Biomedical subjects
P Richard
Publications and source records attributed to P Richard.
Disease severity in dominant Emery Dreifuss is increased by mutations in both emerin and desmin proteins.
Individuals with the same genetic disorder often show remarkable differences in clinical severity, a finding generally attributed to the genetic background. We identified two patients with genetically proven Emery-Dreifuss muscular dystrophy (EDMD) who followed an unusual course and had uncommon clinicopathological findings. We hypothesized digenic inheritance and looked for additional molecular explanations. Mutations in additional separate genes were identified in both patients. The first patient was a member of a family with molecularly proven X-linked EDMD. However, the clinical features were unusually severe for this condition in the propositus: he presented at 2.5 years with severe proximal weakness and markedly elevated serum creatine kinase. Muscle weakness rapidly progressed, leading to loss of independent ambulation by the age of 12. In addition, the patient developed cardiac conduction system disease requiring pacing at the age of 11 and severe dilated cardiomyopathy in the early teens. Despite pacing, he had several syncopal episodes attributed to ventricular dysrhythmias. As these resemble the cardiac features of patients with the autosomal dominant variant of EDMD, we examined the lamin A/C gene, identifying a de-novo mutation in the propositus. The second patient had a cardioskeletal myopathy, similar to his mother who had died more than 20 years previously. Because of the dominant family history, a laminopathy was suspected and a mutation in exon 11 of the LMNA gene was identified. This mutation, however, was not present in his mother, but instead, surprisingly, was identified in his virtually asymptomatic father. Unusual accumulations of desmin found in the cardiac muscle of the propositus prompted us to examine the desmin gene in this patient, and in so doing, we identified a desmin mutation, in addition to the LMNA mutation in the propositus. These cases suggest that separate mutations in related proteins that are believed to interact, or that represent different parts of a presumed functional pathway, may synergistically contribute to disease severity in autosomal dominant EDMD. Furthermore, digenic inheritance may well contribute to the clinical severity of many other neuromuscular disorders.
[Management of a giant paraovarian cyst].
A 19-year-old healthy woman was referred in a gynecological surgery unit for the management of a giant paraovarian cyst. Ultrasound and tomodensitometry revealed a 36 x 25 cm intra abdominal mass. Paraovarian cyst being usually benign, we decided on a mini invasive surgery by laparoscopy. After this exploration, our patient underwent a very short suprapubian laparotomy. Pathologic result was a benign paraovarian cyst. Despite the unusual size of this tumor, first laparoscopic investigation permitted to avoid a median laparotomy.
[Fatal giant cell arteritis with severe bilateral involvement of the vertebral arteries].
With steroid therapy, it is commonly considered that prognosis is good in giant cell arteritis. However serious or even fatal complications may occur. Here we report the case of a patient who developed fatal giant cell arteritis with severe stenosis of both vertebral arteries and right carotid siphon. Several similar cases have been reported in the literature. Initially diagnosis may be difficult because neurological manifestations are intermittent and classical signs of giant cell arteritis may be lacking. In such condition the reason of poor outcome is unknown and therapy remains empiric.
"In situ-like" mantle cell lymphoma: a report of two cases.
Mantle cell lymphoma (MCL) is a B cell neoplasm that most often shows a diffuse growth pattern. Two cases of MCL are reported here, both with a previous diagnosis of lymphoid hyperplasia. Morphologically, germinal centres are hyperplasic with a normal or discretely enlarged mantle zone, where foci of irregularly shaped small lymphocytes are seen. These are positive for CD20, CD5 and cyclin D1, confirming a diagnosis of in situ-like MCL. This type differs from the mantle zone pattern in that the neoplastic mantle zone is very thin and there is very little or no spread of tumour cells into interfollicular areas. To the best of our knowledge, this is the first report on such a pattern of MCL, which is important to recognise, as it can be confused with lymphoid hyperplasia.
Heart involvement in lamin A/C related diseases.
The LMNA gene encodes lamins A and C, components of the nuclear envelope. Its mutations cause a wide range of diseases named laminopathies involving either specific tissues in isolated fashion (cardiac and skeletal muscles, peripheral nerve, adipose tissue) or several tissues in a generalized way (premature ageing syndromes and related disorders). The striated muscle laminopathies include a variety of well clinically characterized disorders where cardiac muscle involvement represents the common feature that coexists with or without skeletal muscle disease. The cardiac disease of LMNA mutated patients is classically defined by conduction system and rhythm disturbances occurring early in the course of the disease, followed by dilated cardiomyopathy and heart failure. These features are life threatening and often responsible of cardiac sudden death. When associated, the skeletal muscle involvement is characterized by muscle weakness and wasting of variable topography with or without early joint contractures and spinal rigidity. Specific management of the cardiac disease to includes antiarrhythmic drugs, cardiac devices such as implantable cardioverter for primary and secondary prevention of sudden death, and heart transplantation at the end stage of heart failure. A large number of LMNA mutations leading to striated muscle laminopathies have been reported without so far any clear and definite phenotype/genotype relation. Finally, among the diverse hypotheses for pathomechanisms of LMNA mutations, the structural hypothesis suggesting a defective role of lamins A/C in maintaining the structural integrity of the nuclear envelope in striated muscles under constant mechanical stress is highly attractive to link the LMNA mutations and the cardiac disease.
[Diagnostic value of a two-dimensional echocardiographic score for left ventricular hypertrophy validated by the Imatron CT scan in familial hypertrophic cardiomyopathy].
The aim of this study was to validate a two-dimensional echocardiographic score for left ventricular hypertrophy in familial hypertrophic cardiomyopathy (HCM) by fast CT scan and to study the diagnostic value by an indexed threshold value in affected and genotyped families in comparison with the classical diagnostic method of maximal wall thickness (E max). The study was performed successively in two patient groups with HCM. The echo/CT scan population comprised 26 patients. They underwent echocardiography and Imatron CT scanning. The E max and 2D echo score (sum of the thickness of 4 segments) were measured by echocardiography and compared to the left ventricular mass obtained by the CT method. The 2D echo score was closely correlated to the CT left ventricular mass (r = 0.85) with a higher correlation coefficient than the E max (r = 0.78). The echo/generic population comprised 109 genotyped adults with an identified mutation. The E max and 2D echo score were measured. The genotype was the reference for diagnosis. A theoretical value of the 2D echo score was determined in healthy individuals by a multiple linear regression model of ages, sex and body surface area. A threshold value for abnormality was established after analysis of the ROC. The sensitivity and specificity were 63% and 100% respectively for E max and 73% and 96% respectively for the indexed 2D echo score. The improvement in sensitivity was marked in young adults (< 50 years) with 69% for the indexed 2D echo score versus 54% for E max, p < 0.04. The authors conclude that the indexed 2D score has been validated as an index of hypertrophy by the Imatron CT and has a better diagnostic value than E max, especially in young adults. This echocardiographic criterion could be proposed as an alternative diagnostic sign for screening families.
Lifetime of charge carriers in multiwalled nanotubes.
The nature of low-energy excitations in multiwalled nanotubes (MWNTs) is investigated by means of two-color time-resolved photoemission. A careful analysis of the ballistic transport, secondary excitations, and band structure effects was employed in order to extract single electron lifetimes from the observed relaxation trend. It is demonstrated that in the vicinity of the Fermi level the energy dependence of e-e scattering times is inversely proportional to approximately the square of the excitation energy. This result provides strong evidence that electron transport in MWNTs exhibits a Fermi-liquid behavior, indicating that long-range e-e interaction along the tube vanishes due to screening.
Extreme variability of skeletal and cardiac muscle involvement in patients with mutations in exon 11 of the lamin A/C gene.
Mutations of the LMNA gene, encoding the nuclear envelope proteins lamins A and C, give rise to Emery-Dreifuss muscular dystrophy and to limb-girdle muscular dystrophy 1B (EDMD and LGMD1B). With one exception, all the reported EDMD and LGMD1B mutations are confined to the first 10 exons of the gene. We report four separate cases, with mutations in the same codon of LMNA exon 11, characterized by remarkable variability of clinical findings, in addition to features not previously reported. One patient had congenital weakness and died in early childhood. In two other patients, severe cardiac problems arose early and, in one of these, cardiac signs preceded by many years the onset of skeletal muscle weakness. The fourth case had a mild and late-onset LGMD1B phenotype. Our cases further expand the clinical spectrum associated with mutations in the LMNA gene and provide new evidence of the role played by the C-terminal domain of lamin A.
Two patients with 'Dropped head syndrome' due to mutations in LMNA or SEPN1 genes.
Dropped head syndrome is characterized by severe weakness of neck extensor muscles with sparing of the flexors. It is a prominent sign in several neuromuscular conditions, but it may also be an isolated feature with uncertain aetiology. We report two children in whom prominent weakness of neck extensor muscles is associated with mutations in lamin A/C (LMNA) and selenoprotein N1 (SEPN1) genes, respectively. This report expands the underlying causes of the dropped head syndrome which may be the presenting feature of a congenital muscular dystrophy.
[Autosomal dominant limb-girdle muscular dystrophy associated with conduction defects (LGMD1B): a description of 8 new families with the LMNA gene mutations].
INTRODUCTION: Limb girdle muscular dystrophy type 1b (LGMD1B), due to LMNA gene mutations, is a relatively rare form of LGMD characterized by proximal muscle involvement associated with heart involvement comprising atrio-ventricular conduction blocks and dilated cardiomyopathy. Its clinical and genetic diagnosis is crucial for cardiac management and genetic counselling. Seven LMNA mutations have been previously reported to be responsible for LGMD1B. PATIENTS AND METHODS: We describe the neurological and cardiologic features of 14 patients belonging to 8 families in whom we identified 6 different LMNA mutations, 4 of them having never been reported. Results. Eleven patients had an LGMD1B phenotype with scapulohumeral and pelvic-femoral involvement. Thirteen patients had cardiac disease associating conduction defects (12 patients) or arrhythmias (9 patients). Seven patients needed cardiac device (pacemaker or implantable cardiac defibrillator) and two had heart transplantation. CONCLUSION: This study allowed us to specify the clinical characteristics of this entity and to outline the first phenotype/genotype relations resulting from these observations.
Bleeding esophageal GIST.
We present a case of esophageal gastrointestinal stromal tumor presenting as gastrointestinal bleeding.
Experimental compaction of anisotropic granular media.
We report on experiments to measure the temporal and spatial evolution of packing arrangements of anisotropic and weakly confined granular material, using high-resolution gamma-ray adsorption. In these experiments, the particle configurations start from an initially disordered, low-packing-fraction state and under vertical solicitations evolve to a dense state. We find that the packing fraction evolution is slowed by the grain anisotropy but, as for spherically shaped grains, can be well fitted by a stretched exponential. For a given type of grains, the characteristic times of relaxation and of convection are found to be of the same order of magnitude. On the contrary, compaction mechanisms in the media strongly depend on the grain anisotropy.
[Apical left ventricular aneurysm without atrio-ventricular block due to a lamin A/C gene mutation].
UNLABELLED: Mutations in LMNA gene encoding two ubiquitously expressed nuclear proteins, lamins A and C, give rise to up to 7 different pathologies affecting specific tissues. Three of these disorders affect cardiac and/or skeletal muscles with atrio-ventricular conduction disturbances, dilated cardiomyopathy and sudden cardiac death as common features. RESULTS: A new LMNA mutation (1621C>T, R541C) was found in two members of a French family with a history of ventricular rhythm disturbances and an uncommon form of systolic left ventricle dysfunction. The two patients: the proband and his daughter, were affected and exhibited an atypical form of dilated cardiomyopathy with an unexplained left ventricle aneurysm revealed by ventricular rhythm disturbances without atrio-ventricular block. CONCLUSION: This finding reinforces the highly variable phenotypic expression of LMNA mutation and emphasizes the fact that LMNA mutations can be associated with different cardiac phenotypes.
[Interventricular management of patients over the age of 75 with acute coronary syndromes without persistent ST elevation].
The aim ot tnis study was to assess the results of interventional strategy in patients over 75 years of age admitted to hospital with acute coronary syndromes (ACS) without persistent ST elevation. Over three months, patients over the age of 75 undergoing coronary angiography for ACS were included in a multicentre register and followed up for 6 months. A total of 126 patients with an average age of 79 were included: 70% had at least one poor prognostic factor. The treatment on admission included: Aspirin (84%), Clopidogrel (60%), anti GpIIb-IIIa (12%) and Heparin (81%, of which 3/4 of cases were low molecular weight heparins). Coronary angiography (average delay 80 hours) showed single, double and triple vessel disease in 21, 29 and 35% of cases respectively. Coronary angioplasty was proposed in 83 patients and carried out in 82. Eleven patients underwent coronary artery bypass grafting and 31 were treated medically. During the hospital phase, there were 3 major cardiovascular complications: 1 death during coronary angiography, 1 intra-stent thrombosis and 1 death in the group undergoing bypass grafting, with no major bleeding complications. At 6 months, there were 8 (6.5%) major cardiovascular adverse events with 6 in the "angioplasty" group; 5 deaths (3 cardiac deaths), 3 myocardial infarcts. Two thirds of patients were asymptomatic. The authors conclude that interventional strategy in ACS of elderly patients is associated with a low rate of major adverse events. The benefits of this strategy should be confirmed by randomised trial.
Towards the molecular elucidation of congenital myasthenic syndromes: identification of mutations in MuSK.
Congenital myasthenic syndromes (CMS) are rare genetic diseases affecting the neuromuscular junction (NMJ) and characterized by a dysfunction of the neurotransmission. They are heterogeneous at the pathophysiological level and can be classified in three categories according to their origin: presynaptic, synaptic or postsynaptic. The strategy for the diagnosis and characterization of CMS relies on the clinic, EMG, muscle biopsy, identification of mutations in genes known to be responsible for CMS and the demonstration that the gene mutations are the cause of the disease by using experimental approaches. As an example of such strategy, we report briefly here the characterization of the first case of a human neuromuscular transmission dysfunction due to mutations in the gene encoding a postsynaptic molecule, the muscle-specific receptor tyrosine kinase (MuSK). Gene analysis identified two heteroallelic mutations, a frameshift mutation (c.220insC) and a missense mutation (V790M). The muscle biopsy showed marked pre- and postsynaptic structural abnormalities of the neuromuscular junction as well as a severe decrease in acetylcholine receptor epsilon-subunit and MuSK expression. In vitro and in vivo expression experiments were performed using mutant MuSK reproducing the human mutations. The results obtained strongly suggested that the missense mutation, in the presence of a null mutation on the other allele, was responsible for the severe synaptic changes observed in the patient and, hence, is causing the disease. However the molecular origin of a large number of CMS is still unknown. There are hundreds of molecules known to be present at the NMJ and mutations in the genes coding for these synaptic molecules are likely to be responsible for a neuromuscular block.
Time-resolved photoimaging of image-potential states in carbon nanotubes.
The first experimental evidence for the existence of image-potential states in carbon nanotubes is presented. The observed features constitute a new class of surface image states due to their quantized centrifugal motion. Measurements of binding energies and the temporal evolution of image state electrons were performed using femtosecond time-resolved photoemission. The associated lifetimes are found to be significantly longer than those of n=1 image state on graphite, indicating a substantial difference in electron decay dynamics between tubular and planar graphene sheets.
Interference effect in electron emission in heavy ion collisions with h2 detected by comparison with the measured electron spectrum from atomic hydrogen.
Direct evidence of the interference effect in the electron emission spectra from ionization of molecular hydrogen in collisions with bare C and F ions at relatively low collision energies is presented. Oscillations due to the interference are deduced by comparing the measured double differential cross sections of the electrons emitted from molecular hydrogen to those emitted from atomic hydrogen, rather than using the calculated cross sections for H as in a previous report. We believe these experimental data provide stronger support for the evidence of the interference effect. We show that it is not only a feature of very high energy collisions, but also a feature to be observed in relatively lower energy collisions.