, PrP(C)-dependent inhibition of excessive activity of this highly calcium-permeable glutamate receptor. 相似文献
885.
Jarvis E Bruce HS Patel NH 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(Z1):10634-10639
The diverse array of body plans possessed by arthropods is created by generating variations upon a design of repeated segments formed during development, using a relatively small "toolbox" of conserved patterning genes. These attributes make the arthropod body plan a valuable model for elucidating how changes in development create diversity of form. As increasingly specialized segments and appendages evolved in arthropods, the nervous systems of these animals also evolved to control the function of these structures. Although there is a remarkable degree of conservation in neural development both between individual segments in any given species and between the nervous systems of different arthropod groups, the differences that do exist are informative for inferring general principles about the holistic evolution of body plans. This review describes developmental processes controlling neural segmentation and regionalization, highlighting segmentation mechanisms that create both ectodermal and neural segments, as well as recent studies of the role of Hox genes in generating regional specification within the central nervous system. We argue that this system generates a modular design that allows the nervous system to evolve in concert with the body segments and their associated appendages. This information will be useful in future studies of macroevolutionary changes in arthropod body plans, especially in understanding how these transformations can be made in a way that retains the function of appendages during evolutionary transitions in morphology. 相似文献
886.
Huang ZM Chinen M Chang PJ Xie T Zhong L Demetriou S Patel MP Scherzer R Sviderskaya EV Bennett DC Millhauser GL Oh DH Cleaver JE Wei ML 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(2):553-558
Protein-trafficking pathways are targeted here in human melanoma cells using methods independent of oncogene mutational status, and the ability to up-regulate and down-regulate tumor treatment sensitivity is demonstrated. Sensitivity of melanoma cells to cis-diaminedichloroplatinum II (cDDP, cis-platin), carboplatin, dacarbazine, or temozolomide together with velaparib, an inhibitor of poly (ADP ribose) polymerase 1, is increased by up to 10-fold by targeting genes that regulate both protein trafficking and the formation of melanosomes, intracellular organelles unique to melanocytes and melanoma cells. Melanoma cells depleted of either of the protein-trafficking regulators vacuolar protein sorting 33A protein (VPS33A) or cappuccino protein (CNO) have increased nuclear localization of cDDP, increased nuclear DNA damage by platination, and increased apoptosis, resulting in increased treatment sensitivity. Depleted cells also exhibit a decreased proportion of intracellular, mature melanosomes compared with undepleted cells. Modulation of protein trafficking via cell-surface signaling by binding the melanocortin 1 receptor with the antagonist agouti-signaling protein decreased the proportion of mature melanosomes formed and increased cDDP sensitivity, whereas receptor binding with the agonist melanocyte-stimulating hormone resulted in an increased proportion of mature melanosomes formed and in decreased sensitivity (i.e., increased resistance) to cDDP. Mutation of the protein-trafficking gene Hps6, known to impair the formation of mature melanosomes, also increased cDDP sensitivity. Together, these results indicate that targeting protein-trafficking molecules markedly increases melanoma treatment sensitivity and influences the degree of melanosomes available for sequestration of therapeutic agents. 相似文献
887.
PP Ng M Jia KG Patel JD Brody JR Swartz S Levy R Levy 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(36):14526-14531
Clinical studies of idiotype (Id) vaccination in patients with lymphoma have established a correlation between the induced anti-Id antibody responses and favorable clinical outcomes. To streamline the production of an Id vaccine, we engineered a small diabody (Db) molecule containing both a B-cell-targeting moiety (anti-CD19) and a lymphoma Id. This molecule (αCD19-Id) was designed to penetrate lymph nodes and bind to noncognate B cells to form an antigen presentation array. Indeed, the αCD19-Id molecule accumulated on B cells in vivo after s.c. administration. These noncognate B cells, decorated with the diabody, could then stimulate the more rare Id-specific B cells. Peptide epitopes present in the diabody linker augmented the response by activating CD4(+) helper T cells. Consequently, the αCD19-Id molecule induced a robust Id-specific antibody response and protected animals from tumor challenge. Such diabodies are produced in a cell-free protein expression system within hours of amplification of the specific Ig genes from the B-cell tumor. This customized product can now be available to vaccinate patients before they receive other, potentially immunosuppressive, therapies. 相似文献
888.
Jørgensen KK Lindström L Cvancarova M Castedal M Friman S Schrumpf E Foss A Isoniemi H Nordin A Holte K Rasmussen A Bergquist A Vatn MH Boberg KM 《Scandinavian journal of gastroenterology》2012,(47):1021-1029
Abstract Objective. Several studies have implicated primary sclerosing cholangitis (PSC) as an additional risk factor for colorectal neoplasia in inflammatory bowel disease (IBD). Some reports have indicated that the risk is even higher in PSC-IBD patients after liver transplantation (Ltx), but this issue is controversial. We aimed to compare the risk of colorectal neoplasia in PSC-IBD patients before and after Ltx and to identify risk factors for colorectal neoplasia post-transplant. Material and methods. In a multicenter study within the Nordic Liver Transplant Group, we assessed the risk of colorectal neoplasia by using the competing risk regression analysis. Results. Among the 439 PSC patients included, 353 (80%) had IBD at the time of Ltx and 15 (3%) patients developed de novo IBD post-Ltx. The median duration of IBD was 15 (0-50) years at the time of Ltx and follow-up after Ltx was 5 (0-20) years. Ninety-one (25%) PSC-IBD patients developed colorectal neoplasia. The cumulative risk of colorectal neoplasia was higher after than before Ltx (HR: 1.9, 95% CI: 1.3-2.9, p = 0.002). A multivariate analysis demonstrated aminosalicylates and ursodeoxycholic acid as significantly associated with an increased risk of colorectal neoplasia post-Ltx. Duration and activity of IBD did not significantly affect the risk of neoplasia. Conclusion. The even higher risk of colorectal neoplasia in PSC-IBD patients after when compared with that of before Ltx underscores the importance of regular surveillance colonoscopies post-Ltx. The association of aminosalicylates and ursodeoxycholic acid to the development of colorectal neoplasia after Ltx should be further investigated. 相似文献
889.
Gallwitz B Rosenstock J Rauch T Bhattacharya S Patel S von Eynatten M Dugi KA Woerle HJ 《Lancet》2012,380(9840):475-483
890.
Yen EF Pokhrel B Bianchi LK Roy HK Du H Patel A Hall CR Witt BL 《Digestive diseases and sciences》2012,57(1):161-169