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41.
Nadge Sarrazin Estelle Chavret-Reculon Corinne Bachelin Mehdi Felfli Rafik Arab Sophie Gilardeau Elena Brazhnikova Elisabeth Dubus Lydia Yaha-Cherif Jean Lorenceau Serge Picaud Serge Rosolen Pierre Moissonnier Pierre Pouget Anne Baron-Van Evercooren 《Proceedings of the National Academy of Sciences of the United States of America》2022,119(10)
White matter disorders of the central nervous system (CNS), such as multiple sclerosis (MS), lead to failure of nerve conduction and long-lasting neurological disabilities affecting a variety of sensory and motor systems, including vision. While most disease-modifying therapies target the immune and inflammatory response, the promotion of remyelination has become a new therapeutic avenue to prevent neuronal degeneration and promote recovery. Most of these strategies have been developed in short-lived rodent models of demyelination, which spontaneously repair and do not reflect the size, organization, and biology of the human CNS. Thus, well-defined nonhuman primate models are required to efficiently advance therapeutic approaches for patients. Here, we followed the consequence of long-term toxin-induced demyelination of the macaque optic nerve on remyelination and axon preservation, as well as its impact on visual functions. Findings from oculomotor behavior, ophthalmic examination, electrophysiology, and retinal imaging indicate visual impairment involving the optic nerve and retina. These visual dysfunctions fully correlated at the anatomical level, with sustained optic nerve demyelination, axonal degeneration, and alterations of the inner retinal layers. This nonhuman primate model of chronic optic nerve demyelination associated with axonal degeneration and visual dysfunction, recapitulates several key features of MS lesions and should be instrumental in providing the missing link to translate emerging repair promyelinating/neuroprotective therapies to the clinic for myelin disorders, such as MS.White matter disorders are a large group of neurological diseases of various origins. Those affecting the central nervous system (CNS), such as multiple sclerosis (MS), lead to failure of nerve conduction, axon degeneration, and result in long-lasting neurological disabilities and tissue atrophy (1). The loss of myelin and healthy axons are believed to be responsible for irreversible damages, which affect a variety of sensory and motor systems, including vision. In MS, 70% of patients are affected with optic neuritis. It can manifest in an acute episode with decreased vision that can recover over several weeks in the majority of patients, while permanent visual symptoms persist in 40 to 60% of patients (2, 3). Chronic optic neuritis can lead to significant optic nerve atrophy and retinal alterations, affecting mainly the retinal inner layers, including the retinal nerve fiber and ganglion cell layers (4). Several visual assays, including visual fields (VF) (5), pupillary responses to luminance and color (pupillary light reflex, PLR) (6), electroretinograms (ERG) (7), optical coherence tomography (OCT) (4, 8), and visual evoked potential (VEP) (9–11) are routinely performed to assess noninvasively the anatomical and electrophysiological perturbations of visual functions in MS. While functional recovery was reported in some patients (9), the lack of anatomical–electrophysiological correlation has prevented to attribute directly these improvements to remyelination or other regenerative processes.Animal models of demyelination induced by toxins, such as lyso-phosphatidylcholine (LPC), are suitable for studying the mechanisms of demyelination/remyelination and developing approaches aimed at promoting CNS remyelination, as they show little inflammation and, therefore, provide means to assay directly the effect of a therapy on remyelination. However, most of these models are developed in short-lived rodents and spontaneously repair, thus lacking the long-lasting progressive degenerative disease context of MS. Besides, these models do not reflect the size or complex organization of the human primate CNS (12). They do not inform on the biology of primate cells, which differs from rodents (13, 14), nor on the security, toxicity, and long-term efficacy of cell- or compound-based promyelinating/neuroprotective therapies. Thus, experiments in long-lived nonhuman primates appear an essential step toward clinical trials.While promoting remyelination may prevent axon degeneration, only a few promyelination strategies have been translated to the clinic (15,16). One of the roadblocks is the absence of studies addressing the clinical benefit of promyelination approaches that could be applied to the clinic (17). A positive correlation between changes in VEP parameters and the degree of demyelination/remyelination was established in rodents (18–21), cats (22), and dogs (23), and exploited successfully to follow promyelination therapies in rodents (24, 25). OCT has been used to identify loss of optic nerve and retinal damages in animal models of myelin disorders as well (23, 26). While used seldomly in nonhuman primates (27), none of these clinical assays were exploited to monitor the impact of optic nerve demyelination in nonhuman primates.We previously demonstrated that LPC injection in the macaque optic nerve induced demyelination with fair axon preservation but little remyelination up to 2 mo post demyelination (28). Taking advantage of the fact that nonhuman primates are long-lived and are able to perform several tasks awake, as do humans, we questioned whether this model could be used to follow the consequence of long-term demyelination on axon preservation, and whether multimodal noninvasive assays, such as VF, VEP, OCT, and PLR could be instrumental to follow/predict the functional and anatomical outcome of optic nerve demyelination. Using multidisciplinary approaches, we provide compelling evidence that LPC-induced demyelination of the macaque optic nerve leads to modified VF, VEP, PLR, and altered inner retinal layers, but preserved photoreceptors based on OCT and ERG. These clinical and functional anomalies were correlated at the histological level with failed remyelination and progressive optic nerve axon loss, followed by neuronal and fiber loss of the inner retinal layers. The postmortem validation of OCT, VEP, and PLR as pertinent markers of optic nerve demyelination/degeneration could further help the translation of therapeutic strategies toward the clinic for myelin diseases associated with long-term demyelination of the optic nerve. 相似文献
42.
Morand PC Burgel PR Carlotti A Desmazes-Dufeu N Farhi D Martin C Kanaan R Mangialavori L Palangié E Dusser D Poyart C Hubert D 《Journal of clinical microbiology》2011,49(2):750-751
Tuberculosis (TB) is rarely observed in cystic fibrosis (CF) patients. We report the first case of mediastinal TB, associated with leg pain and skin rash, in an adult patient with CF, and discuss factors suggestive of TB in the course of CF. 相似文献
43.
44.
Cell surface expression of the epithelial Na channel and a mutant
causing Liddle syndrome: A quantitative approach 下载免费PDF全文
Dmitri Firsov Laurent Schild Ivan Gautschi Anne-Marie Mrillat Estelle Schneeberger BernardC. Rossier 《Proceedings of the National Academy of Sciences of the United States of America》1996,93(26):15370-15375
The epithelial amiloride-sensitive sodium channel (ENaC) controls transepithelial Na+ movement in Na+-transporting epithelia and is associated with Liddle syndrome, an autosomal dominant form of salt-sensitive hypertension. Detailed analysis of ENaC channel properties and the functional consequences of mutations causing Liddle syndrome has been, so far, limited by lack of a method allowing specific and quantitative detection of cell-surface-expressed ENaC. We have developed a quantitative assay based on the binding of 125I-labeled M2 anti-FLAG monoclonal antibody (M2Ab*) directed against a FLAG reporter epitope introduced in the extracellular loop of each of the α, β, and γ ENaC subunits. Insertion of the FLAG epitope into ENaC sequences did not change its functional and pharmacological properties. The binding specificity and affinity (Kd = 3 nM) allowed us to correlate in individual Xenopus oocytes the macroscopic amiloride-sensitive sodium current (INa) with the number of ENaC wild-type and mutant subunits expressed at the cell surface. These experiments demonstrate that: (i) only heteromultimeric channels made of α, β, and γ ENaC subunits are maximally and efficiently expressed at the cell surface; (ii) the overall ENaC open probability is one order of magnitude lower than previously observed in single-channel recordings; (iii) the mutation causing Liddle syndrome (β R564stop) enhances channel activity by two mechanisms, i.e., by increasing ENaC cell surface expression and by changing channel open probability. This quantitative approach provides new insights on the molecular mechanisms underlying one form of salt-sensitive hypertension. 相似文献
45.
Neuronal and astrocytic damage in systemic lupus erythematosus patients with central nervous system involvement 总被引:4,自引:0,他引:4
OBJECTIVE: Symptoms originating from the central nervous system (CNS) frequently occur in patients with systemic lupus erythematosus (SLE). CNS involvement in lupus is associated with increased morbidity and mortality. Currently, reliable markers for activity in this condition are absent. The goal of this study was to determine the level of the light subunit of the neurofilament triplet protein (NFL) and that of glial fibrillary acidic protein (GFAP) in the cerebrospinal fluid of SLE patients with clinically verified CNS involvement and compare them with the levels in SLE patients without CNS involvement. METHODS: We assessed cerebrospinal fluid obtained from 99 patients with SLE and 99 age-matched controls for the presence of soluble molecules indicating neuronal destruction and astrogliosis-NFL and GFAP, respectively. Patients were evaluated clinically, with magnetic resonance imaging (MRI) of the brain, cerebrospinal fluid analyses, and neuropsychiatric tests. RESULTS: In the group of lupus patients with CNS involvement, intrathecal levels of NFL and GFAP were increased an average of 7-fold (P = 0.0001) and 3-fold (P = 0.05), respectively, compared with the levels in SLE patients without overt CNS disease. Intrathecal levels of NFL correlated significantly with cerebrospinal fluid levels of interleukin-6 (IL-6) (P = 0.005), IL-8 (P = 0.005), pleocytosis (P = 0.05), the albumin ratio (P = 0.0005), and the presence of oligoclonal IgG bands (P = 0.005). Cerebrospinal fluid levels of both NFL and GFAP also showed a significant correlation with MRI abnormalities (P = 0.001). Successful cyclophosphamide treatment of CNS lupus resulted in significantly decreased levels of both proteins; levels of GFAP reached those observed in healthy subjects. CONCLUSION: This study is the first to show biochemical signs of neuronal and astrocytic damage in patients with neuropsychiatric lupus. It is suggested that biochemical markers of brain damage should be used as a followup tool in this patient group. 相似文献
46.
Comparison of versions 1.0 AND 1.5 of the UltraSensitive AMPLICOR HIV-1 MONITOR test for subjects with low viral load 下载免费PDF全文
Jackson JB Piwowar-Manning E Johnson-Lewis L Bassett R Demeter LM Brambilla D 《Journal of clinical microbiology》2004,42(6):2774-2776
We compared the performance of two UltraSensitive AMPLICOR HIV-1 MONITOR kits (version 1.5 [v1.5] versus v1.0) by retesting 404 plasma samples with low viral loads (<3,000 copies/ml) with both kits. With 292 samples that initially had <50 copies/ml by the v1.0 kit, the v1.5 assay was more sensitive than the v1.0 assay for samples with human immunodeficiency virus type 1 RNA near the 50-copy/ml cutoff (P = 0.0146). Median numbers of copies per milliliter were similar for 112 samples with 50 to 3,000 copies/ml with no difference in sensitivity with a 200-copy/ml cutoff. 相似文献
47.
The rate of heat storage mediates an anticipatory reduction in exercise intensity during cycling at a fixed rating of perceived exertion 总被引:6,自引:2,他引:6
Ross Tucker Trevor Marle Estelle V. Lambert Timothy D. Noakes 《The Journal of physiology》2006,574(3):905-915
The aim of the present study was to examine the regulation of exercise intensity in hot environments when exercise is performed at a predetermined, fixed subjective rating of perceived exertion (RPE). Eight cyclists performed cycling trials at 15°C (COOL), 25°C (NORM) and 35°C (HOT) (65% humidity throughout), during which they were instructed to cycle at a Borg rating of perceived exertion (RPE) of 16, increasing or decreasing their power output in order to maintain this RPE. Power output declined linearly in all three trials and the rate of decline was significantly higher in HOT than in NORM and COOL (2.35 ± 0.73 W min−1 , 1.63 ± 0.70 and 1.61 ± 0.80 W min−1 , respectively, P < 0.05). The rate of heat storage was significantly higher in HOT for the first 4 min of the trials only, as a result of increasing skin temperatures. Thereafter, no differences in heat storage were found between conditions. We conclude that the regulation of exercise intensity is controlled by an initial afferent feedback regarding the rate of heat storage, which is used to regulate exercise intensity and hence the rate of heat storage for the remainder of the anticipated exercise bout. This regulation maintains thermal homeostasis by reducing the exercise work rate and utilizing the subjective RPE specifically to ensure that excessive heat accumulation does not occur and cellular catastrophe is avoided. 相似文献
48.
Leucine supplementation improves muscle protein synthesis in elderly men independently of hyperaminoacidaemia 总被引:3,自引:0,他引:3
Isabelle Rieu Michèle Balage Claire Sornet Christophe Giraudet Estelle Pujos Jean Grizard Laurent Mosoni Dominique Dardevet 《The Journal of physiology》2006,575(1):305-315
The present study was designed to assess the effects of dietary leucine supplementation on muscle protein synthesis and whole body protein kinetics in elderly individuals. Twenty healthy male subjects (70 ± 1 years) were studied before and after continuous ingestion of a complete balanced diet supplemented or not with leucine. A primed (3.6 μmol kg−1 ) constant infusion (0.06 μmol kg−1 min−1 ) of l -[1-13 C]phenylalanine was used to determine whole body phenylalanine kinetics as well as fractional synthesis rate (FSR) in the myofibrillar fraction of muscle proteins from vastus lateralis biopsies. Whole body protein kinetics were not affected by leucine supplementation. In contrast, muscle FSR, measured over the 5-h period of feeding, was significantly greater in the volunteers given the leucine-supplemented meals compared with the control group (0.083 ± 0.008 versus 0.053 ± 0.009% h−1 , respectively, P < 0.05). This effect was due only to increased leucine availability because only plasma free leucine concentration significantly differed between the control and leucine-supplemented groups. We conclude that leucine supplementation during feeding improves muscle protein synthesis in the elderly independently of an overall increase of other amino acids. Whether increasing leucine intake in old people may limit muscle protein loss during ageing remains to be determined. 相似文献
49.
The prion protein, and an increasing number of other cellular proteins, can undergo conformational transitions leading to
soluble oligomers and insoluble aggregates. We have previously shown that the transition of the prion protein from its native
form to its infectious (PrPSc) conformation can be monitored with epitope specific antibodies while the protein is immobilized on the surface of a Biacore
surface plasmon resonance sensor chip. (Leclerc et al EMBO J 20:1547–1554 2001). The folding pathways leading to insoluble aggregates (amyloids) and soluble oligomers are believed to be distinct. We report
here the use of epitope-specific antibody Fab fragments and surface plasmon resonance measurements on immobilized PrP to investigate
the conditions leading to either folding pathway. We found that full-length SHaPrP(29-231) and truncated SHaPrP(90-231) prion
protein can be induced to undergo the transition to proteinase K-resistant PrPSc aggregates on a sensor chip. This transition is temperature and buffer dependent and can be blocked by the presence of antibody
Fab fragments binding to epitopes important for the conformational change. We demonstrate that the use of monoclonal antibodies
combined with surface plasmon resonance technology is suitable to monitor the environmental conditions leading to conformational
changes in the prion protein. The methodology is applicable to other amyloid- and oligomer-forming proteins and should be
useful for the evaluation of antibodies or small molecules preventing protein misfolding. 相似文献
50.
Soumaya Mougou-Zerelli Sophie Thomas Emmanuelle Szenker Sophie Audollent Nadia Elkhartoufi Candice Babarit Stéphane Romano Rémi Salomon Jeanne Amiel Chantal Esculpavit Marie Gonzales Estelle Escudier Bruno Leheup Philippe Loget Sylvie Odent Jo?lle Roume Marion Gérard Anne-Lise Delezoide Suonavy Khung Sophie Patrier Marie-Pierre Cordier Raymonde Bouvier Jéléna Martinovic Marie-Claire Gubler Nathalie Boddaert Arnold Munnich Férechté Encha-Razavi Enza Maria Valente Ali Saad Sophie Saunier Michel Vekemans Tania Attié-Bitach 《Human mutation》2009,30(11):1574-1582
Meckel-Gruber syndrome (MKS) is a lethal fetal disorder characterized by diffuse renal cystic dysplasia, polydactyly, a brain malformation that is usually occipital encephalocele, and/or vermian agenesis, with intrahepatic biliary duct proliferation. Joubert syndrome (JBS) is a viable neurological disorder with a characteristic “molar tooth sign” (MTS) on axial images reflecting cerebellar vermian hypoplasia/dysplasia. Both conditions are classified as ciliopathies with an autosomal recessive mode of inheritance. Allelism of MKS and JBS has been reported for TMEM67/MKS3, CEP290/MKS4, and RPGRIP1L/MKS5. Recently, one homozygous splice mutation with a founder effect was reported in the CC2D2A gene in Finnish fetuses with MKS, defining the 6th locus for MKS. Shortly thereafter, CC2D2A mutations were also reported in JBS. The analysis of the CC2D2A gene in our series of MKS fetuses, identified 14 novel truncating mutations in 11 cases. These results confirm the involvement of CC2D2A in MKS and reveal a major contribution of CC2D2A to the disease. We also identified three missense CC2D2A mutations in two JBS cases. Therefore, and in accordance with the data reported regarding RPGRIP1L, our results indicate phenotype–genotype correlations, as missense and presumably hypomorphic mutations lead to JBS while all null alleles lead to MKS. Hum Mutat 30:1–9, 2009. © 2009 Wiley-Liss, Inc. 相似文献