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Banzet S Sanchez H Chapot R Peinnequin A Bigard X Koulmann N 《Metabolism: clinical and experimental》2012,61(3):389-394
Both calcineurin-A and peroxisome proliferator activated receptor gamma coactivator 1α (PGC-1α) are key players in the acquisition and maintenance of slow-oxidative skeletal muscle phenotype. Whether calcineurin can control PGC-1α expression has been proposed but is still controversial. Our aim was to examine the relationship between calcineurin activation and PGC-1α expression in nonexercising skeletal muscles of rats. We first examined PGC-1α and modulatory calcineurin-interacting protein-1 messenger RNA (mRNA) (a marker of calcineurin activity) expression patterns within rat single myofibers, classified according to their phenotype (type I, IIa, IIx, and IIb). Secondly, we measured PGC-1α mRNA and protein in soleus and plantaris muscles of rats treated or not by cyclosporin A or FK506, 2 pharmacological inhibitors of calcineurin activity. In single myofibers, no differences were found in PGC-1α mRNA levels, whereas modulatory calcineurin-interacting protein-1 mRNA was substantially higher in type I and IIa compared with type IIx and IIb fibers. In cyclosporin A- and FK506-treated animals, no decrease in PGC-1α mRNA and protein was found, despite an efficient blockade of calcineurin activity. Taken together, our results show that, in weight-bearing skeletal muscles, basal PGC-1α expression, necessary to maintain slow-oxidative phenotype, is independent of calcineurin activity. 相似文献
84.
NF Gnädig S Beaucourt G Campagnola AV Bordería M Sanz-Ramos P Gong H Blanc OB Peersen M Vignuzzi 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(34):E2294-E2303
Based on structural data of the RNA-dependent RNA polymerase, rational targeting of key residues, and screens for Coxsackievirus B3 fidelity variants, we isolated nine polymerase variants with mutator phenotypes, which allowed us to probe the effects of lowering fidelity on virus replication, mutability, and in vivo fitness. These mutator strains generate higher mutation frequencies than WT virus and are more sensitive to mutagenic treatments, and their purified polymerases present lower-fidelity profiles in an in vitro incorporation assay. Whereas these strains replicate with WT-like kinetics in tissue culture, in vivo infections reveal a strong correlation between mutation frequency and fitness. Variants with the highest mutation frequencies are less fit in vivo and fail to productively infect important target organs, such as the heart or pancreas. Furthermore, whereas WT virus is readily detectable in target organs 30 d after infection, some variants fail to successfully establish persistent infections. Our results show that, although mutator strains are sufficiently fit when grown in large population size, their fitness is greatly impacted when subjected to severe bottlenecking, which would occur during in vivo infection. The data indicate that, although RNA viruses have extreme mutation frequencies to maximize adaptability, nature has fine-tuned replication fidelity. Our work forges ground in showing that the mutability of RNA viruses does have an upper limit, where larger than natural genetic diversity is deleterious to virus survival. 相似文献
85.
Lefebvre H 《Annales d'endocrinologie》2012,73(2):135-137
Corticotroph deficiency usually results from exogenous glucocorticoid therapy or, more rarely, from hypothalamopituitary damages. Its diagnostic may be difficult, especially when the deficit in ACTH secretion is partial. Stimulation tests are then necessary to investigate the integrity of the hypothalamopituitary-adrenal axis. The insulin tolerance test has become the gold standard, but its utilization is limited by several contra-indications. The metyrapone and cosyntropin tests represent currently used alternatives but their sensitivity is not optimal. Measurement of basal plasma dehydroepiandrosterone sulfate may allow excluding corticotroph deficiency when normal. Finally, cortisol replacement in patients with corticotropic deficiency is based on hydrocortisone administration. However, the dose regimens employed in clinical practice do not allow mimicking the nycthemeral rhythm of cortisol secretion and are still disputed. 相似文献
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Baudo F Collins P Huth-Kühne A Lévesque H Marco P Nemes L Pellegrini F Tengborn L Knoebl P;EACH registry contributors 《Blood》2012,120(1):39-46
Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies to coagulation FVIII. Bleeding episodes at presentation are spontaneous and severe in most cases. Optimal hemostatic therapy is controversial, and available data are from observational and retrospective studies only. The EACH2 registry, a multicenter, pan-European, Web-based database, reports current patient management. The aim was to assess the control of first bleeding episodes treated with a bypassing agent (rFVIIa or aPCC), FVIII, or DDAVP among 501 registered patients. Of 482 patients with one or more bleeding episodes, 144 (30%) received no treatment for bleeding; 31 were treated with symptomatic therapy only. Among 307 patients treated with a first-line hemostatic agent, 174 (56.7%) received rFVIIa, 63 (20.5%) aPCC, 56 (18.2%) FVIII, and 14 (4.6%) DDAVP. Bleeding was controlled in 269 of 338 (79.6%) patients treated with a first-line hemostatic agent or ancillary therapy alone. Propensity score matching was applied to allow unbiased comparison between treatment groups. Bleeding control was significantly higher in patients treated with bypassing agents versus FVIII/DDAVP (93.3% vs 68.3%; P = .003). Bleeding control was similar between rFVIIa and aPCC (93.0%; P = 1). Thrombotic events were reported in 3.6% of treated patients with a similar incidence between rFVIIa (2.9%) and aPCC (4.8%). 相似文献
89.
Collins P Baudo F Knoebl P Lévesque H Nemes L Pellegrini F Marco P Tengborn L Huth-Kühne A;EACH registry collaborators 《Blood》2012,120(1):47-55
Acquired hemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive regimen is unclear; therefore, data from 331 patients entered into the prospective EACH2 registry were analyzed. Steroids combined with cyclophosphamide resulted in more stable complete remission (70%), defined as inhibitor undetectable, factor VIII more than 70 IU/dL and immunosuppression stopped, than steroids alone (48%) or rituximab-based regimens (59%). Propensity score-matched analysis controlling for age, sex, factor VIII level, inhibitor titer, and underlying etiology confirmed that stable remission was more likely with steroids and cyclophosphamide than steroids alone (odds ratio = 3.25; 95% CI, 1.51-6.96; P < .003). The median time to complete remission was approximately 5 weeks for steroids with or without cyclophosphamide; rituximab-based regimens required approximately twice as long. Immunoglobulin administration did not improve outcome. Second-line therapy was successful in approximately 60% of cases that failed first-line therapy. Outcome was not affected by the choice of first-line therapy. The likelihood of achieving stable remission was not affected by underlying etiology but was influenced by the presenting inhibitor titer and FVIII level. 相似文献
90.
Ouédraogo DD Nonguierma V Napon C Kabré A Tiéno H Guira O Kaboré J Drabo JY 《Rheumatology international》2012,32(7):2149-2153
To study the prevalence and semiotic characteristics of neuropathic pain in the common low back pain to the Black African subject. This was a prospective cross-sectional survey carried on from April 1 2009 to August 31 2009 in consultations of rheumatology, neurology, and neurosurgery at the University Hospital Yalgado Ouédraogo in Ouagadougou (Burkina Faso). All patients with a low back pain or a common lomboradiculalgie were included. DN4 questionnaire was used for the diagnosis of neuropathic pain. One hundred and seven patients have been recruited during the study period; Sixty-four (59.80%) were female (sex ratio M/F: 0.67). The average age was 34.11?±?13.46?years of age with extremes of 20 and 79. The average duration of disease was 48.53?months with extremes of 10?days and 50?years. Eighty-seven patients (81.31%) had a disease duration, which was 3?months longer. Sixty-six patients (61.70%) had a predominant lomboradiculalgie; among the remaining 41, low back pain predominated. Average intensity of pain was 62.81?±?22.43 (on a scale of 100). A sign of Lasèque was present in the 41 (38.30%) patients. Fifty-three (49.5%) patients had a neuropathic pain. The prevalence of neuropathy signs according to the DN4 questionnaire was as follows: burning (n?=?37; 34.58%), painful cold (n?=?13; 12.15%), electric shocks (n?=?31; 38.97%), pins and needles (n?=?34; 31.77%), tingling (n?=?35; 32.71%), numbness (n?=?45; 42.05%), itching (n?=?18; 16.82%), touch hypoesthesia (n?=?35; 32.71%), pinprick (n?=?33; 30.84%), and tactile allodynia (n?=?21; 19.62%). Among the studied variables, the presence of a radiculalgy was statistically associated with neuropathic pain. The lomboradiculalgie of the Black African subject associates neuropathic pain observed in half of patients. Treatment must therefore always take account of this association. However, further studies are needed before any definitive conclusion. 相似文献