ABSTRACT
Duchenne muscular dystrophy (DMD) is one of the most common forms of hereditary muscular dystrophies in childhood and is characterized by steady progression and early disability. It is known that physical therapy can slow down the rate of progression of the disease. According to global recommendations, pool exercises, along with stretching, are preferable for children with DMD, as these types of activities have a balanced effect on skeletal muscles and allow simultaneous breathing exercises. The present study aimed to evaluate the effectiveness of regular pool exercises in patients with Duchenne muscular dystrophy who are capable of independent movement during 4 months of training. 28 patients with genetically confirmed Duchenne muscular dystrophy, who were aged 6.9 ± 0.2 years, were examined. A 6-min distance walking test and timed tests, namely, rising from the floor, 10-meter running, and stair climbing and descending, muscle strength of the upper and lower extremities were assessed on the baseline and during dynamic observation at 2 and 4 months. Hydrorehabilitation course lasted 4 months and was divided into two stages: preparatory and training (depend on individual functional heart reserve (IFHR)). Set of exercises included pool dynamic aerobic exercises. Quantitative muscle MRI of the pelvic girdle and thigh was performed six times: before training (further BT) and after training (further AT) during all course. According to the results of the study, a statistically significant improvement was identified in a 6-min walking test, with 462.7 ± 6.2 m on the baseline and 492.0 ± 6.4 m after 4 months (p < 0.001). The results from the timed functional tests were as follows: rising from the floor test, 4.5 ± 0.3 s on the baseline and 3.8 ± 0.2 s after 4 months (p < 0.001); 10 meter distance running test, 4.9 ± 0.1 s on the baseline and 4.3 ± 0.1 s after 4 months (p < 0.001); 4-stair climbing test, 3.7 ± 0.2 s on the baseline and 3.2 ± 0.2 s after 4 months (p < 0.001); and 4-stair descent test, 3.9 ± 0.1 s on the baseline and 3.2 ± 0.1 s after 4 months (p < 0.001). Skeletal muscle quantitative MRI was performed in the pelvis and the thighs in order to assess the impact of the procedures on the muscle structure. Muscle water T2, a biomarker of disease activity, did not show any change during the training period, suggesting the absence of deleterious effects and negative impact on disease activity. Thus, a set of dynamic aerobic exercises in water can be regarded as effective and safe for patients with DMD.
ABSTRACT
PURPOSE: Quantitative cardiac MRI, and more particularly T1 mapping, has become a most important modality to characterize myocardial tissue. In this work, the value of a radial variant of the conventional modified Look-Locker inversion recovery sequence (raMOLLI) is demonstrated. METHODS: The raMOLLI acquisition scheme consisted of five radial echo trains of 80 spokes acquired using either a fast low-angle shot (FLASH) or a true fast imaging with steady-state-precession (TrueFISP) readout at different time points after a single magnetization inversion. View sharing combined with a compressed sensing algorithm allowed the reconstruction of 50 images along the T1 relaxation recovery curve, to which a dictionary-fitting approach was applied to estimate T1 . The sequence was validated on a nine-vial phantom, on 19 healthy subjects, and one patient suffering from dilated cardiomyopathy. RESULTS: The raMOLLI sequence allowed a significant decrease of myocardial T1 map acquisition time down to five heartbeats, while exhibiting a higher degree of accuracy and a comparable precision on T1 value estimation than the conventional modified Look-Locker inversion recovery sequence. The FLASH readout demonstrated a better robustness to B0 inhomogeneities than TrueFISP, and was therefore preferred for in vivo acquisitions. CONCLUSIONS: This sequence represents a good candidate for ultrafast acquisition of myocardial T1 maps. Magn Reson Med 79:1387-1398, 2018. © 2017 International Society for Magnetic Resonance in Medicine.
Subject(s)
Cardiac Imaging Techniques/methods , Heart/diagnostic imaging , Image Processing, Computer-Assisted/methods , Magnetic Resonance Imaging/methods , Adult , Cardiomyopathy, Dilated/diagnostic imaging , Computer Simulation , Female , Heart Rate/physiology , Humans , Male , Phantoms, Imaging , Young AdultABSTRACT
Because respiratory failure remains a major issue in Duchenne Muscular Dystrophy patients, respiratory muscles are a key target of systemic therapies. In the Golden Retriever Muscular Dystrophy (GRMD) dogs, the disease shows strong clinical and histological similarities with the human pathology, making it a valuable model for preclinical therapeutic trials. We report here the first nuclear magnetic resonance (NMR) imaging anatomical study of the diaphragm in GRMD dogs and healthy controls. Both T1- and T2-weighted images of the diaphragm of seven healthy and thirteen GRMD dogs, from 3 to 36 months of age, were acquired on a 3 tesla NMR scanner. Abnormalities of texture and shape were revealed and consisted of increases in signal intensity on T2-weighted images and in signal heterogeneity on both T1- and T2-weighted images of the dystrophic diaphragm. These abnormalities were associated with a significant thickening of the muscle and we identified a clear 8-mm-threshold distinguishing clinically preserved GRMD dogs from those more severely affected. In this study, we demonstrated the feasibility of NMR imaging of the diaphragm and depicted several anatomical and mesoscopic anomalies in the dystrophic diaphragm. NMR imaging of the diaphragm shows a promise as an outcome measure in preclinical trials using GRMD dogs.
Subject(s)
Diaphragm/diagnostic imaging , Muscular Dystrophy, Animal/diagnostic imaging , Animals , Dogs , Dystrophin/deficiency , Magnetic Resonance ImagingABSTRACT
PURPOSE: To introduce an ultrashort echo time (UTE) based method for quantitative mapping of short-T2 signals in skeletal muscle (SKM) in the presence of fat, with the aim of monitoring SKM fibrosis. METHODS: From a set of at least five UTE images of the same slice, a long- T2* map, a fat-fraction map, and a map of short-T2 -signal fraction are extracted. The method was validated by numerical simulations and in vitro studies on collagen solutions. Finaly, the method was applied to image the short-T2 signals in the leg of eight healthy volunteers. RESULTS: The imaged short-T2 -signal fractions in the collagen solutions correlated with their respective collagen concentrations ( R=0.999, P=0.009). Short-T2 tissues such as cortical bone and fasciae were highlighted in the resulting short-T2 fraction maps. A significant fraction of short-T2 signal was systematically observed in the skeletal muscle of all of the subjects (4.5±1.2%). CONCLUSION: The proposed method allows the quantitative imaging of short-T2 components in tissues containing fat. By also having the fat-fraction and T2* maps as outcomes, long-T2 suppression is accomplished without requiring modifications to the basic UTE sequence. Although the hypersignal observed in the fasciae suggests that the short-T2 signal observed in SKM might arise from interstitial connective tissue, further investigation is necessary to confirm this statement. Magn Reson Med 78:997-1008, 2017. © 2016 International Society for Magnetic Resonance in Medicine.
Subject(s)
Image Processing, Computer-Assisted/methods , Magnetic Resonance Imaging/methods , Muscle, Skeletal/diagnostic imaging , Subtraction Technique , Adult , Collagen/chemistry , Female , Humans , Male , Phantoms, ImagingABSTRACT
Sepsis, or systemic inflammatory response syndrome, is the major cause of critical illness resulting in admission to intensive care units. Sepsis is caused by severe infection and is associated with mortality in 60% of cases. Morbidity due to sepsis is complicated by neuromyopathy, and patients face long-term disability due to muscle weakness, energetic dysfunction, proteolysis and muscle wasting. These processes are triggered by pro-inflammatory cytokines and metabolic imbalances and are aggravated by malnutrition and drugs. Skeletal muscle regeneration depends on stem (satellite) cells. Herein we show that mitochondrial and metabolic alterations underlie the sepsis-induced long-term impairment of satellite cells and lead to inefficient muscle regeneration. Engrafting mesenchymal stem cells improves the septic status by decreasing cytokine levels, restoring mitochondrial and metabolic function in satellite cells, and improving muscle strength. These findings indicate that sepsis affects quiescent muscle stem cells and that mesenchymal stem cells might act as a preventive therapeutic approach for sepsis-related morbidity.
Subject(s)
Mesenchymal Stem Cell Transplantation , Mitochondria, Muscle/metabolism , Satellite Cells, Skeletal Muscle/pathology , Sepsis/complications , Stem Cells/pathology , Animals , Cells, Cultured , Cytokines/genetics , Cytokines/metabolism , Gene Expression Regulation , Male , Mice , Mice, Transgenic , Peritonitis/complications , Reactive Oxygen Species/metabolism , Regeneration , Sepsis/metabolism , Stem Cells/metabolismABSTRACT
Myofibrillar myopathies (MFM) have been described in the mid-1990s as a group of diseases sharing common histological features, including an abnormal accumulation of intrasarcoplasmic proteins, the presence of vacuoles and a disorganization of the intermyofibrillar network beginning at the Z-disk. The boundaries of this concept are still uncertain, and whereas six genes (DES, CRYAB, LDB3/ZASP, MYOT, FLNC and BAG3) are now classically considered as responsible for MFM, other entities such as FHL1 myopathy or Hereditary Myopathy with Early Respiratory Failure linked to mutations of titin can now as well be included in this group. The diagnosis of MFM is not always easy; as histological lesions can be focal, and muscle biopsy may be disappointing; this has led to a growing importance of muscle imaging, and the selectivity of muscle involvement has now been described in several disorders. Due to the rarity of these myopathies, if some clinical patterns (such as distal myopathy associated with cardiomyopathy due to desmin mutations) are now well known, surprises remain possible and should lead to systematic testing of the known genes in case of a typical histological presentation. In this paper, we aim at reviewing the data acquired on the six main genes listed above as well as presenting the experience from two French reference centres, Paris and Marseilles.
Subject(s)
Myofibrils/pathology , Myopathies, Structural, Congenital/pathology , Adolescent , Adult , Child , Female , Humans , Male , Middle Aged , Muscle Proteins/genetics , Muscle, Skeletal/pathology , Myofibrils/genetics , Myopathies, Structural, Congenital/genetics , Myopathies, Structural, Congenital/therapy , Young AdultABSTRACT
OBJECTIVE: Mutations in one of the 3 genes encoding collagen VI (COLVI) are responsible for a group of heterogeneous phenotypes of which Bethlem myopathy (BM) represents the milder end of the spectrum. Genotype-phenotype correlations and long-term follow-up description in BM remain scarce. METHODS: We retrospectively evaluated the long-term clinical evolution, and genotype-phenotype correlations in 35 genetically identified BM patients (23 index cases). RESULTS: Nineteen patients showed a typical clinical picture with contractures, proximal weakness and slow disease progression while 11 presented a more severe evolution. Five patients showed an atypical presentation, namely a limb girdle muscle weakness in 2 and a congenital myopathy pattern with either no contractures, or only limited to ankles, in 3 of them. Pathogenic COL6A1-3 mutations were mostly missense or in frame exon-skipping resulting in substitutions or deletions. Twenty one different mutations were identified including 12 novel ones. The mode of inheritance was, autosomal dominant in 83% of the index patients (including 17% (N=4) with a de novo mutation), recessive in 13%, and undetermined in one patient. Skipping of exon 14 of COL6A1 was found in 35% of index cases and was mostly associated with a severe clinical evolution. Missense mutations were detected in 39% of index cases and associated with milder forms of the disease. CONCLUSIONS: Long-term follow-up identified important phenotypic variability in this cohort of 35 BM patients. However, worsening of the functional disability appeared typically after the age of 40 in 47% of our patients, and was frequently associated with COL6A1 exon 14 skipping.
Subject(s)
Collagen Type VI/genetics , Contracture/genetics , Muscular Dystrophies/congenital , Adolescent , Adult , Age of Onset , Aging , Biopsy , Child , Child, Preschool , Cohort Studies , Contracture/pathology , Disease Progression , Exons/genetics , Female , Follow-Up Studies , Genotype , Humans , Magnetic Resonance Imaging , Male , Muscle Weakness/etiology , Muscular Dystrophies/genetics , Muscular Dystrophies/pathology , Mutation , Mutation, Missense/genetics , Neurologic Examination , Phenotype , Retrospective Studies , Tomography, X-Ray Computed , Young AdultABSTRACT
The potential ergogenic effects of oral salbutamol intake were demonstrated for decades but the underlying mechanisms remain to elucidate. We hypothesized that improved exercise performance after acute oral salbutamol administration is associated with changes in muscle metabolism. Twelve healthy, nonasthmatic, moderately trained, male subjects were recruited to compare in a double-blind crossover randomized study, an oral dose of salbutamol (4 mg) and a placebo. After treatment administration, subjects performed repetitive plantar flexions to exhaustion in a 3T magnet. Continuous (31) P nuclear magnetic resonance spectroscopy assessment of the calf muscles was performed at rest, during exercise, and during recovery. No significant difference between treatments was detected in metabolite concentration at rest (P > 0.05). Creatine phosphate and inorganic phosphate changes during and immediately after exercise were similar between treatments (P > 0.05). Intramuscular pH (pHi) was significantly higher at rest, at submaximal exercise but not at exhaustion with salbutamol (pHi at 50% of exercise duration, 6.8 ± 0.1/6.9 ± 0.1 for placebo and salbutamol, respectively, P < 0.05). The maximal power (28 ± 7 W/23 ± 7 W; P = 0.001) and total work (1702 ± 442 J/1381 ± 432 J; P = 0.003) performed during plantar flexions were significantly increased with salbutamol. Salbutamol induced significant improvement in calf muscle endurance with similar metabolic responses during exercise, except slight differences in pHi. Other mechanisms than changes in muscle metabolism may be responsible for the ergogenic effect of salbutamol administration.
Subject(s)
Adrenergic beta-2 Receptor Agonists/pharmacology , Albuterol/pharmacology , Muscle Fatigue/drug effects , Muscle, Skeletal/drug effects , Phosphates/metabolism , Phosphocreatine/drug effects , Adult , Cross-Over Studies , Double-Blind Method , Humans , Hydrogen-Ion Concentration , Leg , Magnetic Resonance Spectroscopy , Male , Muscle, Skeletal/metabolism , Phosphocreatine/metabolism , Phosphorus Isotopes , Physical Endurance/drug effects , Young AdultABSTRACT
We describe the case of a 56-year-old man presenting a primary pulmonary epithelioid angiosarcoma versus malignant epithelioid hemangioendothelioma still alive, without recurrence at nearly two years after the beginning of the symptoms. The primary pulmonary angiosarcoma is extremely rare, being reported only in a handful of cases. Metastatic involvement of the lung (90%) is far more common than primary pulmonary involvement (10%). Various predisposing condition for the development of angiosarcoma have been described. Early diagnosis is not common, because of the rarity of angiosarcoma in the lung and consequent low index of suspicion. Due to the paucity of cases, there are no defined treatment regimens for this entity. However, there is a tendency for surgical intervention in all reported cases.
Subject(s)
Hemangioendothelioma, Epithelioid/diagnosis , Hemangiosarcoma/diagnosis , Lung Neoplasms/diagnosis , Diagnosis, Differential , Hemangioendothelioma, Epithelioid/therapy , Hemangiosarcoma/therapy , Humans , Lung Neoplasms/therapy , Male , Middle AgedABSTRACT
BACKGROUND: In October 2009, in the context of an A(H1N1)v2009 influenza pandemic, a vaccination campaign was launched in France, in which one of the priority groups was pregnant women, on account of the high risk of developing complications following infection by this virus. OBJECTIVE: The aim of this multicentric, prospective, observational study was to assess safety and pregnancy outcomes in a cohort of pregnant women when receiving the A(H1N1)v2009 influenza pandemic vaccine. METHODS: This was a prospective study that followed up pregnant women recruited mainly in vaccination centres and maternity departments. Following the expected delivery date, follow-up data were collected concerning the delivery, the infant, and, if appropriate, the reasons why the pregnancy did not reach its term. RESULTS: Between 1 November 2009 and 31 March 2010, 2,415 pregnant women were included at the time of vaccination; 97.6 % of women received a vaccine without adjuvant and 2.4 % received an adjuvanted vaccine. Ninety-two (3.9 %) women were vaccinated during the first trimester of pregnancy, 1,090 (46.5 %) during the second trimester, and 1,162 (49.6 %) during the third trimester. One hundred and thirty-three adverse events (5.5 % of women) were reported, of which 12 were unexpected or serious. There were 2,246 (93.0 %) known pregnancy outcomes with 12 spontaneous abortions (0.5 %), 6 stillbirths (0.3 %), and 4 therapeutic abortions (0.2 %). There were 65 neonates with congenital anomalies, among which 31 were major. But only one congenital malformation (1.4 %) was reported for the 92 women vaccinated in their first trimester. Of the women, 93.3 % were delivered full term and 6.7 % preterm. For 96 (4.2 %) neonates, a disorder was reported in the neonatal period and 130 (5.6 %) were transferred to the neonatology department. CONCLUSIONS: This study suggests that exposure to the A(H1N1)v2009 pandemic influenza vaccine during pregnancy does not increase the risk of adverse pregnancy outcomes. However, because of the relatively small number of women exposed during the first trimester, other studies are needed to exclude an increased risk of malformation.
Subject(s)
Congenital Abnormalities/etiology , Influenza A Virus, H1N1 Subtype/immunology , Influenza Vaccines/adverse effects , Pregnancy Complications/etiology , Adolescent , Adult , Cohort Studies , Congenital Abnormalities/epidemiology , Female , Follow-Up Studies , France/epidemiology , Humans , Infant, Newborn , Influenza Vaccines/therapeutic use , Influenza, Human/immunology , Influenza, Human/prevention & control , Male , Middle Aged , Pregnancy , Pregnancy Complications/epidemiology , Pregnancy Complications, Infectious/immunology , Pregnancy Complications, Infectious/prevention & control , Pregnancy Outcome , Prospective Studies , Risk , Young AdultABSTRACT
OBJECTIVE: To report the follow-up of continuing pregnancies after first-trimester exposure to mifepristone. DESIGN: Observational prospective study. SETTING: France. SAMPLE: Patients exposed to mifepristone during the first 12 weeks of pregnancy. METHODS: Women were included in the study when they or their doctors asked a French pharmacovigilance centre or the Paris Teratogen Information Service about the risk of mifepristone exposure in early pregnancy. Exclusion criteria were requests received after 22 weeks of gestation or subsequent elective termination of pregnancy without a pathological examination of the fetus. Data on maternal history and drug exposure were collected on first contact, and pregnancy outcomes were documented at follow-up. MAIN OUTCOME MEASURES: Rate of major congenital malformations. RESULTS: A total of 105 pregnancies were included, with 46 exposed to mifepristone alone, and 59 exposed to both mifepristone and misoprostol. There were 94 live births (90.4%) and 10 (9.6%) miscarriages (including one with major malformation). Elective termination of pregnancy was performed after the subsequent diagnosis of trisomy 21 in one case. The overall rate of major congenital malformations was 4.2% (95% CI 1.2-10.4%), with two cases among 38 patients exposed to mifepristone alone, and two cases among 57 patients exposed to both mifepristone and misoprostol. CONCLUSIONS: This first prospective study found that the rate of major malformations after first-trimester exposure to mifepristone is only slightly higher than the expected 2-3% rate in the general population. Such findings provide reassuring data for risk evaluation for continuation of pregnancy after mifepristone exposure.
Subject(s)
Abortifacient Agents, Steroidal/adverse effects , Abortion, Spontaneous/epidemiology , Congenital Abnormalities/epidemiology , Mifepristone/adverse effects , Misoprostol/adverse effects , Premature Birth/epidemiology , Adult , Female , Follow-Up Studies , France , Humans , Pregnancy , Pregnancy Outcome , Pregnancy Trimester, First , Prospective StudiesABSTRACT
BACKGROUND: Homozygous mutations in ANO5, a gene encoding anoctamin 5, a putative calcium-activated chloride channel, have recently been reported in patients with adult-onset myopathies or isolated high-CK levels. Cardiomyopathy has not previously been reported in these populations despite a proven expression of anoctamin 5 in the cardiac muscle. METHODS: Patients presenting for the management of high-CK levels or overt myopathy with proven ANO5 mutations were prospectively investigated between June 2010 and March 2012 in Pitié Salpêtrière Hospital, according to a standardised protocol. Neurological and cardiological clinical examinations, CK assessment, electrocardiogram (ECG), and echocardiography were performed, as well as cardiac MRI and coronary CT angiography in patients with left ventricular (LV) dysfunction. RESULTS: Our study included 19 consecutive patients (male=15, age=46.2 ± 12.7 years) from 16 families. Five had asymptomatic high-CK levels and 14 had overt myopathy. One patient had a personal history of stable coronary artery disease with normal ventricular function. ECG showed ventricular premature beats in one patient. Echocardiography displayed LV dilatation in two patients, LV dysfunction in one, and both abnormalities in two who fulfilled criteria for dilated cardiomyopathy which was confirmed by cardiac MRI and normal CT angiography. CONCLUSIONS: Dilated cardiomyopathy is a potential complication in patients with myopathies due to mutations in the ANO5 gene whose screening requires specific procedures.
Subject(s)
Cardiomyopathy, Dilated/diagnosis , Cardiomyopathy, Dilated/genetics , Chloride Channels/genetics , Mutation/genetics , Adult , Aged , Anoctamins , Cardiomyopathy, Dilated/physiopathology , Female , Humans , Male , Middle Aged , Prospective StudiesABSTRACT
The Golden Retriever Muscular Dystrophy (GRMD) dog is the closest animal counterpart of Duchenne muscular dystrophy in humans and has, for this reason, increasingly been used in preclinical therapeutic trials for this disease. The aim of this study was to describe the abnormalities in canine dystrophic muscle non-invasively, quantitatively, thoroughly and serially by means of NMR imaging. Thoracic and pelvic limbs of five healthy and five GRMD dogs were imaged in a 3T NMR scanner at 2, 4, 6 and 9months of age. Standard and fat-saturated T(1)-, T(2)- and proton-density-weighted images were acquired. A measurement of T(1) and a two-hour kinetic study of muscle enhancement after gadolinium-chelate injection were also performed. Ten out of the 15 indices evaluated differed between healthy and GRMD dogs. The maximal relative enhancement after gadolinium injection and the proton-density-weighted/T(2)-weighted signal ratio were the most discriminating indices. Inter-muscle heterogeneity was found to vary significantly for most of the indices. The body of data that has been acquired here will help in designing and interpreting preclinical trials using dystrophin-deficient dogs.
Subject(s)
Magnetic Resonance Spectroscopy/methods , Muscle, Skeletal/pathology , Muscular Dystrophy, Animal/diagnosis , Animals , Dogs , Image Processing, Computer-Assisted , Longitudinal StudiesABSTRACT
In this paper, we propose a novel approach for segmenting the skeletal muscles in MRI automatically. In order to deal with the absence of contrast between the different muscle classes, we proposed a principled mathematical formulation that integrates prior knowledge with a random walks graph-based formulation. Prior knowledge is represented using a statistical shape atlas that once coupled with the random walks segmentation leads to an efficient iterative linear optimization system. We reveal the potential of our approach on a challenging set of real clinical data.
Subject(s)
Image Processing, Computer-Assisted/methods , Magnetic Resonance Imaging/methods , Muscle, Skeletal/pathology , Algorithms , Artificial Intelligence , Humans , Imaging, Three-Dimensional , Markov Chains , Models, Statistical , Models, Theoretical , Pattern Recognition, Automated/methods , Probability , Reproducibility of Results , SoftwareABSTRACT
Muscle perfusion, and capillary and intramyocytic oxygenation can be probed non-invasively in vivo by functional NMR techniques, arterial spin labelling combined with imaging, BOLD imaging and deoxymyoglobin (1)H spectroscopy, respectively. After adequate adaptation of equipment, these measurements can be performed in parallel, together with (31)P spectroscopy and provide a comprehensive analysis of various facets of oxygen metabolism in dynamic protocols, in humans as well as in animal models.
Subject(s)
Magnetic Resonance Imaging , Magnetic Resonance Spectroscopy , Muscle, Skeletal/metabolism , Oxygen Consumption/physiology , Oxygen/metabolism , HumansABSTRACT
A totally noninvasive set-up was developed for comprehensive NMR evaluation of mouse skeletal muscle function in vivo. Dynamic pulsed arterial spin labeling-NMRI perfusion and blood oxygenation level-dependent (BOLD) signal measurements were interleaved with (31)P NMRS to measure both vascular response and oxidative capacities during stimulated exercise and subsequent recovery. Force output was recorded with a dedicated ergometer. Twelve exercise bouts were performed. The perfusion, BOLD signal, pH and force-time integral were obtained from mouse legs for each exercise. All reached a steady state after the second exercise, justifying the pointwise summation of the last 10 exercises to compensate for the limited (31)P signal. In this way, a high temporal resolution of 2.5 s was achieved to provide a time constant for phosphocreatine (PCr) recovery (τ(PCr)). The higher signal-to-noise ratio improved the precision of τ(PCr) measurement [coefficient of variation (CV) = 16.5% vs CV = 49.2% for a single exercise at a resolution of 30 s]. Inter-animal summation confirmed that τ(PCr) was stable at steady state, but shorter (89.3 ± 8.6 s) than after the first exercise (148 s, p < 0.05). This novel experimental approach provides an assessment of muscle vascular response simultaneously to energetic function in vivo. Its pertinence was illustrated by observing the establishment of a metabolic steady state. This comprehensive tool offers new perspectives for the study of muscle pathology in mice models.
Subject(s)
Energy Metabolism , Magnetic Resonance Spectroscopy/methods , Muscle, Skeletal/physiology , Animals , Electric Stimulation , Hindlimb/blood supply , Magnetic Resonance Spectroscopy/instrumentation , Male , Mice , Muscle, Skeletal/anatomy & histology , Perfusion , Phosphocreatine/metabolism , Physical Conditioning, Animal/physiologyABSTRACT
Inhibiting myostatin (mstn) causes spectacular increase in muscle mass, spurring research for therapeutic approaches against neuromuscular disorders. Yet, possible functional deterioration and compromised force production have been reported in isolated muscle of null mstn(-/-) mice. We analyzed vascular and metabolic response to repeated electro-stimulated exercise in vivo in mstn(-/-) mice compared with FVB wild-type controls (WT), using interleaved multi-parametric functional nuclear magnetic resonance (NMR) imaging and spectroscopy. At steady-state exercise, specific force of plantar flexion, phosphocreatine consumption measured by phosphorus spectroscopy and maximum perfusion measured by arterial spin-labeled (ASL) NMR imaging were identical in both groups. After exercise, phosphorus spectroscopy revealed reduced oxidative mitochondrial capacity in mstn(-/-), whereas early recovery perfusion was identical and oxygen extraction, estimated from the blood oxygen level-dependent (BOLD) contrast, was decreased when compared with WT. Hyperemia was prolonged, indicating specific regulation of the perfusional response in mstn(-/-) mice. Histology showed an increased proportion of type IIb fibers in hypertrophied muscles, but the distribution of capillary contacts per fiber between oxidative and glycolytic fibers was unaltered in mstn(-/-) compared with WT. These integrated results formed coherent evidence of a congruous, non-pathologic shift toward a more glycolytic metabolism in this model of mstn(-/-).
Subject(s)
Muscle, Skeletal/physiology , Myostatin/deficiency , Animals , Exercise Test , Glycolysis/genetics , Hyperemia/metabolism , Magnetic Resonance Imaging , Magnetic Resonance Spectroscopy , Male , Mice , Mice, Knockout , Muscle, Skeletal/blood supply , Muscle, Skeletal/metabolism , Myostatin/genetics , Phosphocreatine/metabolismABSTRACT
1H-NMR (nuclear magnetic resonance) imaging is regularly proposed to non-invasively monitor cell therapy protocols. Prior to transplantation, cells must be loaded with an NMR contrast agent (CA). Most studies performed so far make use of superparamagnetic iron oxide particles (SPIOs), mainly for favorable detection sensitivity. However, in the case of labeled cell death, SPIO recapture by inflammatory cells might introduce severe bias. We investigated whether NMR signal changes induced by preloading with SPIOs or the low molecular weight gadolinium (Gd)-DTPA accurately monitored the outcome of transplanted cells in a murine model of acute immunologic rejection. CA-loaded human myoblasts were grafted in the tibialis anterior of C57BL/6 mice. NMR imaging was repeated regularly until 3 months post-transplantation. Label outcome was evaluated by the size of the labeled area and its relative contrast to surrounding tissue. In parallel, immunohistochemistry assessed the presence of human cells. Data analysis revealed that CA-induced signal changes did not strictly reflect the graft status. Gd-DTPA label disappeared rapidly yet with a 2-week delay compared with immunohistochemical evaluation. More problematically, SPIO label was still visible after 3 months, grossly overestimating cell survival (<1 week). SPIOs should be used with extreme caution to evaluate the presence of grafted cells in vivo and could hardly be recommended for the long-term monitoring of cell transplantation protocols.
Subject(s)
Contrast Media/pharmacokinetics , Ferrosoferric Oxide/pharmacokinetics , Gadolinium DTPA/pharmacokinetics , Magnetic Resonance Spectroscopy , Myoblasts/transplantation , Transplantation Immunology , Animals , Cell Death , Cell Survival , Cell Transplantation/methods , Cells, Cultured , Contrast Media/toxicity , Disease Models, Animal , Ferrosoferric Oxide/toxicity , Flow Cytometry , Gadolinium DTPA/toxicity , Half-Life , Hindlimb , Humans , Macrophages , Mice , Mice, Inbred C57BL , Myoblasts/cytology , Myoblasts/drug effects , Nanoparticles , Phagocytosis , Prussian Blue Reaction , Time Factors , Transplantation, Heterologous/methodsABSTRACT
Extracorporeal photopheresis (ECP) was given to 23 patients with steroid-refractory acute GVHD (aGVHD, grade II (n=10), III (n=7) or IV (n=6)). The median duration of ECP was 7 months (1-33) and the median number of ECP cycles in each patient was 10. Twelve patients (52%) had complete responses. Eleven patients (48%) survived and 12 died, 10 of GVHD with or without infections and two of leukaemia relapse. The average grade of GVHD was reduced from 2.8 (on the first day of ECP) to 1.4 (on day +90 from ECP) (P=0.08), and the average dose of i.v. methylprednisolone from 2.17 to 0.2 mg/kg/d (P=0.004). Complete responses were obtained in 70, 42 and 0% of patients, respectively, with grades II, III and IV aGVHD; complete responses in the skin, liver and gut were 66, 27 and 40%. Patients treated within 35 days from onset of aGVHD had higher responses (83 vs 47%; P=0.1). A trend for improved survival was seen in grade III-IV aGVHD treated with ECP as compared to matched controls (38 vs 16%; P 0.08). ECP is a treatment option for patients with steroid refractory aGVHD and should be considered early in the course of the disease.