Biomedical subjects

D Chateau

Publications and source records attributed to D Chateau.

At least 19 recordsLinked to original sources

PubMed2000

Functional mitochondrial heterogeneity in heteroplasmic cells carrying the mitochondrial DNA mutation associated with the MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and strokelike episodes).

Most mitochondrial DNA (mtDNA) alterations associated with human disorders are heteroplasmic, i.e. mutant mtDNA molecules coexist with normal ones within the cell. We addressed the possibility of intermitochondrial exchanges through histologic analyses of cybrid clones with increasing proportion of the MELAS (A3243G) mtDNA transfer RNA point mutation. MtDNA-dependent cytochrome c oxidase activity and protein composition as well as mitochondrial membrane potential appeared heterogeneous in individual cells from clonal heteroplasmic cell populations on the basis of confocal and electron microscopy. The number of defective cells increased with increasing mutation load. We conclude that in the presence of a heteroplasmic mtDNA mutation in the cell type that we studied, intermitochondrial molecular exchanges cannot provide an efficient even distribution of the complementing molecules such as wild-type mtDNA, transfer RNA, or protein. Mitochondria in these heteroplasmic cells cannot, therefore, be considered a single functional unit.

Cell Fusion↗

PubMed2000

Exposure to print and word recognition processes.

The effect of exposure to print on the efficiency of phonological and orthographic word recognition processes was examined by comparing two groups of university students having similar reading comprehension scores but different levels of exposure to print. Participants with a high level of exposure to print were faster and more accurate in naming pseudowords, in choosing the correct member of a homophone pair, and in making lexical decisions when nonwords were pseudohomophones. In the lexical decision task, low-print-exposure participants were more sensitive to the frequency of the orthographic patterns in the stimuli. The results of a form priming task demonstrated that high-print-exposure participants more quickly and strongly activated the orthographic representations of common words and subsequently more strongly activated the corresponding phonological representations. Even among successful students, differences in exposure to print produce large differences in the efficiency of both orthographic and phonological word recognition processes.

Adult↗

PubMed2000

[Familial myopathy with desmin storage seen as a granulo-filamentar, electron-dense material with mutation of the alphaB-cristallin gene].

Two familial cases of a myopathy remarkable by the presence of a granulo-filamentar, electron dense material were reported in 1978. In a second step, in 1988, it was demonstrated that this material contained an abnormally-phosphorylated desmin. During the last twenty years, the occurrence of new cases in this family confirmed the autosomal dominant inheritance of the disease, and made it potentially informative for molecular genetics studies. This allowed first to map the disease on chromosome11q21-23, and afterwards to identify a mutation within a gene coding for a chaperone protein, alphaBcrystallin. An extensive clinical, pathological and genetic study of this princeps family is herein reported in detail. First, it showed the possible detection of histopathological changes in presymptomatic patients. Second, it allowed to demonstrate the simultaneous occurrence of both alphaBcrystallin and desmin in the granulo-filamentar aggregates. Third, this study provided a precise knowledge of the evolution rate of the disease. The analysis of similar observations reported in the literature clearly shows the clinical, pathological and genetic heterogeneity of this new neuro-muscular disorder.

Actin Cytoskeleton↗

PubMed2000

Multi-minicore disease--searching for boundaries: phenotype analysis of 38 cases.

Multi-minicore disease (MmD) is a congenital myopathy morphologically defined by the presence of multiple small zones of sarcomeric disorganization and lack of oxidative activity ("minicores") in muscle fibers. The dinical expression of MmD is considered to be greatly variable, and the morphological lesions are nonspecific; therefore, its boundaries are poorly defined, and its molecular bases are not known. To better define the phenotypic characteristics of MmD, we analyzed a large series of 38 patients with multiple minicores in muscle fibers in the absence of any other potential cause. According to clinical features, 4 subgroups were identified. Most patients (30 cases) shared a common highly consistent phenotype marked by the axial predominance of muscle weakness and a high occurrence of severe respiratory insufficiency and scoliosis ("classical" form). Other forms were characterized by pharyngolaryngeal involvement and total lack of head control (2 cases), antenatal onset with arthrogryposis (3 cases), and slowly progressive weakness with marked hand amyotrophy (3 cases). Type 1 fiber predominance and hypotrophy as well as centrally located nuclei were found in every subgroup. MmD is thus phenotypically heterogeneous, but a typical recognizable phenotype does exist. This phenotype classification should be helpful when undertaking research into the molecular defects that cause MmD.

Biopsy↗

PubMed1999

Prevention of autoimmune attack by targeting specific T-cell receptors in a severe combined immunodeficiency mouse model of myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease targeting the skeletal muscle acetylcholine receptor. We have previously demonstrated a selection bias of CD4+ T cells expressing the Vbeta5.1 T-cell receptor gene in the thymus of HLA-DR3 patients with MG. To evaluate the pathogenicity of these cells, severe combined immunodeficiency mice engrafted with MG thymic lymphocytes were treated with anti-Vbeta5.1 antibody. Signs of pathogenicity (eg, acetylcholine receptor loss and complement deposits at the muscle end plates of chimeric mice) were prevented in anti-Vbeta5.1-treated severe combined immunodeficiency chimeras. Pathogenicity was mediated by autoantibodies against acetylcholine receptor. Thymic cells depleted of Vbeta5.1-positive cells in vitro before cell transfer were nonpathogenic, indicating that Vbeta5.1-positive cells are involved in the production of pathogenic autoantibodies. Acetylcholine receptor loss was prevented by Vbeta5.1 targeting in HLA-DR3 patients only, demonstrating specificity for HLA-DR3-peptide complexes. The action of the anti-Vbeta5.1 antibody involved both the in vivo depletion of Vbeta5.1-expressing cells and an increase in the interferon-gamma/interleukin-4 ratio, pointing to an immune deviation-based mechanism. This demonstration that a selective and specific T-helper cell population is involved in controlling pathogenic autoantibodies in MG holds promise for the treatment of MG.

Adolescent↗

PubMed1999

Adult onset reducing body myopathy.

We report the case of a 28 year-old woman with left scapuloperoneal syndrome since the age of 24. The course was slowly progressive and diffuse weakness was observed 4 years later. Serum creatine kinase levels were moderately elevated (x3 normal value) and EMG showed mixed neurogenic and myogenic patterns. Muscle biopsy showed type I predominance and numerous reducing bodies in muscle fibers. Reducing bodies were strongly immunoreactive with antibodies to dystrophin, alpha-sarcoglycan, vimentin and ubiquitin. Desmin immunoreactivity was increased at the periphery of some reducing bodies but alphaB crystallin, alpha actinin, titin and nebulin were negative. Western blot analysis showed an increase in dystrophin, vimentin and desmin expression. Ultrastructurally, reducing bodies were composed of tubulofilamentous material, 17 nm in diameter, and immunoreactive with anti-Dys 2 antibody. Granulofilamentous material, immunoreactive with anti-desmin antibody was observed at the periphery of some reducing bodies. This report further highlights the proteinic composition of reducing bodies and shows that late onset reducing body myopathy may occur.

Adult↗

PubMed1998

Autosomal recessive oculopharyngodistal myopathy in light of distal myopathy with rimmed vacuoles and oculopharyngeal muscular dystrophy.

We investigated two Japanese siblings presenting with oculopharyngodistal myopathy, whose healthy parents were consanguineous. To clarify their disease characteristics, we compared them with four patients with distal myopathy with rimmed vacuoles linked to chromosome 9p1-q1, and 36 patients with oculopharyngeal muscular dystrophy linked to 14q11.2-q13. The first symptom in the patients with autosomal recessive oculopharyngodistal myopathy was weakness of the tibialis anterior muscle. Their biceps muscles showed initial and advanced myogenic changes, with rimmed vacuoles in 3% and 6% of the muscle fibers, respectively. In contrast, patients with distal myopathy with rimmed vacuoles revealed many rimmed vacuoles, on average in 20% of the fibers, and their oculopharyngeal muscles were spared. None of the patients with oculopharyngeal muscular dystrophy showed distal dominant weakness and the occurrence of rimmed vacuoles was rare. Ultrastructural studies in groups of autosomal recessive oculopharyngodistal myopathy and distal myopathy with rimmed vacuoles disclosed a collection of cytoplasmic filaments of 16-18 nm, but oculopharyngeal muscular dystrophy-specific intranuclear inclusions of 8.5 nm were not found. Thus, the phenotype of autosomal recessive oculopharyngodistal myopathy is distinct from distal myopathy with rimmed vacuoles and oculopharyngeal muscular dystrophy, but shares some ultrastructural characteristics with distal myopathy with rimmed vacuoles and hereditary inclusion body myopathy.

Chromosomes, Human, Pair 14↗

PubMed1998

Autosomal dominant late adult onset distal leg myopathy.

A distal myopathy characterised by an autosomal dominant inheritance, with clinical onset around the age of 60, early involvement of posterior leg and thigh muscles, and normal or slightly-elevated creatine kinase levels was identified in three members of a French kindred. Tibialis anterior muscles were involved only in the most severely-affected sibling. Histological features included large multiple nonrimmed vacuolation and focal intrasarcoplasmic masses which immunoreacted with the anti-desmin antibody. Cytoplasmic and intranuclear tubulofilamentous inclusions were observed by electron microscopy. The condition of this familial syndrome is discussed in relation to previously-identified autosomal dominant distal myopathies and inclusion body myopathies.

Age of Onset↗

PubMed1998

A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy.

Desmin-related myopathies (DRM) are inherited neuromuscular disorders characterized by adult onset and delayed accumulation of aggregates of desmin, a protein belonging to the type III intermediate filament family, in the sarcoplasma of skeletal and cardiac muscles. In this paper, we have mapped the locus for DRM in a large French pedigree to a 26-cM interval in chromosome 11q21-23. This region contains the alphaB-crystallin gene (CRYAB), a candidate gene encoding a 20-kD protein that is abundant in lens and is also present in a number of non-ocular tissues, including cardiac and skeletal muscle. AlphaB-crystallin is a member of the small heat shock protein (shsp) family and possesses molecular chaperone activity. We identified an R120G missense mutation in CRYAB that co-segregates with the disease phenotype in this family. Muscle cell lines transfected with the mutant CRYAB cDNA showed intracellular aggregates that contain both desmin and alphaB-crystallin as observed in muscle fibers from DRM patients. These results are the first to identify a defect in a molecular chaperone as a cause for an inherited human muscle disorder.

Animals↗

PubMed1998

Mutation in the human acetylcholinesterase-associated collagen gene, COLQ, is responsible for congenital myasthenic syndrome with end-plate acetylcholinesterase deficiency (Type Ic).

Congenital myasthenic syndrome (CMS) with end-plate acetylcholinesterase (AChE) deficiency is a rare autosomal recessive disease, recently classified as CMS type Ic (CMS-Ic). It is characterized by onset in childhood, generalized weakness increased by exertion, refractoriness to anticholinesterase drugs, and morphological abnormalities of the neuromuscular junctions (NMJs). The collagen-tailed form of AChE, which is normally concentrated at NMJs, is composed of catalytic tetramers associated with a specific collagen, COLQ. In CMS-Ic patients, these collagen-tailed forms are often absent. We studied a large family comprising 11 siblings, 6 of whom are affected by a mild form of CMS-Ic. The muscles of the patients contained collagen-tailed AChE. We first excluded the ACHE gene (7q22) as potential culprit, by linkage analysis; then we mapped COLQ to chromosome 3p24.2. By analyzing 3p24.2 markers located close to the gene, we found that the six affected patients were homozygous for an interval of 14 cM between D3S1597 and D3S2338. We determined the COLQ coding sequence and found that the patients present a homozygous missense mutation, Y431S, in the conserved C-terminal domain of COLQ. This mutation is thought to disturb the attachment of collagen-tailed AChE to the NMJ, thus constituting the first genetic defect causing CMS-Ic.

Acetylcholinesterase↗

PubMed1997

Retinoid receptors in rat vaginal and uterine epithelia: changes with ovarian steroids.

In rats, vaginal epithelium shows cyclic changes with an alternating pattern of keratinization under estrogen control and mucification under progesterone control. Since retinoids suppress keratinizing differentiation, in this paper we studied the expression of the major retinoid receptors normally present in keratinizing squamous epithelia: RAR alpha, RAR gamma and RXR alpha. In cyclic rats and steroid-treated ovariectomized rats, RXR alpha and RAR gamma were detected in basal and suprabasal cells while RAR alpha was mainly localized in suprabasal cells. No changes in RAR gamma expression were observed in correlation with ovarian steroids. During diestrus and in ovariectomized rats, the superficial cuboid cells expressed the three receptors. In the uterine epithelium, RAR alpha, RAR gamma and RXR alpha expression was induced by estrogens. Retinoic acid treatment did not modify retinoid receptor expression in vaginal and uterine epithelia. These data suggest specific roles for the different receptors in the complex process of vaginal epithelium proliferation and differentiation under estrogens and retinoic acid control.

Animals↗

PubMed1997

Oculopharyngeal muscular dystrophy in Japan.

Oculopharyngeal muscular dystrophy (OPMD) in the European population has been frequently diagnosed, but except for one black family, the occurrence in other ethnic groups is uncertain. We identified two unrelated OPMD Japanese families, including 34 affected individuals. Major clinical manifestations were bilateral ptosis and dysphagia starting after age 40. Histologic studies of limb muscles revealed mild myogenic changes, occasional rimmed vacuoles, and small angulated fibers. By contrast, cricopharyngeal muscle showed a marked loss of fibers and massive proliferation of connective tissue. Intranuclear tubulofilamentous inclusions (ITFI) of 8.5 nm outer diameter were observed in 2-5% of the nuclei in four different biopsied muscles. One patient with recurrent aspirations underwent successful cricopharyngeal myotomy. Aerodynamic examination was useful to evaluate velopharyngeal closure function. Our investigations revealed that OPMD is a geographically widespread disorder, and ITFI may be the specific morphologic hallmark.

Biopsy↗

PubMed1997

Morphological changes in muscle fibers in oculopharyngeal muscular dystrophy.

The study of muscle biopsies of 29 cases of oculopharyngeal muscular dystrophy (OPMD) showed the two main morphological features of this disease: rimmed vacuoles (in 26 cases) and intranuclear inclusions (in all cases). These inclusions are made of 8.5 nm tubular filaments and the areas occupied by them are lighter than the surrounded nucleoplasm. This can be seen by light microscopy, facilitating the detection of the tubulo-filamentous inclusions which can only be identified with certitude by electron microscopy. In a given ultrathin section the area occupied by these inclusions varied from 2% to 5% of the nuclei. The intranuclear inclusions are the morphological marker of OPMD and their finding in a muscle biopsy allows the exact diagnosis of this disease. The origin and biochemical nature of the intranuclear inclusions is unknown.

Adult↗

PubMed1996

Regulation of differentiation and keratin 10 expression by all-trans retinoic acid during the estrous cycle in the rat vaginal epithelium.

In rodents, the vaginal epithelium shows cyclic changes with an alternating pattern of keratinization under estrogen control and mucification under progesterone control. Retinoids are powerful regulators of cell differentiation, an excess of retinoids suppressing the keratinizing differentiation of keratinocytes. Here, we have examined the vaginal epithelium during the estrous cycle and compare the effects of retinoids on both types of hormonally induced differentiation, i.e. keratinization and mucification. All-trans retinoic acid was administered either by daily injections during the estrous cycle or by a single injection before the estrogen rise; these two protocols gave similar results. Retinoic acid suppressed estrogen-induced vaginal keratinization and cytokeratin K10 expression (a biochemical marker of terminal differentiation). Progesterone-induced mucification was not impaired; however, retinoic acid impeded mucous cell desquamation, suggesting an effect of retinoic acid on cell adhesiveness. Retinoic acid induced the appearance of apoptotic-like cells, as revealed by immunocytochemical staining of DNA fragmentation.

Animals↗

PubMed1996

Vaginal keratinization during the estrous cycle in rats: a model for evaluating retinoid activity.

A model is described for evaluating the activity of a retinoid based on its effect on the keratinization of the vaginal epithelium that occurs on estrus (day 4) of a 4-day cycle in female rats. This keratinization process is dependent on the endogenous estradiol (E2) secreted between the evening of diestrus 2 (day 2) and that of proestrus (day 3). Various doses of all-transretinoic acid (tRA) were injected at different time points during the estrous cycle and the vaginal keratinization was assessed by microscope examination of unstained native or Papanicolaou-stained smear preparations. Additionally, the preovulatory E2 secretion was measured and ovaries were histologically examined. A single injection of 10 mg/kg tRA either on diestrus 2 (evening) or on proestrus (early morning) was able to induce a complete inhibition of the vaginal keratinization in more than 80% of the cases. This can be considered as a direct effect on the vaginal epithelial differentiation since neither the E2 secretion nor the ovulatory process were affected. The inhibition of vaginal keratinization can be used as a rapid and convenient in vivo model for screening retinoid candidates with antikeratinizing activity.

Animals↗

PubMed1996

Oculopharyngeal muscular dystrophy in two unrelated Japanese families.

The occurrence of oculopharyngeal muscular dystrophy (OPMD) in Orientals is uncertain. We identified two unrelated Japanese families, including 30 affected individuals (14 men, 16 women, mean age 58 years) of OPMD through four generations, with complete penetrance. Their major clinical manifestations were late-onset bilateral ptosis and dysphagia. Histologic studies of slightly affected muscles reveal mild myogenic changes, occasional rimmed vacuoles, and small angulated fibers. By contrast, the severely involved cricopharyngeal muscle showed marked loss of fibers and massive proliferation of connective tissue. Ultrastructural studies of four different biopsied muscles disclosed subsarcolemmal intranuclear tubulofilamentous inclusions, identical to those of non-Japanese OPMD patients.

Aged↗

PubMed1995

Expression of NADPH-diaphorase in the rat forebrain during development.

Expression of NADPH-diaphorase (NADPH-d) was studied in the rat telencephalon and diencephalon from embryonic day 15 (E15) to postnatal day 30 (P30). The study has focused on the first appearance of NADPH-d staining in some areas which show high expression during adult life. The time of appearance ranged from E15 to the first days following birth, depending on the location of the cells. In many regions, neuronal processes, when staining appeared, were observed in close relationship with cerebral vessels. A possible role for nitric oxide in brain development should be explored.

Aging↗

PubMed1995

X-linked vacuolated myopathy: complement membrane attack complex on surface membrane of injured muscle fibers.

We describe a probable recessive X-linked myopathy characterized by the presence of vacuolated muscle fibers. Four males and their shared maternal grandfather were affected. Clinical characteristics include juvenile onset, very slow progression, and predominant proximal muscle involvement. The clinical picture and the morphological findings are compared with those previously described in a family. By immunofluorescence, all histologically abnormal muscle fibers, in particular those vacuolated, showed a strong deposition of the complement C5b-9 membrane attack complex over the whole muscle fiber surface. Weak immunostaining for membrane attack complex was also found in endomysial capillaries and perimysial vessel walls. Muscle fibers showed sarcolemmal immunolabeling with anti-major histocompatibility complex I, which was also present on the margins of many vacuoles. All vacuoles were stained by antidystrophin antibody, which colocalized in most of them with antilaminin immunostaining. Taken together, these results suggest that the deposition of membrane attack complex on the damaged cell surface membrane could be important in the pathogenesis of this muscle disorder, and that the membrane-bounded vacuoles could be a consequence of sarcolemmal invagination.

Adult↗