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Biomedical subjects

I Ferrer

Publications and source records attributed to I Ferrer.

At least 181 records · Page 10Linked to original sources
PubMed1997

Wolfram syndrome: a neuropathological study.

Neuropathological examination was carried out on a patient aged 37 years who had suffered from Wolfram syndrome. Atrophy of the olfactory bulbs and tracts, atrophy of the optic nerves and chiasm, loss of neurons in the lateral geniculate nuclei mainly affecting the small cell layers, atrophy of the superior colliculus, loss of fibers in the cochlear nerve and mild loss of neurons in the cochlear nuclei and inferior colliculus, mild olivopontocerebellar atrophy, and demyelination of the pyramidal tracts were the main neuropathological findings. These correlated with anosmia, loss of vision, loss of hearing, cerebellar symptoms and signs, Babinski sign, and clonus, respectively, clinically observed in this patient. Mild neuron loss and gliosis in the preoptic and paraventricular area of the hypothalamus and mild motor neuron loss in the spinal cord did not reach thresholds of impaired function, although loss of neurons in discrete bulbar nuclei might have accounted for the late episode of food aspiration and suffocation. The relationship between memory loss, personality disturbances, and signs of prefrontal release and mild loss of neurons in the anterior and dorso-medial nuclei of the thalamus remains unclear.

Adult↗
PubMed1997

Bcl-2, Bax and Bcl-x expression following hypoxia-ischemia in the infant rat brain.

Severe hypoxic-ischemic cerebral damage was produced in 8-day-old rats following permanent bilateral carotid artery occlusion and 15 min of ischemia. Cellular damage consisted of early necrosis and appearance of cells with apoptotic-like morphology (karyorrhectic cells) and cells with granular chromatin degeneration in the cerebral cortex, hippocampus, thalamus, stratum and amygdala. Expression of Bcl-2, Bax and Bcl-x was examined in control and hypoxic-ischemic rats using immunohistochemistry and Western blotting. Members of the Bcl-2 family were expressed in the vast majority of, if not all, neurons in control pups. Bcl-2, Bax and Bcl-x immunoreactivity decreased in necrotic cells, but about 60% of cells with apoptotic-like morphology and cells with granular chromatin degeneration were stained with antibodies to Bcl-2, Bax or Bcl-x. Although the total number of stained cells decreased with time, recruitment of cells with apoptotic morphology and cells with granular chromatin degeneration was still found up to 48 h. Western blots showed a band at about p28 and p21, respectively for Bcl-2 and Bax in control and hypoxic-ischemic pups at 6, 12 and 24 h. Two bands at about p37 and p30, representing Bcl-xL and Bcl-xS, respectively, were found in samples stained with antibodies to Bcl-x. No gross changes in the intensity of these bands were observed in ischemic pups at 6, 12 and 24 h, except for a slight decrease in Bcl-2 at 24 h, and a slight and inconstant increase of the putative Bcl-xS at 12 h. These results suggest that Bcl-2, Bax, Bcl-xL and Bcl-xS do not play a leading role in the fate of damaged nerve cells following a severe hypoxic-ischemic insult of the developing brain.

Animals↗
PubMed1997

Immunological characterization of a neuronal antibody (anti-Tr) associated with paraneoplastic cerebellar degeneration and Hodgkin's disease.

We studied an autoantibody (called anti-Tr), found in the serum and CSF of five patients with paraneoplastic cerebellar degeneration (PCD) and Hodgkin's disease (HD). Anti-Tr antibodies labelled the cytoplasm of Purkinje cells of human and rat cerebellum. The molecular layer of rat cerebellum showed a characteristic dotted pattern suggestive of immunoreactivity of dendritic spines of Purkinje cells. Patients with cerebellar disorders without HD (159) or HD without PCD (30) did not harbor anti-Tr antibodies. Immunoblots of human Purkinje cells or rat and mouse cerebellum were negative. Anti-Tr antibodies, as defined in this study, appear specific for HD-associated PCD. The immunohistochemical pattern described in the rat cerebellum coupled with the absence of reactivity in the immunoblot may be used to identify anti-Tr antibodies.

Adolescent↗
PubMed1997

Strong c-Jun/AP-1 immunoreactivity is restricted to apoptotic cells following intracerebral ibotenic acid injection in developing rats.

Strong c-Jun immunoreactivity, as revealed with the antibody c-Jun/activator protein 1 (AP-1) which is raised against the amino acids 91-105 mapping with the amino terminal domain of mouse c-Jun p39, is observed in apoptotic cells, but not in necrotic cells, following intracerebral injection of ibotenic acid in the developing rat brain processed for immunohistochemistry. Immunostaining occurs in the cytoplasm and dendrites, thus suggesting impaired nuclear translocation of c-Jun in apoptotic cells. Western blotting of total brain homogenates, using the same antibody, shows a band at p39 which is more marked in treated animals than in age-matched controls. In addition, increased c-Jun N-terminal kinase 1 (JNK-1) expression, as revealed on Western blots, is found in rats treated with ibotenic acid when compared with controls. In contrast, apoptotic cells are not stained with antibodies to Jun B and Jun D. These results give further support to previous studies showing strong c-Jun expression in apoptotic cells at determinate stages of development, and emphasize that intracellular distribution of c-Jun, possible post-translational modifications of c-Jun due to phosphorylation at specific transactivation sites, and lack of associated Jun B and Jun D expression may differentiate the Jun response in apoptotic cells from other forms of cellular response involving c-Jun which are not associated with cell death.

Animals↗
PubMed1997

The heat shock stress response after brain lesions: induction of 72 kDa heat shock protein (cell types involved, axonal transport, transcriptional regulation) and protein synthesis inhibition.

The cerebral stress response is examined following a variety of pathological conditions such as focal and global ischemia, administration of excitotoxins, and hyperthermia. Expression of 72 kDa heat shock protein (Hsp70) and hsp70 mRNA, the mechanism underlying induction of hsp70 mRNA involving activation of heat shock factor 1, and inhibition of cerebral protein synthesis are different aspects of the stress response considered here. The results are compared with those in the literature on induction, transcriptional regulation, expression, and cellular location of Hsp70, with a view to getting more insight into the function of the stress response in the injured brain. The present results illustrate that Hsp70 can be expressed in cells affected at various degrees following an insult that will either survive or dic as the brain lesion develops, depending on the severity of cell injury. This indicates that, under certain circumstances, synthesized Hsp70 might be necessary but not sufficient to ensure cell survival. Other situations involve uncoupling between synthesis of hsp70 mRNA and protein, probably due to very strict protein synthesis blockade, and often result in cell loss. Cells eventually will die if protein synthesis rates do not go back to normal after a period of protein synthesis inhibition. The stress response is a dynamic event that is switched on in neural cells sensitive to a brain insult. The stress response is, however, tricky, as affected cells seem to need it, have to deal transiently with it, but eventually be able to get rid of it, in order to survive. Putative therapeutic treatments can act either selectively, potentiating the synthesis of Hsp70 protein and recovery of protein synthesis, or preventing the stress response by deadening the insult severity.

Animals↗
PubMed1997

Differential cellular distribution and dynamics of HSP70, cyclooxygenase-2, and c-Fos in the rat brain after transient focal ischemia or kainic acid.

Cerebral ischemia and also excitotoxicity induce the expression of 72,000 mol. wt heat shock protein (Hsp70), c-Fos, and cyclooxygenase-2. In the present work we have examined whether Hsp70, c-Fos and cyclooxygenase-2 are expressed by the same cells in the rat brain at 6, 12 and 24 h following transient focal ischemia or kainic acid administration, by means of single and double immunohistochemistry. At 6 h after kainic acid, some co-localization of Hsp70 with c-Fos and cyclooxygenase-2 was seen in pyramidal hippocampal neurons and superficial cortical layers, however by 24 h such colocalization became rare within the cortex but was partially maintained in the hippocampus. Cyclooxygenase-2 was seen in many neurons that were also immunoreactive for c-Fos in superficial cortical layers, dentate gyrus and pyramidal cell layer of the hippocampus from 6 h after kainic acid. Co-localization of cyclooxygenase-2 and c-Fos was also observed in superficial cortical layers within the ipsilateral hemisphere at 6 h following focal ischemia. Also, some co-localization of Hsp70 with c-Fos and cyclooxygenase-2 was seen at this time. However, by 24 h cyclooxygenase-2 and c-Fos-immunoreactive cells were restricted to perifocal regions, and only a very limited co-localization with Hsp70 was seen in perifocal neurons located in the border of the penumbra-like area that surrounds the ischemic core and is strongly immunoreactive for Hsp70. This study shows a selective and dynamic cellular expression of inducible proteins following either ischemia or kainic acid, with a remarkable neuronal co-localization of c-Fos and cyclooxygenase-2. The results suggest that, first, stimuli underlying neuronal c-Fos expression can also lead to the induction of cyclooxygenase-2; second, transient co-localization of Hsp70 and c-Fos can take place in non-vulnerable neurons; and finally, expression of c-Fos, cyclooxygenase-2, and/or Hsp70 at a given time-point is part of the response to altered environmental conditions and can be related to the particular cellular sensitivity rather than the pathological outcome.

Animals↗
PubMed1997

Radiation-induced apoptosis in developing rats and kainic acid-induced excitotoxicity in adult rats are associated with distinctive morphological and biochemical c-Jun/AP-1 (N) expression.

Ionizing radiation produces apoptosis in the developing rat brain. Strong c-Jun immunoreactivity, as revealed with the antibody c-Jun/AP-1 (N) which is raised against the amino acids 91-105 mapping with the amino terminal domain of mouse c-Jun p39, is simultaneously observed in the nucleus and cytoplasm of apoptotic cells. Western blotting of total brain homogenates, using the same antibody, shows a p39 band in control rats which is accompanied by a strong, phosphorylated p62 double-band in irradiated animals. In addition, increased c-Jun N-terminal kinase 1 expression, as found on western blots, is found in irradiated rats when compared with controls. Intraperitoneal injection of kainic acid at convulsant doses to the adult rat produces cell death with morphological features of necrosis, together with the appearance of cells with fine granular chromatin degeneration and small numbers of apoptotic-like cells, in the entorhinal and piriform cortices, basal amygdala, certain thalamic nuclei, and CA1 region of the hippocampus. c-Jun expression in kainic acid-treated rats, as revealed with the c-Jun/AP-1 (N) antibody, is found in the nuclei of a minority of cells in the same areas. The vast majority of c-Jun-immunoreactive cells have normal nuclear morphology, whereas necrotic cells are negative and only a few cells with fine granular chromatin condensation and apoptotic cells following kainic acid injection are stained with c-Jun antibodies. Western blotting, using the same antibody, shows a p39 band in control rats, which is accompanied by a band at about p26 from 6 h onwards following kainic acid injection. Decreased c-Jun N-terminal kinase 1 expression, as revealed on western blots, is observed in kainic acid-treated rats. These results show that the antibody c-Jun/AP-1 (N) recognizes three different forms of c-Jun-related immunoreactivity in normal and pathological states, which are associated with the different outcome of cells. These results stress the necessity of examining in detail the composition of c-Jun-immunoreactive bands and the metabolic state of c-Jun(s) in different paradigms of cell death and survival.

Animals↗
PubMed1997

Stat3 is present in the developing and adult rat cerebellum and participates in the formation of transcription complexes binding DNA at the sis-inducible element.

Stat3 is a member of a recently identified family of proteins named STATs for their ability to act as signal transducers and activators of transcription. Stimulation of epidermal growth factor or cytokine receptors can cause activation of Stat3 and transduction of specific responses to the nucleus. Here the presence of Stat3 has been examined in the rat cerebellum at different times during postnatal development and adulthood by means of immunohistochemistry and western blotting. In addition, DNA binding activity at the sis-inducible element that is present in the promoter of the c-fos gene has been studied by electrophoretic mobility shift assay. The results have shown that Stat3 p92 is abundant in the rat cerebellum. Stat3 was found in the external granule cell layer and also within the molecular layer from postnatal day (P) 0 to P7. From P15 to the adult, the internal granule cell layer and Purkinje cells were also stained for Stat3. Nuclear extracts were found to contain DNA binding activity to the sis-inducible element during development and adulthood. Supershift assays demonstrated that Stat3 mediates the formation of one protein-DNA complex. The present results suggest that Stat3 participates in intracellular signaling and is involved in maintaining basal c-fos expression in the cerebellum of the developing and adult rat under physiological conditions.

Acute-Phase Proteins↗
PubMed1997

Methylazoxymethanol acetate-induced apoptosis in the external granule cell layer of the developing cerebellum of the rat is associated with strong c-Jun expression and formation of high molecular weight c-Jun complexes.

Intraperitoneal administration of methylazoxymethanol (MAM) acetate (0.05 microl/g of body weight) in male Sprague-Dawley rats aged 3 days produced cell death in the external granule layer of the cerebellum which peaked at 48 hours (h) and was followed by removal of cellular debris at 72 h. Dying cells had the morphological features of apoptosis and were stained with the method of in situ labeling of nuclear DNA fragmentation. Strong c-Jun immunoreactivity was observed in apoptotic cells during the whole process of MAM-induced apoptosis. No differences of c-Fos immunoreactivity were observed between control and MAM-treated rats throughout the period studied. Western blotting of cerebellar homogenates in control rats disclosed two bands which reacted with both c-Jun antibodies, one located at p39 that corresponds to the molecular weight of c-Jun, and the other at about p62. MAM-treated rats showed a robust band at p62, together with a thinner band located immediately above it, which was accompanied by a reduction of the p39 band. The specificity of the immunoreaction was tested by incubating the antibodies with the appropriate control peptides. No difference between control and MAM-treatad rats was observed in Western blots processed with antibodies to c-Fos during this study. These results show that MAM-induced apoptosis in the external granule cell layer of the rat is associated with strong c-Jun expression, which is restricted to apoptotic cells, and with the formation of high-molecular-weight c-Jun complexes. Taken together, the present observations suggest that c-Jun may participate in the genetic cascade of events leading to apoptotic cell death in the developing cerebellum.

Alkylating Agents↗
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↗
PubMed1997

[Bilateral asymmetric degeneration of the striatum as a cause of senile hemiballism].

We report the case of an 82-years old woman with sporadic acute hemiballism associated with bilateral striatal degeneration of non vascular origin which was most severe in the side contralateral to the hemiballism. The patient's neuropathological lesions resembled those of patients with senile chorea. Although hemiballism has never been described as an isolated manifestation of primary degeneration of the striatum, it may so occur in elderly patients with hemiballism.

Aged↗
PubMed1997

BDNF and TrkB co-localize in CA1 neurons resistant to transient forebrain ischemia in the adult gerbil.

Delayed cell death of projection cells in the CA1 area of the hippocampus is produced in the adult gerbil following 5 minutes (min) of transient forebrain ischemia. Parvalbumin-immunoreactive local-circuit neurons are resistant to the ischemic insult. Brain-Derived Neurotrophic Factor (BDNF) immunoreactivity is localized in all neurons of the CA1 area in control gerbils. However, TrkB immunoreactivity is observed in a minority of BDNF-immunoreactive neurons in the CA1 area. The number of BDNF-immunoreactive cells in CA1 is dramatically reduced in ischemic gerbils as early as 24 h after ischemia, but the number of TrkB-immunoreactive cells in the CA1 area is maintained following ischemia. Moreover, about 90% of BDNF-immunoreactive cells and about 85% of TrkB-immunoreactive cells in ischemic gerbils co-localize the calcium-binding protein parvalbumin. Finally, BDNF and TrkB are coexpressed in about 95% of CA1 neurons surviving the ischemic insult. These results indicate that a subpopulation of CA1 hippocampal neurons coexpressing TrkB, parvalbumin and BDNF is resistant to transient forebrain ischemia in the gerbil. These results also suggest that a subpopulation of CA1 hippocampal neurons in the gerbil hippocampus is endowed with a putative BDNF/TrkB autocrine regulatory loop that may be involved in both cell survival and synaptic remodeling of the damaged gerbil hippocampus following transient forebrain ischemia.

Animals↗
PubMed1997

Signal transducer and activator of transcription 1 in human muscle: implications in inflammatory myopathies.

Polymyositis (PM) and dermatomyositis (DM) are two major and distinct inflammatory myopathies. Cytokines, implicated in the immune process, have been recognized in the muscle tissue from PM and DM patients, but their functional in situ role has not been identified. We analyzed the expression of the signal transducer and activator of transcription 1 (STAT1), a molecule whose up-regulation indicates the interaction of cytokines, or growth factors, with their target receptors in muscle fibers and inflammatory infiltrates in PM and DM. An immunohistochemical analysis was performed using monoclonal antibodies to STAT1 in 57 muscle biopsies from 10 patients with DM, 10 with PM, and 37 controls. The profile of STAT1 up-regulation was also investigated in cultured muscle stimulated by interferon-gamma, epidermal growth factor, platelet-derived growth factor, and interleukin-2, using semiquantitative polymerase chain reaction and Western blot. High STAT1 expression was observed in many perifascicular atrophic muscle fibers from DM patients in 10/10 biopsies. In contrast, only a few muscle fibers undergoing necrosis were STAT1 positive in 2/10 patients with PM and in 2/37 controls. STAT1 reactivity was noted in most cells of the infiltrates in DM, PM, and controls. In vitro, STAT1 was stimulated by interferon-gamma but not by the other molecules studied. These results suggest that in DM, but not in PM, there is distinctive functional local cytokine activity able to increase STAT1 expression in muscle fibers. As interferon-gamma specifically activates STAT1 in vitro, this cytokine in conjunction with ischemia is probably involved in perifascicular muscle fiber pathology in DM.

Blotting, Western↗
PubMed1997

Kainic acid-induced excitotoxicity is associated with a complex c-Fos and c-Jun response which does not preclude either cell death or survival.

c-fos and c-jun mRNA induction and c-Fos and c-Jun protein expression were examined in the brains of adult rats subjected to systemic kainic acid (KA) injection at convulsant doses. Induction of c-fos and c-jun mRNA, as seen with in situ hybridization, occurred in the piriform and entorhinal cortices, neocortex, amygdala, hippocampus, dentate gyrus, and discrete thalamic nuclei. This was followed by c-Fos protein expression, as revealed with immunohistochemistry, in the same regions. However, the distribution of c-Jun protein expression differed depending on the antibody used. The distribution of cells immunostained with the antibody c-Jun (AB-1) was similar to that of c-jun mRNA, but the distribution of cells immunostained with the antibody c-Jun/AP1 (N) was restricted to a few neurons in the pyramidal cell layer of CA1 and CA3, layer II of the piriform and entorhinal cortices, basal amygdala, and discrete thalamic nuclei. Although the regional distribution of c-Fos- and c-Jun-immunoreactive cells in the hippocampus, layer II of the entorhinal and piriform cortices, basal amygdala, and discrete thalamic nuclei matched the distribution of cells committed to dying, c-Fos- and c-Jun-immunoreactive cells in the neocortex and dentate gyrus survived. Therefore, the present data show that c-fos and c-jun are not predictors of either cell death or survival, but rather, markers of cells sensitive to KA excitotoxicity. Western blots to c-Fos showed a double band at p62 in samples containing the hippocampus and entorhinal and piriform cortices (hip samples) and in samples containing the neocortex (cortex samples). The upper band was abolished following preincubation of the samples with alkaline phosphatase, thus suggesting c-Fos phosphorylation. Western blots to c-Jun (AB-1) showed a single band at about p39 in hip and cortex. However, Western blots to c-Jun/AP1 (N) identified two bands. One band at about p39 was seen in control rats and the cortex of KA-treated rats. Another band at p26 was observed only in hip samples of KA-treated rats. In addition, decreased c-Jun N-terminal kinase 1 (JNK-1) expression, as revealed on Western blots, was coincidental with the appearance of the p26 c-Jun-immunoreactive band in KA-treated rats. These results show that c-Fos and different Jun-related antigens are expressed following KA excitotoxicity, and that posttranslational modifications involving phosphorylation of c-Fos and Jun(s) may occur following KA injection. These results also stress the necessity of examining the composition of Fos and Jun-related antigens and the metabolic state of Fos and Jun(s) in different experimental models of nervous system injury.

Animals↗
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

Jun expression is found in neurons located in the vicinity of subacute plaques in patients with multiple sclerosis.

The expression of members of the Fos and Jun families is examined by immunohistochemistry in the brains of two patients with multiple sclerosis (MS). Strong c-Jun immunoreactivity is observed in the cytoplasm of neurons located in the vicinity of subacute plaques, but not in neurons of brain compartments not compromised by MS and in the neighborhood of chronic plaques. Strong c-Jun immunoreactivity also contrast with weak c-Jun immunoreactivity of corresponding neurons in control brains. In addition, punctate Jun D immunoreactivity is observed in the neuropil of the same areas that express c-Jun. No immunoreaction is found to c-Fos, Fos-related antigens and Jun B in these areas. The present results suggest that selective Jun neuronal expression in the vicinity of subacute plaques is a consistent reaction to demyelination and axonal damage.

Adult↗
PubMed1996

A nuclear defect in the 4p16 region predisposes to multiple mitochondrial DNA deletions in families with Wolfram syndrome.

Wolfram syndrome is a progressive neurodegenerative disorder transmitted in an autosomal recessive mode. We report two Wolfram syndrome families harboring multiple deletions of mitochondrial DNA. The deletions reached percentages as high as 85-90% in affected tissues such as the central nervous system of one patient, while in other tissues from the same patient and from other members of the family, the percentages of deleted mitochondrial DNA genomes were only 1-10%. Recently, a Wolfram syndrome gene has been linked to markers on 4p16. In both families linkage between the disease locus and 4p16 markers gave a maximum multipoint lod score of 3.79 at theta = 0 (P<0.03) with respect to D4S431. In these families, the syndrome was caused by mutations in this nucleus-encoded gene which deleteriously interacts with the mitochondrial genome. This is the first evidence of the implication of both genomes in a recessive disease.

Adult↗