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991.
Requirement of CD3 Complex–associated Signaling Functions for Expression of Rearranged T Cell Receptor β VDJ Genes in Early Thymic Development
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992.
OBJECTIVE: To evaluate activity limitations 3 years after diagnosis of early rheumatoid arthritis (RA) in relation to grip force and sex. METHODS: A total of 217 patients, 153 women and 64 men, with recent-onset RA were included. Activity limitations were reported using the Health Assessment Questionnaire (HAQ) and the Evaluation of Daily Activities Questionnaire (EDAQ). The relationships between activity limitations versus grip force (measured by the Grippit), walking speed, functional impairment, grip ability, pain, plasma C-reactive protein, the 28-joint disease activity score and its components, the physician's global assessment of disease activity, and sex were analyzed by partial least squares (PLS). RESULTS: Women had significantly lower grip force and more activity limitations (HAQ and EDAQ) than men. The PLS analyses demonstrated that grip force was the strongest regressor of activity limitation, closely followed by walking speed. However, within subgroups based on grip force (group 1 = grip force <114 N, group 2 = 116-206 N, group 3 = 214-321 N, group 4 = grip force >328 N) and including sexes, women and men had corresponding degrees of activity limitation as reported by the HAQ and EDAQ. CONCLUSION: Our results indicate that the more pronounced activity limitations seen in women with RA, as compared with men, may be explained by lower grip force rather than sex. 相似文献
993.
Inhibition of IFN-alpha signaling by a PKC- and protein tyrosine phosphatase SHP-2-dependent pathway 总被引:1,自引:0,他引:1
Du Z Shen Y Yang W Mecklenbrauker I Neel BG Ivashkiv LB 《Proceedings of the National Academy of Sciences of the United States of America》2005,102(29):10267-10272
Cytokine signaling by the Jak-STAT pathway is subject to complex negative regulation that limits the amplitude and duration of signal transduction. Inhibition of signaling also mediates negative crosstalk, whereby factors with opposing biological activities crossinhibit each other's function. Here, we investigated a rapidly inducible mechanism that inhibited Jak-STAT activation by IFN-alpha, a cytokine that is important for antiviral responses, growth control, and modulation of immune responses. IFN-alpha-induced signaling and gene activation were inhibited by ligation of Fc receptors and Toll-like receptors 7 and 8 in a PKCbeta-dependent manner. Neither PKCbeta nor PKCdelta influenced responses of cells treated with IFN-alpha alone. Inhibition of IFN-alpha signaling correlated with suppression of IFN-alpha-dependent antiviral responses. PKC-mediated inhibition did not require de novo gene expression but involved the recruitment of PKCbeta to the IFN-alpha receptor and interaction with protein tyrosine phosphatase SHP-2, resulting in augmented phosphatase activity. PKC-mediated inhibition of IFN-alpha signaling was abolished in SHP-2-deficient cells, demonstrating a pivotal role for SHP-2 in this inhibitory pathway. Together, our data describe a rapidly inducible, direct mechanism of inhibition of Jak-STAT signaling mediated by a PKCbeta-SHP-2 signaling pathway. 相似文献
994.
Jazet IM Ouwens DM Schaart G Pijl H Keizer H Maassen JA Meinders AE 《Metabolism: clinical and experimental》2005,54(12):1552-1678
This study investigates the molecular mechanisms underlying the blood glucose-lowering effect of a 2-day very low-energy diet (VLED, 1883 kJ/d) in 12 obese (body mass index, 36.3 +/- 1.0 kg/m2 [mean +/- SEM]) type 2 diabetic (HbA(1C) 7.3% +/- 0.4%) patients simultaneously taken off all glucose-lowering therapy, including insulin. Endogenous glucose production (EGP) and glucose disposal ([6,6-2H2]-glucose) were measured before and after the VLED in basal and hyperinsulinemic (40 mU/m2 per minute) euglycemic conditions. Insulin signaling and expression of GLUT-4, FAT/CD36, and triglycerides were assessed in muscle biopsies, obtained before the clamp and after 30 minutes of hyperinsulinemia. Fasting plasma glucose decreased from 11.3 +/- 1.3 to 10.3 +/- 1.0 mmol/L because of a decreased basal EGP (14.2 +/- 1.0 to 11.9 +/- 0.7 micromol/kg per minute, P = .009). Insulin-stimulated glucose disposal did not change. No diet effect was found on the expression of the insulin receptor and insulin receptor substrate-1 or on phosphatidylinositol 3'-kinase activity, or on FAT/CD36 expression pattern, GLUT-4 translocation, or triglyceride distribution in either the basal or insulin-stimulated situation. Unexpectedly, basal PKB/Akt phosphorylation on T308 and S473 increased after the diet, at equal protein expression. In conclusion, a 2-day VLED lowers fasting plasma glucose via a decreased basal EGP without an effect on glucose disposal. Accordingly, no changes in activation of phosphatidylinositol 3'-kinase, triglyceride distribution, FAT/CD36 expression, and GLUT-4 translocation were found in skeletal muscle biopsies. 相似文献
995.
Bots M Kolfschoten IG Bres SA Rademaker MT de Roo GM Krüse M Franken KL Hahne M Froelich CJ Melief CJ Offringa R Medema JP 《Blood》2005,105(3):1153-1161
Tumors have several mechanisms to escape from the immune system. One of these involves expression of intracellular anticytotoxic proteins that modulate the execution of cell death. Previously, we have shown that the serine protease inhibitor (serpin) SPI-6, which inactivates the cytotoxic protease granzyme B (GrB), is capable of preventing cytotoxic T lymphocyte (CTL)-mediated apoptosis. Despite its potent antiapoptotic activity, SPI-6 does not prevent membranolysis induced by cytotoxic lymphocytes. We now provide evidence that several colon carcinoma cell lines do resist membranolysis and that this protection is dependent on SPI-6 but also requires expression of a closely related serpin called SPI-CI (serine protease inhibitor involved in cytotoxicity inhibition). Expression of SPI-CI is absent from normal colon but observed in placenta, testis, early during embryogenesis, and in cytotoxic lymphocytes. SPI-CI encodes a chymotrypsin-specific inhibitor and irreversibly interacts with purified granzyme M. Moreover, SPI-CI can protect cells from purified perforin/GrM-induced lysis. Our data therefore indicate that SPI-CI is a novel immune escape molecule that acts in concert with SPI-6 to prevent cytotoxic lymphocyte-mediated killing of tumor cells. 相似文献
996.
997.
998.
Magnetic resonance imaging as a tool to image neuroinflammation in a rat model of Parkinson's disease – phagocyte influx to the brain is promoted by bilberry‐enriched diet
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Ana Virel Anna Rehnmark Greger Orädd Sonia Olmedo‐Díaz Erik Faergemann Ingrid Strömberg 《The European journal of neuroscience》2015,42(10):2761-2771
Neuroinflammation is a chronic event in neurodegenerative disorders. In the rat model of Parkinson's disease, including a striatal injection of the neurotoxin 6‐hydroxydopamine (6‐OHDA), antioxidant treatment affects the inflammatory process. Despite a heavy accumulation of microglia early after the injury, dopamine nerve fibre regeneration occurs. It remains unclear why this heavy accumulation of microglia is found early after the lesion in antioxidant‐treated animals, or even more, what is the origin of these microglia. In this study magnetic resonance imaging (MRI) was used to elucidate whether the inflammatory response was generated from the blood or from activated brain microglia. Superparamagnetic iron oxide (SPIO) nanoparticles were injected intravenously prior to a striatal 6‐OHDA injection to tag phagocytes in the blood. Rats were fed either with bilberry‐enriched or control diet. T2*‐weighted MRI scans were performed 1 week after the lesion, and hypointense areas were calculated from T2*‐weighted images, to monitor the presence of SPIO particles. The results revealed that feeding the animals with bilberries significantly promoted accumulation of blood‐derived immune cells. Gadolinium‐enhanced MRI demonstrated no difference in leakage of the blood–brain barrier independent of diets. To conclude, bilberry‐enriched diet promotes an influx of periphery‐derived immune cells to the brain early after injury. 相似文献
999.
1000.
Mohamad A Mikati MD Yong‐hui Jiang MD PhD Michael Carboni MD Vandana Shashi MD Slave Petrovski PhD Rebecca Spillmann PhD Carol J. Milligan PhD Melody Li PhD Annette Grefe MD Allyn McConkie PhD Samuel Berkovic MD Ingrid Scheffer MD Saul Mullen MD Melanie Bonner PhD Steven Petrou PhD David Goldstein PhD 《Annals of neurology》2015,78(6):995-999
We report 2 patients with drug‐resistant epilepsy caused by KCNT1 mutations who were treated with quinidine. Both mutations manifested gain of function in vitro, showing increased current that was reduced by quinidine. One, who had epilepsy of infancy with migrating focal seizures, had 80% reduction in seizure frequency as recorded in seizure diaries, and partially validated by objective seizure evaluation on EEG. The other, who had a novel phenotype, with severe nocturnal focal and secondary generalized seizures starting in early childhood with developmental regression, did not improve. Although quinidine represents an encouraging opportunity for therapeutic benefits, our experience suggests caution in its application and supports the need to identify more targeted drugs for KCNT1 epilepsies. Ann Neurol 2015;78:995–999 相似文献