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Biomedical subjects

M Olivé

Publications and source records attributed to M Olivé.

At least 19 recordsLinked to original sources
PubMed2006

NARP-MILS syndrome caused by 8993 T>G mitochondrial DNA mutation: a clinical, genetic and neuropathological study.

The 8993 T>G mutation in mitochondrial DNA has been associated with variable syndromes of differing severity ranging from maternally inherited Leigh's syndrome (MILS) to neuropathy, ataxia, retinitis pigmentosa (NARP), depending on the mutation loads in affected patients. We report a kindred with several members in the same generation suffering NARP or Leigh's syndrome due to a 8993 T>G mutation. Post-mortem studies of the brain in one affected member clinically presenting with a neurological disorder intermediate between adult Leigh's syndrome and NARP showed symmetrical lesions of the basal ganglia and brainstem closely resembling those usually described in typical Leigh's syndrome. Analysis of mtDNA in different tissues showed a high proportion of mutant genome in brainstem, cerebral cortex, putamen, cerebellum and thalamus. These observations illustrate the continuum of clinical and neuropathological manifestations associated with the 8993 T>G mutation of the mtDNA.

Adenosine Triphosphatases↗
PubMed2005

Involvement of clusterin and the aggresome in abnormal protein deposits in myofibrillar myopathies and inclusion body myositis.

Myofibrillar myopathies (MM) are characterized morphologically by the presence of non-hyaline structures corresponding to foci of dissolution of myofibrils, and hyaline lesions composed of aggregates of compacted and degraded myofibrillar elements. Inclusion body myositis (IBM) is characterized by the presence of rimmed vacuoles, eosinophilic inclusions in the cytoplasm, rare intranuclear inclusions, and by the accumulation of several abnormal proteins. Recent studies have demonstrated impaired proteasomal expression and activity in MM and IBM, thus accounting, in part, for the abnormal protein accumulation in these diseases. The present study examines other factors involved in protein aggregation in MM and IBM. Clusterin is a multiple-function protein which participates in Abeta-amyloid, PrP(res) and a-synuclein aggregation in Alzheimer disease, prionopathies and a-synucleinopathies, respectively. gamma-Tubulin is present in the centrosome and is an intracellular marker of the aggresome. Moderate or strong clusterin immunoreactivity has been found in association with abnormal protein deposits, as revealed by immunohistochemistry, single and double-labeling immunofluorescence and confocal microscopy, in MM and IBM, and in target structures in denervation atrophy. Gamma-Tubulin has also been observed in association with abnormal protein deposits in MM, IBM, and in target fibers in denervation atrophy. These morphological findings are accompanied by increased expression of clusterin and gamma-tubulin in muscle homogenates of MM and IBM cases, as revealed by gel electrophoresis and Western blots. Together, these observations demonstrate involvement of clusterin in protein aggregates, and increased expression of aggresome markers in association with abnormal protein inclusions in MM and IBM and in targets, as crucial events related to the pathogenesis of abnormal protein accumulation and degradation in these muscular diseases.

Adult↗
PubMed2001

Connexin 31 (GJB3) is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment.

Mutations in the connexin 31 (GJB3) gene have been found in subjects with dominant and recessive deafness and in patients with erythrokeratodermia variabilis. We report here a dominant mutation in the GJB3 gene (D66del) in a family affected with peripheral neuropathy and sensorineural hearing impairment. A wide range of disease severity for peripheral neuropathy, from asymptomatic cases to subjects with chronic skin ulcers in their feet and osteomyelitis leading to amputations, was detected in D66del patients. Mild, often asymmetrical, hearing impairment was found in all but one patient with mutation D66del of this family and the same mutation was present in an independent family ascertained because of hearing impairment. We have found mouse connexin 31 (Gjb3) gene expression in the cochlea and in the auditory and sciatic nerves, showing a pattern similar to that of Gjb1 (connexin 32), of which the human ortholog (GJB1) is involved in X-linked peripheral neuropathy. This expression pattern, together with auditory-evoked brainstem anomalous response in D66del patients, indicates that hearing impairment due to GJB3 mutations involves alterations in both the cochlea and the auditory nerve. Peripheral neuropathy is the third phenotypic alteration linked to GJB3 mutations, which enlarges the list of genes that cause this group of heterogeneous disorders.

Adult↗
PubMed2000

Bcl-2 and bax immunohistochemistry in denervation-reinnervation and necrosis-regeneration of rat skeletal muscles.

Bcl-2 and Bax immunohistochemistry was examined in the skeletal muscle of rats after cutting the sciatic nerve, as a model of denervation and reinnervation, and in the anterior tibialis muscle of rats after an intramuscular injection of metoclopramide, as a model of necrosis and regeneration of muscle fibers, to better understand the role of these proteins in muscle disorders. An increase in Bax immunoreactivity was seen in long-standing denervated and reinnervated muscle fibers. Bcl-2 and Bax immunoreactivity was limited to macrophages in necrotic muscle fibers at 24 h after the intramuscular injection of metoclopramide. However, increased Bax immunoreactivity was observed in regenerating muscle fibers by the fourth day after the injection. Muscle fiber nuclei with the morphological features of apoptosis were not observed in rat muscles after the intramuscular injection of metoclopramide or after the severing of the sciatic nerve. Furthermore, using the Tunel method, no stained nuclei were observed in the two groups of animals. Our observations in the experimental models of skeletal muscle denervation-reinnervation and necrosis-regeneration here described suggest that modification in the intensity of the Bax protein is not related to the process of cell death but rather that increased Bax expression is associated with muscle fiber regeneration.

Animals↗
PubMed1999

Bcl-2 and Bax protein expression in human myopathies.

Expression of the apoptosis-related proteins Bcl-2 and Bax was analysed by means of immunohistochemistry in muscle biopsies from 13 patients suffering from different muscular diseases (inclusion body myositis n=4, polymyositis n=3, Becker muscular dystrophy n=4, necrotizing myopathy n=2, and controls n=4), in an attempt to learn about the role of these proteins in human muscle diseases associated with muscle fiber necrosis and regeneration. Increased Bcl-2 and Bax immunoreactivity was observed as fine granular precipitates in the cytoplasm or as subsarcolemmal aggregates in pathological cases. Increased Bcl-2 and Bax immunoreactivity was detected in some necrotic fibers, regenerating fibers, ring fibers and some apparently normal muscle fibers. In addition, increased Bcl-2 and Bax immunoreactivity was observed in the periphery of rimmed vacuoles and in muscle fibers with abnormal mitochondria in patients suffering from inclusion body myositis. Double-labelling immunohistochemistry disclosed co-localization of both proteins in about 50% of Bcl-2-immunoreactive fibers. Finally, double-labelling immunohistochemistry using N-CAM antibodies revealed that some Bax-positive fibers were regenerating fibers. Since increased Bax immunoreactivity was not restricted to necrotic muscle fibers, the present results suggest that over-expression of this protein in human myopathies is probably independent of the process of cell death.

Adolescent↗
PubMed1998

[Neuropathy by n-hexanes: a generalized disorder of the intermediate filaments].

BACKGROUND: Chronic inhalation of glues containing n-hexanes produces neurofilament (NF) accumulation which induces sensory-motor polyneuropathy. In vitro assays have shown this toxic substance causes intermediate filaments (IF) aggregation in non-neuronal cells. OBJECTIVE: To describe intermediate filament changes in human pathology due to n-hexanes. PATIENTS AND METHODS: Sural nerve and skin biopsy samples from 2 patients who suffered from a severe sensory-motor polyneuropathy after prolonged inhalation of glue containing n-hexane were examined with electron microscopy and vimentin and phosphorylated NF immunocytochemistry. RESULTS: Abnormal accumulations of NF and NF-immunoreactive products occurred in nerve fibers and increased numbers of fibrils were observed in endoneurial endothelial cells of the sural nerve. In addition, abnormal vimentin-immunoreactive deposition was seen in fibroblasts and capillaries of the skin. The present results suggest that high doses of n-hexane cause a diffuse IF disorder in a similar form as occurs in giant axonal neuropathy. CONCLUSION: IF aggregation can occur in non-neuronal cells in humans, as has been previously proved in in vitro experiments. The presence of IF accumulations in Schwann cells, as seen in the ultrastructural examination, together with the electrophysiological findings showing an early decrease of sensory and motor nerve conduction velocities, suggests the existence of a primary myelinic disorder associated with axonal damage.

Adhesives↗
PubMed1997

Apoptosis is not the mechanism of cell death of muscle fibers in human muscular dystrophies and inflammatory myopathies.

Muscle biopsies from patients affected by muscular dystrophies and polymyositis were processed with the method of in situ labeling of nuclear DNA fragmentation in order to assess whether apoptosis occurs in these diseases. Apoptotic nuclei were seen in the mononuclear cell infiltrates in inflammatory myopathies but not in dying muscle fibers, thus confirming the general opinion that death of muscle fibers in human diseases is not produced by a mechanism of apoptosis.

Animals↗
PubMed1997

Expression of myogenic regulatory factors (MRFs) in human neuromuscular disorders.

Immunohistochemical studies using antibodies to myogenic regulatory factors (MRFs) Myo D, myogenin, myf-5, and myf-6, and transcription factors c-Fos and c-Jun, were performed on muscle biopsies from patients suffering from Duchenne and Becker muscular dystrophies, polymyositis, and denervation atrophy, to investigate whether expression of these factors occurs during degeneration and regeneration of adult muscle fibres. Strong Myo D, myogenin, myf-5 and myf-6 immunoreactivity was observed in the nuclei of small regenerating fibres and satellite cells, as revealed by double-labelling immunohistochemistry with N-CAM antibodies, in Duchenne and Becker muscular dystrophies and in polymyositis. This suggests that the myogenic programme is activated during regeneration of adult human muscle fibres. In addition, strong myf-6 and c-Jun immunoreactivity was found in the cytoplasm of some necrotic muscle fibres in patients with Duchenne and Becker muscular dystrophies and in patients with polymyositis. The latter findings suggest that strong cytoplasmic expression of myf-6 and c-Jun is related to the process of muscle fibre degeneration that occurs in these conditions. Increased Myo D, myogenin, myf-5 and myf-6 immunoreactivity was not observed in the nuclei of denervated muscle fibres, although strong c-Fos and c-Jun immunoreactivity was seen in the nuclei of denervated muscle fibres; this suggests that denervation triggers the expression of these transcription factors. Taken together, these observations demonstrate that MRFs and c-Fos and c-Jun are selectively expressed in different human muscular disorders.

Adolescent↗
PubMed1996

Strong c-Jun immunoreactivity is associated with apoptotic cell death in human tumors of the central nervous system.

Strong c-Jun immunoreactivity, but not c-Fos expression, was observed in typical apoptotic cells in medulloblastomas, central neuroblastomas, malignant astrocytomas and glioblastomas, and in lymphocyte-like cells bearing nuclear fragmented DNA in medulloblastomas. In contrast, only a few proliferating cells, as revealed with PCNA immunohistochemistry, colocalized c-Jun. These results support the concept that strong c-Jun expression is associated with certain forms of cell death in human tumors of the central nervous system.

Apoptosis↗
PubMed1996

CREB-1 and CREB-2 immunoreactivity in the rat brain.

This study is focused to learn about the cellular localization of transcription factors binding to the cAMP response element-CREBs-in the brain of normal rats and in animals subjected to excitotoxic cell damage. For this purpose, CREB-1 and CREB-2 immunoreactivity is examined in the developing and adult rat brain under physiological conditions, and following systemic kainic acid (KA) injection at convulsant doses in the adult, as a validated experimental model of excitotoxic injury. CREB-1 immunoreactivity is constitutively expressed in periventricular glia and Bergmann glia, and appears in reactive astrocytes following KA-induced excitotoxic cell damage. In contrast, CREB-2 is constitutively expressed in all neurons of the cerebrum, cerebellum and brain stem in the developing and adult brain. CREB-2 immunoreactivity is not increased following KA excitotoxic cell damage. These results demonstrate that CREB-1 and CREB-2 in the brain of the rat are localized in separate cellular compartments and that their expression is differentially regulated in pathologic states.

Animals↗
PubMed1996

Selective c-Jun overexpression is associated with ionizing radiation-induced apoptosis in the developing cerebellum of the rat.

Immunohistochemistry to Bcl-2, Bax, c-Myc, c-Fos, Fos-related, c-Jun, Jun B and Jun D was used to study the involvement of these factors in ionizing radiation-induced apoptosis in the cerebellum of the developing rat. Selective c-Jun overexpression was observed during the whole process of radiation-induced cell death. Furthermore, c-Jun overexpression was restricted to apoptotic cells, as shown by double labeling with the method of in situ labeling of nuclear DNA fragmentation and c-Jun immunohistochemistry. This is the first in vivo evidence that selective c-Jun overexpression is associated with apoptotic cell death in the developing nervous system following ionizing radiation.

Animals↗
PubMed1996

Transforming growth factor-alpha (TGF-alpha) and epidermal growth factor-receptor (EGF-R) immunoreactivity in normal and pathologic brain.

Transforming growth factor alpha (TGF-alpha) and epidermal growth factor-receptor (EGF-R) immunoreactivity is observed in the majority of neurons, and in maturing astrocytes, in the developing and adult brain of humans and different species of animals. TGF-alpha and EGF-R co-localize in most neurons and maturing astrocytes, suggesting that most TGF-alpha-producing cells are EGF-R-expressing cells. TGF-alpha and EGF-R immunoreactivity decrease in damaged areas following different insults. However, EGF-R appears in reactive glia, mostly reactive astrocytes, within and surrounding the damaged areas. TGF-alpha and EGF-R immunoreactivity is found in neurons of patients affected by Alzheimer's disease and other forms of dementia, and in neurons of patients suffering from epilepsy owing to different causes, thus pointing to the conclusion that TGF-alpha does not play a significant role in these pathologies. However, EGF-R immunoreactivity occurs in reactive astrocytes and microglia in subacute but not chronic lesions in human cases. Since TGF-alpha is a membrane-anchored growth factor, which may be cleaved leading to the formation of soluble forms, and both the membrane-anchored and soluble forms have the capacity to activate the EGF-R, it is feasible that TGF-alpha in the nervous system may act upon EGF-R-containing neurons through different mechanisms. In addition to distant effects resulting from the release of soluble TGF-alpha, local effects may be produced by establishing direct cell-to-cell contacts (juxtacrine stimulation), or in cells expressing both TGF-alpha and EGF-R (autocrine stimulation).

Animals↗
PubMed1995

Amoeboid microglial response following X-ray-induced apoptosis in the neonatal rat brain.

The phagocytic response following X-ray-induced apoptosis in the neonatal rat brain was examined by immunohistochemistry with the antibodies OX-6 and OX-42 which recognize MHC class II antigens and the CR3 complement receptor, respectively. Few OX-6-immunoreactive cells were observed in control rats, and in rats irradiated at postnatal day 2 and examined during the first 2 postnatal weeks. However, a transient increase in the number of OX-42-immunoreactive amoeboid microglia, containing large numbers of apoptotic cells, occurred at 6, 24 and 48 h after irradiation when compared with age-matched controls. These results show that X-ray-induced apoptosis promotes a short-lasting phagocytic response.

Animals↗
PubMed1995

Transforming growth factor-alpha immunoreactivity in the developing and adult brain.

Transforming growth factor-alpha immunoreactivity is examined in the developing and adult brain of cats and rats, and in the adult human brain in cryostat sections immediately processed free-floating with a well-characterized monoclonal antibody which does not cross-react with epidermal growth factor. Transforming growth factor-alpha immunoreactivity is observed in neurons of the cerebral neocortex, subiculum, hippocampus, striatum, thalamus, amygdala, basal forebrain, mesencephalon, cerebellar cortex, dentate nucleus and brainstem during development and in adulthood. The intensity of the immunoreaction directly correlates with the size of the cytoplasm. Diffuse transforming growth factor-alpha immunoreactivity also occurs in the white matter of the cerebrum, cerebellum and brainstem in the kitten, but not in the adult cat. In addition to neurons, numbers of glial cells in the cerebellar white matter, brainstem and cerebral hemispheres during development, and a few glial cells in the cerebellar cortex, diencephalon, cerebral cortex and white matter in adults are strongly transforming growth factor-alpha immunoreactive. These results support the concept that transforming growth factor-alpha is widely distributed in the brain of mammals, localizes in both neurons and glial cells, and is development dependent. These findings also suggest that transforming growth factor-alpha may play a role in the developing and adult central nervous system.

Adult↗
PubMed1995

Evidence of internucleosomal DNA fragmentation and identification of dying cells in X-ray-induced cell death in the developing brain.

Newborn Sprague-Dawley rats received a single dose of 2 Gy X-rays and were killed 6 hr later. Dying cells were characterized by extreme chromatin condensation and nuclear fragmentation. Dying cells were distributed in the primary and secondary germinal zones and in other brain regions. Among these latter, dying cells occurred in the cortical layers of the olfactory bulb, layers II-III and VIb of the neocortex, piriform and entorhinal cortex, stratum oriens and pyramidale of the hippocampus, striatum, thalamus, amygdala, brainstem, internal granular layer of the cerebellum, and cerebral and cerebellar white matter. Dying cells were immature cells, neurons and glial cells (including radial glia). In-situ labeling of nuclear DNA fragmentation identified individual cells bearing fragmented DNA. Since the number of cells stained with this method was larger than the number of dying cells, as revealed with current histological techniques, it is suggested that nuclear DNA fragmentation precedes chromatin condensation and nuclear fragmentation in X-ray-induced apoptosis. Furthermore, agarose gel electrophoresis of extracted DNA from irradiated brains showed a "ladder" pattern which is typical of internucleosomal DNA fragmentation and endonuclease activation.

Aging↗