Muscle metabolism changes with training in the nonamputated limb after vascular amputation: Interest of phosphorus 31 NMR spectroscopy

International audienceAbstract: Objective: To determine by P-31 nuclear magnetic resonance (NMR) spectroscopy the efficacy of training in improving aerobic metabolism of calf muscle in nonamputated limb after recent vascular amputation; to assess the possible associated microcirculatory changes; and to evaluate the need for noninvasive monitoring techniques during training in the nonamputated limb after recent vascular amputation. Design: Prospective study, before and after training. Subjects served as their own controls and were compared with a control group. Setting: Rehabilitation center of a university hospital. Patients: Ten unilateral vascular amputated patients were included with ankle systolic index between 0.5 and 0.8 in the nonamputated limb, and 10 control subjects without cardiovascular disease or risk factors of atherosclerosis with ankle systolic index of >.95. Intervention: Walking with prosthesis at self-selected velocity over increasing walking distance, arm training at a workload of 60% of a maximal arm test, and analytical exercises of the nonamputated leg (dynamic contractions against low resistance), Subjects received training as inpatients, 5 days a week. Main Outcome Measures: Before and after training, ankle systolic index, forefoot transcutaneous oxygen tension (TcPo2) and veno-arteriolar reflex, and digital plethysmography of the second toe with reactive hyperemia test were studied. Changes in calf muscle pH, phosphocreatine (PCr), and inorganic phosphate (Pi) were measured by P-31 NMR spectroscopy at rest and during a plantar flexion-type incremental protocol. Results: There was no significant difference in ankle systolic index (.63 +/- .10 vs .64 +/- .07) or in TcPo2 (42 +/- 11 vs 44 +/- 10mmHg), and there was reappearance of veno-arteriolar reflex in 3 cases, of a plethysmographic signal in 2 cases, and of the positivity of the reactive hyperemia test in 3 cases. No differences were found with P-31 NMR spectroscopy at rest before and after training. At the same workload (1 watt) the difference of the ratio (PCr/(PCr + Pi)) of rest to effort (PCr depletion) was significantly increased in the amputated patients (.423 +/- .159 vs .145 +/- .058; p <.01). This difference of ratio was lower after training (.360 +/- .158 vs .423 +/- .159; p <.05). The pH was less acid between the two periods. Conclusion: Vascular monitoring with systolic index and TcPo2 is necessary to follow and to prevent serious ischemia of the nonamputated limb. Claudication is often not detected because of early exhaustion during walking. Training after recent vascular amputation improves the skeletal muscle oxydative capacity

Expression of the multidrug resistance glycoprotein 170 in the peripheral blood lymphocytes of rheumatoid arthritis patients. The percentage of lymphocytes expressing glycoprotein 170 is increased in patients treated with prednisolone

International audienceAbstract: The objective was to evaluate the expression of the multidrug resistance P-glycoprotein (P-gp) in peripheral blood lymphocytes (PBL) of patients with rheumatoid arthritis (RA). PBL from 68 RA patients and 44 controls were evaluated. RA patients had a mean disease duration of 10.7 yr, with a mean number of past resistances to DMARDs of 0.82, and were treated with NSAIDs (n = 34), DMARDs (n = 25) and prednisolone (n = 40). Fluorescence flow cytometry was used to assess P-gp membrane expression on PBL. In the RA group, the percentage of PBL expressing P-gp was higher in patients treated with prednisolone than in other patients [mean +/- S.D.: 10.7 +/- 15.8% vs 3.3 +/- 7.6%, P < 0.03, Student] and was not related to other therapies, age, sex, RA duration, number of past resistances to DMARDs, activity, ESR, CRP. The percentage of PBL expressing P-gp did not differ in RA and control groups, but was higher in the prednisolone-treated RA patients than in controls. Prednisolone could induce a rise in the percentage of PBL expressing P-gp. On the contrary, patients with a high percentage of PBL expressing P-gp could be more resistant to DMARDs and need prednisolone earlier. Further studies are needed to address this question and to evaluate the potential implication of P-gp in drug resistance in RA

Effects of low-frequency electrical stimulation of quadriceps and calf muscles in patients with chronic heart failure.

International audienceAbstract: PURPOSE: The aim of this preliminary study was to evaluate the effects of low-frequency electrical stimulation of quadriceps and calf muscles on global exercise capacities, skeletal muscle metabolism, calf muscle volume, and cardiac output in patients with chronic heart failure. METHODS: Fourteen patients with chronic heart failure (mean age of 56.4 years +/- 9.1 SD; mean radionuclide left ventricular ejection fraction of 22.3% +/- 8.8 SD) underwent 5 weeks (1 hour per day, 5 days per week) of low-frequency electrical stimulation of quadriceps and calf muscles. RESULTS: Low-frequency electrical stimulation was well tolerated. Exercise capacity and the calf muscles volumes increased significantly after rehabilitation in comparison with prior rehabilitation (the peak oxygen consumption increased from 17.2 mL/(kgmin) +/- 5.3 SD to 19.6 mL/(kgmin) +/- 5.9 SD; the anaerobic threshold increased from 12.3 mL/(kgmin) +/- 3.2 SD to 15.2 mL/(kgmin) +/- 3.3 SD; the 6-minute walking test increased from 419 m +/- 122 SD to 459 m +/- 114.3 SD; the gastrocnemius volume increased from 259.4 cm3 +/- 58 SD to 273.4 cm3 +/- 74 SD, and the soleus volume increased from 319 cm3 +/- 42.9 SD to 338 cm3 +/- 52.5 SD). The New York Heart Association class was improved after rehabilitation. The P-31 nuclear magnetic resonance spectroscopy of gastrocnemius muscle data were not significantly modified after rehabilitation, thereby inferring that no significant improvement of the muscle metabolism occurred. These data reinforce the hypothesis of an increased muscle mass during stimulation. It is noteworthy that the electrical stimulation did not increase cardiac output at any stage; an enormous asset in favor of this mode of rehabilitation. CONCLUSION: These results suggest that low-frequency muscular electrical stimulation is well tolerated, induces an increased exercise capacity in patients with chronic heart failure, without an undesirable increase in cardiac output

De novo 15q21.1q21.2 deletion identified through FBN1 MLPA and refined by 244K array-CGH in a female teenager with incomplete Marfan syndrome

International audienceInterstitial deletions involving the 15q21.1 band are very rare. Only 4 of these cases have been studied using molecular cytogenetic techniques in order to confirm the deletion of the whole FBN1 gene. The presence of clinical features of the Marfan syndrome (MFS) spectrum associated with mental retardation has been described in only 2/4 patients. Here we report on a 16-year-old female referred for suspicion of MFS (positive thumb and wrist sign, scoliosis, joint hyperlaxity, high-arched palate with dental crowding, dysmorphism, mitral insufficiency with dystrophic valve, striae). She had therefore 3 minor criteria according to the Ghent nosology. She also had speech disabilities but could follow normal school training. Direct sequencing of the FBN1, TGFBR1 and TGFBR2 genes was negative. MLPA revealed a genomic deletion of the whole FBN1 gene, confirmed by loss of heterozygosity of maternal alleles for several microsatellite markers surrounding the FBN1 gene. The deletion was confirmed by FISH using a FBN1 probe and was not found in the parents. Array-CGH permitted to define a 2.97 Mb deletion, which was the smallest 15q microdeletion including FBN1. Contrary to the other published observations, our proband does not exhibit mental retardation, but neuropsychological evaluations revealed an attention deficit as well as a deficit in information-processing speed. Haploinsufficiency of FBN1 is likely to contribute to the presence of MFS features. However, attenuated features could be explained because disturbances of TGF-beta signalling associated with FBN1 mutations do not exert full phenotypic effect through simple haploinsufficiency. Phenotypic variability in other patients with interstitial deletions including 15q21.1 band may reflect differences in deletion size and/or cys/trans modifying factors

9q33.3q34.11 microdeletion: new contiguous gene syndrome encompassing STXBP1, LMX1B and ENG genes assessed using reverse phenotyping

International audienceThe increasing use of array-CGH in malformation syndromes with intellectual disability could lead to the description of new contiguous gene syndrome by the analysis of the gene content of the microdeletion and reverse phenotyping. Thanks to a national and international call for collaboration by Achropuce and Decipher, we recruited four patients carrying de novo overlapping deletions of chromosome 9q33.3q34.11, including the STXBP1, the LMX1B and the ENG genes. We restrained the selection to these three genes because the effects of their haploinsufficency are well described in the literature and easily recognizable clinically. All deletions were detected by array-CGH and confirmed by FISH. The patients display common clinical features, including intellectual disability with epilepsy, owing to the presence of STXBP1 within the deletion, nail dysplasia and bone malformations, in particular patellar abnormalities attributed to LMX1B deletion, epistaxis and cutaneousmucous telangiectasias explained by ENG haploinsufficiency and common facial dysmorphism. This systematic analysis of the genes comprised in the deletion allowed us to identify genes whose haploinsufficiency is expected to lead to disease manifestations and complications that require personalized follow-up, in particular for renal, eye, ear, vascular and neurological manifestations

Differential expression of interferon alpha protein provides clues to tissue specificity across type I interferonopathies

International audienceWhilst upregulation of type I interferon (IFN) signaling is common across the type I interferonopathies (T1Is), central nervous system (CNS) involvement varies between these disorders, the basis of which remains unclear. We collected cerebrospinal fluid (CSF) and serum from patients with Aicardi-Goutières syndrome (AGS), STING-associated vasculopathy with onset in infancy (SAVI), presumed monogenic T1Is (pT1I), childhood systemic lupus erythematosus with neuropsychiatric features (nSLE), non-IFN-related autoinflammation (AI) and non-inflammatory hydrocephalus (as controls). We measured IFN-alpha protein using digital ELISA. Eighty-two and 63 measurements were recorded respectively in CSF and serum of 42 patients and 6 controls. In an intergroup comparison (taking one sample per individual), median CSF IFN-alpha levels were elevated in AGS, SAVI, pT1I, and nSLE compared to AI and controls, with levels highest in AGS compared to all other groups. In AGS, CSF IFN-alpha concentrations were higher than in paired serum samples. In contrast, serum IFN was consistently higher compared to CSF levels in SAVI, pT1I, and nSLE. Whilst IFN-alpha is present in the CSF and serum of all IFN-related diseases studied here, our data suggest the primary sites of IFN production in the monogenic T1I AGS and SAVI are, respectively, the CNS and the periphery. These results inform the diagnosis of, and future therapeutic approaches to, monogenic and multifactorial T1Is

Convergence of patient- and physician-reported outcomes in the French National Registry of Facioscapulohumeral Dystrophy

International audienceFacioscapulohumeral muscular dystrophy (FSHD) is among the most prevalent muscular dystrophies and currently has no treatment. Clinical and genetic heterogeneity are the main challenges to a full comprehension of the physiopathological mechanism. Improving our knowledge of FSHD is crucial to the development of future therapeutic trials and standards of care. National FSHD registries have been set up to this end. The French National Registry of FSHD combines a clinical evaluation form (CEF) and a self-report questionnaire (SRQ), filled out by a physician with expertise in neuromuscular dystrophies and by the patient, respectively. Aside from favoring recruitment, our strategy was devised to improve data quality. Indeed, the pairwise comparison of data from 281 patients for 39 items allowed for evaluating data accuracy. Kappa or intra-class coefficient (ICC) values were calculated to determine the correlation between answers provided in both the CEF and SRQ. Results Patients and physicians agreed on a majority of questions common to the SRQ and CEF (24 out of 39). Demographic, diagnosis- and care-related questions were generally answered consistently by the patient and the medical practitioner (kappa or ICC values of most items in these groups were greater than 0.8). Muscle function-related items, i.e. FSHD-specific signs, showed an overall medium to poor correlation between data provided in the two forms; the distribution of agreements in this section was markedly spread out and ranged from poor to good. In particular, there was very little agreement regarding the assessment of facial motricity and the presence of a winged scapula. However, patients and physicians agreed very well on the Vignos and Brooke scores. The report of symptoms not specific to FSHD showed general poor consistency. Conclusions Patient and physician answers are largely concordant when addressing quantitative and objective items. Consequently, we updated collection forms by relying more on patient-reported data where appropriate. We hope the revised forms will reduce data collection time while ensuring the same quality standard. With the advent of artificial intelligence and automated decision-making, high-quality and reliable data are critical to develop top-performing algorithms to improve diagnosis, care, and evaluate the efficiency of upcoming treatments

Genetic diagnosis of primary immunodeficiencies: A survey of the French national registry

International audienceTo the Editor:Since the mid-1980s, continuous progress in genetics and genomics has accelerated the rapid identification of causative genetic variants leading to primary immunodeficiencies (PIDs; >300 genes),1 with the noticeable exception of B-cell disorders, such as common variable immunodeficiency (CVID). The identification of these mutations not only validates a clinical diagnosis but also is useful in several other respects (more accurate prognosis on phenotype/genotype correlation, targeted therapy, and genetic counseling). [...