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Biomedical subjects

C Desnuelle

Publications and source records attributed to C Desnuelle.

At least 19 recordsLinked to original sources
PubMed2006

Diagnostic challenges in facioscapulohumeral muscular dystrophy.

The diagnosis of facioscapulohumeral muscular dystrophy (FSHD) can be difficult due to its clinical variability and complex genetic cause. We present three challenging cases: one misdiagnosis of FSHD, one patient with FSHD resembling mitochondrial myopathy, and one patient with combined FSHD and limb girdle muscular dystrophy 2A. Detailed clinical and genetic evaluation, including 4qA/4qB allele determination, may be needed for the diagnosis of FSHD.

Adult↗
PubMed2006

[Manual and quantitative muscle testing in neuromuscular disorders. How to assess the consistency of strength measurements in clinical trials?].

Evaluation of functional capacities of patients suffering of neuromuscular disorders, particularly muscle strength, is a critical issue for their diagnosis and follow-up. Within the framework of the natural history of any given disease, such an evaluation may improve the clinician's knowledge of the pathophysiological processes involved, and may help to anticipate and sometimes prevent deleterious consequences as the disease progresses. It is also helpful for identifying correlation between the severity of organic damage and the functional impact of the disease. The measurement of functional capacities must be done with accuracy, sensitivity and reliability, essentially when used as an outcome measure for therapeutic trials. Several evaluation tools for measuring muscle strength are available. They are usually classified into two groups: manual muscle testing (MMT) methods and quantified muscle testing (QMT) methods. In this article, we present the principles of strength measurements, and the different tools and materials that are commonly used in clinical settings. Their limitations and drawbacks are illustrated through several examples. Although QMT is theoretically and potentially more consistent than MMT to precisely follow the muscle capacities of the patients, precise and robust procedures must be elaborated and validated for each tested muscle function. Strength measurements must be performed by trained and experimented clinical evaluators. This issue is critical in the follow up of multicentric therapeutic trials. Inter-rater reliability must be assessed to guarantee the statistical power of the trial.

Clinical Trials as Topic↗
PubMed2006

[Psychological reactions to the announcement of a severe disease diagnosis: the amyotrophic lateral sclerosis example].

To face the traumatic shock after the announcement of a severe and fatal disease, patients build psychological defences that physician must identify and respect as long as they don't endanger the patient's psychological fate and his medical care. ALS patient's do not have any curative perspective thus they will try "to escape" using different strategies the traumatic reality, that they cannot integrate and control. The physician has to prove his understanding and empathy facing these psychological reactions that could become of pathological appearance. The physician has to progressively bring the patient to consult the clinical psychologist; however he has not to forget that he is equally responsible about the way the patient go though his disease.

Amyotrophic Lateral Sclerosis↗
PubMed2006

[Functional scales and motor assessment in amyotrophic lateral sclerosis].

There is a need of standardized and quantitative clinical assessments of ALS patients receiving new treatments. Some clinical scales, that are based on patients interviews and/or on physical examination, allow to quantify the patient functional status over time. The ALSFRS has been validated for that purpose and is one the most commonly used scales in clinical trials. Its revised version (the ALSFRS-R) has recently shown excellent metric properties. Functional scales are part of the clinical evaluation of ALS patients, and complete the quantitative assessment of muscle strength, that includes the Manual Muscular Testing (MMT) and the Maximal Voluntary Isometric Contraction (MVIC). Readers will find in this article a (non-exhaustive) listing of functional and motor scales that can be useful both in clinical trials of experimental agents and in daily practice.

Amyotrophic Lateral Sclerosis↗
PubMed2006

[What physical therapy techniques can be used to improve airway freedom in amyotrophic lateral sclerosis?].

In individuals with ALS rehabilitation is mainly designed to prevent fatigue and contracture, to improve independence and activities for as long as possible, to optimize ability to live with the handicap, and finally to maximize quality of life. The functional impairment must be defined and physical therapy techniques have to be adapted to each patient and reevaluated frequently during the course of the disease. Various types of massage and exercise, monitored by a physical therapist are effective. Strengthening or endurance exercises are controversial as exercise may injure muscle fibres and motor neurons. Isometric exercise, short of fatigue, of unaffected muscles is recommended. Range of motion exercise is critically important for preventing contraction. Assistive and adaptative equipments are essential for maintaining the patient's activities of daily living and home equipment preserves independence. Several orthoses for hand, arm, foot or cervical weakness are available. A wheelchair is an important adaptative device when walking becomes too fatiguing or impossible. Choice for special options and features may require attention. Pulmonary complications are prevented with adapted techniques for bronchic obstruction. Based on the degree of weakness of limb and axial muscles six stages of functional impairment can be defined ranging from fully ambulatory in stage I to bedridden and totally dependent in stage VI. This staging provides a framework for physical therapy evaluation and guidance for appropriate rehabilitation in ALS patients.

Airway Obstruction↗
PubMed2005

Normal growth and regenerating ability of myoblasts from unaffected muscles of facioscapulohumeral muscular dystrophy patients.

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disease characterized by a typical regional distribution, featuring composed patterns of clinically affected and unaffected muscles. No treatment is available for this condition, in which the pathophysiological mechanism is still unknown. Autologous transfer of myoblasts from unaffected to affected territories could be considered as a potential strategy to delay or stop muscle degeneration. To evaluate the feasibility of this concept, we explored and compared the growth and differentiation characteristics of myoblasts prepared from phenotypically unaffected muscles of five FSHD patients and 10 control donors. According to a clinically approved procedure, 10(9) cells of a high degree of purity were obtained within 16-23 days. More than 80% of these cells were myoblasts, as demonstrated by labeling of the muscle markers CD56 and desmin. FSHD myoblasts presented a doubling time equivalent to that of control cells; they kept high proliferation ability and did not show early telomere shortening. In vitro, these cells were able to differentiate and to express muscle-specific antigens. In vivo, they participated to muscle structures when injected into immunodeficient mice. These data suggest that myoblasts expanded from unaffected FSHD muscles may be suitable tools in view of autologous cell transplantation clinical trials.

Animals↗
PubMed2004

[Isokinetic evaluation of the knee flexor muscles after anterior cruciate ligament reconstruction using gracilis and semitendinous tendon grafts].

PURPOSE OF THE STUDY: The purpose of this study was to evaluate recovery of hamstring force after anterior cruciate ligament reconstruction using gracilis and semitendinous tendon grafts. MATERIAL AND METHODS: Isokinetic evaluation of the knee flexor muscles was performed with the system 3 Biodex isokinetic dynameter in twelve patients (mean age 26 years) 12 to 24 months after ligamentoplasty. Concentric (60 degrees /s, 180 degrees /s, 300 degrees /s) and excentric forces were measured. We retained for analysis: 1) moment of maximal force, 2) moment of force at 75 degrees knee flexion, and 3) work. RESULTS: The knee flexor muscles of the operated limb exhibited greater deficit when considering force at 75 degrees knee flexion (24%, 15%, and 18% concentric deficit at 60 degrees /s, 180 degrees /s, and 300 degrees /s respectively, and 20% excentric deficit) than when considering maximal force (14%, 7%, 5% concentric deficit at 60 degrees /s, 180 degrees /s, and 300 degrees /s respectively and 9% excentric deficit). DISCUSSION: This study demonstrates persistent deficit of knee flexor muscle force 12 to 24 months after anterior cruciate ligament repair with hamstring muscle tendons. The deficit reaches 15% to 24% at 75 degrees of knee flexion. The protective role of the hamstring muscles for the cruciate graft submitted to important stress may be compromised by the lack of recovery of knee flexor force more than one year after ligamentoplasty.

Adult↗
PubMed2002

Molecular and functional effects of the T14709C point mutation in the mitochondrial DNA of a patient with maternally inherited diabetes and deafness.

A heteroplasmic T to C transition at nucleotide position 14709 in the mitochondrial tRNA glutamic acid (tRNA(Glu)) gene has previously been associated with maternally inherited diabetes and deafness (MIDD). To investigate the pathogenic mechanism of the T14709C mutation, we have constructed transmitochondrial cell lines by transferring fibroblasts mitochondria from a patient with the mutation into human cells lacking mitochondrial DNA (mtDNA) (rho degrees cells). Clonal cybrid cell lines were obtained containing various levels of the heteroplasmic mutation, or exclusively mutated or wild-type mtDNA. Measurement of respiratory chain enzymatic activities failed to detect a difference between the homoplasmic mutant and homoplasmic wild-type cybrid cell lines. However, a subtle decrease in the steady-state levels of tRNA(Glu) transcripts in some mutant clones. Our studies suggest that the T14709C mutation is insufficient to lead impairment of mitochondrial function in homoplasmic osteosarcoma cybrid clones, and that we cannot exclude that the T14709C mutation affects mitochondrial function by a yet unidentified mechanism.

Base Sequence↗
PubMed2001

A double-blind, placebo-controlled randomized clinical trial of alpha-tocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis. ALS riluzole-tocopherol Study Group.

INTRODUCTION: Increasing evidence suggests that oxidative stress may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). The antioxidant vitamin E (alpha-tocopherol) has been shown to slow down the onset and progression of paralysis in transgenic mice expressing a mutation in superoxide dismutase found in certain forms of familial ALS. The current study was designed to determine whether alpha-tocopherol (500 mg b.i.d.) may be efficacious in the treatment of ALS. METHODS: Two hundred and eighty-nine patients with ALS of less than 5 years duration, treated with riluzole, were enrolled in this study, and were randomly assigned to receive either alpha-tocopherol or placebo daily for one year. The primary outcome measure was the rate of deterioration of function assessed by the modified Norris limb scale. Patients were assessed at entry, and every 3 months thereafter during the study period. Survival was also recorded. Biochemical markers of oxidative stress were measured in a subset of patients on entry and after 3 months of treatment. RESULTS: After 12 months of treatment, alpha-tocopherol had no effect on the primary outcome measure. Survival was not influenced by treatment. Among secondary outcome measures, patients given alpha-tocopherol were less likely to progress from the milder state A to the more severe state B (P=0.046) of the ALS Health State scale. After 3 months treatment, analysis of oxidative stress markers showed an increase in glutathione peroxidase activity in plasma (P = 0.0389) and a decrease in plasma levels of thiobarbituric acid reactive species (P = 0.0055) in the group of patients given alpha-tocopherol in combination with riluzole. CONCLUSION: Although alpha-tocopherol did not appear to affect the survival and motor function in ALS, patients receiving riluzole plus alpha-tocopherol remained longer in the milder states of the ALS Health State scale and showed, after 3 months, changes in biochemical markers of oxidative stress. Further studies are required to confirm the greater sensitivity of the ALS Health State scale over other clinical endpoints.

Aged↗
PubMed2001

[Mitochondrial diseases in adults].

PURPOSE: Mitochondrial diseases have numerous phenotypic expression, and form an heterogeneous group of genetic diseases in which the production of energy fails. Well known in childhood, these mitochondrial diseases can onset in adulthood and may remain unrecognized. We propose a recent review (Medline 1981-2001) of the literature on adult forms of mitochondriopathies, illustrated with a typical case report. CURRENT KNOWLEDGE AND KEY POINTS: Mitochondrial diseases have numerous phenotypic expression in adulthood. Principles of diagnosis are i) recognize a phenotype, ii) prove the mitochondrial abnormalities, iii) realize a genetical analysis. Main varieties of adult phenotypes are studied and separated in 1) skeletal muscular involvement, ocular myopathies above all; 2) mitochondrial cardiomyopathies; 3) neurological involvement (MERRF, MELAS, NARP, MNGIE syndromes); 4) endocrinological involvement and diabetes mellitus; 5) multisystemic diseases with a particular focus on Kearns Sayre syndrome. FUTURE PROSPECTS AND PROJECTS: Phenotypic analysis of a patient with mitochondrial disease is not simple. A "multi-tissues" involvement is the main characteristic feature. Faced with such patients, replacement therapy, genomic therapy and genetic advice are evoked.

Adult↗
PubMed2000

Mitochondrial DNA variations in patients with maternally inherited diabetes and deafness syndrome.

Mitochondrial DNA (mtDNA) variants have been implicated in the pathogenesis of diabetes. A mutation in the tRNA leucine gene at position 3243 has been previously reported in mtDNA of maternally inherited diabetes and deafness (MIDD) patients. Because the true prevalence of the mitochondrial origin in diabetes may be underestimated, we searched for potentially diabetogenic anomalies of mtDNA in 9 patients highly suspected of mitochondrial diabetes selected on maternally inheritance and clinical features. In order to detect high levels of mutant DNA, the mtDNA of muscle sample of 2 patients was totally sequenced and the 22 tRNA genes and flanking sequences of 7 patients were analyzed. A new homoplasmic mutation at position 8381 was found in the ATPase 8 gene of mtDNA of a MIDD patient. The prevalence of three homoplasmic variations (G1888A, T4216G, A4917G) was significantly higher in the small group of MIDD patients compared to controls and other subjects groups. This study demonstrated in our patients sample the high frequency of homoplasmic variations, which could play a role by themselves or in combination, in the pathogenesis of diabetes.

Adult↗
PubMed2000

Importance of searching for associated mitochondrial DNA alterations in patients with multiple deletions.

Multiple mitochondrial DNA (mtDNA) deletions have been reported in patients with autosomal dominant and recessive disorders. We studied several affected and one non-affected individuals belonging to a pedigree in which the inheritance of the pathological trait was compatible with an autosomique dominant transmission. Affected members had late-onset multisystem disorders with multiple mtDNA deletions in skeletal muscle. But this family presented a striking difference from previously described cases, because none of the patients had progressive external ophthalmoplegia (PEO). We also studied one young boy with a no contributary family history. He had a cerebellar ataxia with PEO and multiple mtDNA deletions in muscle. Molecular analysis revealed that in the first family, repeated sequences were present at the breakpoint junctions, whereas such motifs were not found in the young patient's case. In the first family, we evidenced mtDNA point mutations in clones containing breakpoint junctions and a 9-bp motif triplication in the intergenic COII/tRNA(Lys) region, whereas this sequence is repeated twice in the wild type mtDNA. Our results suggest that multiple deletions observed in the two pedigrees result from different molecular mechanisms and point out the role of repeated sequences in the first pedigree. No mtDNA repair system has been described in mammals so far, but the molecular abnormalities found in the first family suggest that a defect in an mtDNA repair system, homologous to the E. coli MutHLS pathway, could be responsible for such a phenotype.

Child↗
PubMed2000

MSH4 acts in conjunction with MLH1 during mammalian meiosis.

MSH4 is a meiosis-specific MutS homolog. In yeast, it is required for reciprocal recombination and proper segregation of homologous chromosomes at meiosis I. MLH1 (MutL homolog 1) facilitates both mismatch repair and crossing over during meiosis in yeast. Germ-line mutations in the MLH1 human gene are responsible for hereditary nonpolyposis cancer, but the analysis of MLH1-deficient mice has revealed that MLH1 is also required for reciprocal recombination in mammals. Here we show that hMSH4 interacts with hMLH1. The two proteins are coimmunoprecipitated regardless of the presence of DNA or ATP, suggesting that the interaction does not require the binding of MSH4 to DNA. The domain of hMSH4 responsible for the interaction is in the amino-terminal part of the protein whereas the region that contains the ATP binding site and helix-turn-helix motif does not bind to hMLH1. Immunolocalization analysis shows that MSH4 is present at sites along the synaptonemal complex as soon as homologous chromosomes synapse. The number of MSH4 foci decreases gradually as pachynema progresses. During this transition, MLH1 foci begin to appear and colocalize with MSH4. These results suggest that MSH4 is first required for chromosome synapsis and that this MutS homologue is involved later with MLH1 in meiotic reciprocal recombination.

Adaptor Proteins, Signal Transducing↗
PubMed1999

[Plea for accelerated rehabilitation after ligament plasty of the knee by a bone-patellar tendon-bone graft].

Knee rehabilitation after ACL repair with bone-tendon-bone graft is still controversial. While there was a tendency to protect the graft and the donor site in the eighties, actual tendency is to propose more aggressive, so called accelerated rehabilitation protocol. An extensive analysis of the literature shows that this accelerated rehabilitation is justified because of histologic, biomechanic, surgical and clinical arguments. This accelerated rehabilitation is based on seven reasons, at least: 1) the necrosis of the graft, initially observed in animals, does not seem to be as important in humans as demonstrated by histological studies after in vivo biopsies; 2) the use of solid bone-tendon-bone graft, whose resistance is maximum in the early post-operative period and is superior to the resistance of the ACL; 3) the more precise positioning (more "isometric") because of optic magnification allowed by arthroscopy; 4) the absence of graft impingement, routinely controlled, because of a more posterior tibial placement of the graft and the eventual notch-plasty; 5) the solid and confident fixation of the graft because of interference screws; 6) anterior knee pain are less important when early constraints are applied on the knee; 7) finally, undisciplined and demanding patients who refuse all protection for the graft and the donor site, have good and stable results regarding stability of the knees. Early constraints on the knee after bone-tendon-bone graft and interference fixation give better tolerance on the extension mechanism without compromising integrity of the graft and knee stability. Appropriate level of constraints on the ACL graft and the donor site guides the collagenic reorganisation process. Early restoration of normal hyperextension, decreased knee pain and maintenance of muscular trophicity, allowing patients to go back to sport at 4 months, are the most evident benefits of this accelerated rehabilitation. These considerations cannot be applied to the other grafts (fascia lata, semi-tendinous, allografts ...) and to other ways of fixation (sutures, staples, ...).

Animals↗