Biomedical subjects

I Ferrer

Publications and source records attributed to I Ferrer.

At least 217 records · Page 12Linked to original sources

PubMed1996

[Clinico-anatomopathologic analysis of 25 patients with lacunar infarction].

BACKGROUND: Lacunar infarctions (LI) are associated with an excellent functional prognosis and mortality is exceptional during hospital stay. Therefore, clinico-pathological studies on LI are scarce. METHODS: A retrospective analysis was made of 50 consecutive necropsies of patients with cerebrovascular disease (CVD) from the brain archive of the Pathology Department performed from 1976 and 1985. A macroscopic and microscopic study was carried out of visualized LI which were classified in old or cystic, recent and through perivascular dilation. A clinico-pathologic evaluation was made by analyzing cerebrovascular risk factors, the associated neurological syndromes and mortality causes. RESULTS: Fifty percent of brains with CVD analyzed (25 out of 50) had LI. The total of LI was 107, with a mean of 4.2 +/- 3.4 LI per brain. The main location was at the basal ganglia (54.7%), mainly the putamen (35.8%). The most common lesional diameters ranged from 1 to 4 mm (68.5%). Arterial hypertension was the main cerebrovascular risk factor (84%). Fifty-two percent of brains with LI (n = 13) were asymptomatic (clinically silent LI) Twenty-four percent had a clinical course consistent with a pseudobulbar syndrome (n = 6). Twenty percent had a pure motor hemiparesis (n = 5) and the remaining 4% had a transient ischemic attack associated with the LI topography (n = 1). Mortality causes in LI were non-neurological in nature in 88% (n = 22), whereas in non-lacunar CVD they were neurological in nature in 60% (n = 15) (p < 0,0007). CONCLUSIONS: LI are usually multiple, with a small lesional diameter (from 1 to 4 mm) and clinically silent. Arterial hypertension was associated with 84% of cases and mortality causes are usually non-neurological in nature (88%).

Aged↗

PubMed1996

[Motor neuron diseases: a type of programmed cell death?].

Motor neuron diseases in humans, which include amyotrophic lateral sclerosis (ALS) and spinal muscular atrophies (SMAs), are characterized by motorneuron loss and chromatolysis in some or many remaining cells of the anterior horn of the spinal cord. Motorneurons are filled with phosphorylated neurofilaments, and ubiquitinated filamentous and granular inclusions which conform Lewy-like bodies in ALS patients. In addition, axonal balloonings filled with phosphorylated neurofilaments are usually observed in ALS patients with predominant signs of spinal motor neuron deficits and rapid clinical course. SMAs also occur in other species. Loss of motorneurons and chromatolytic cells filled with phosphorylated neurofilaments are the main pathologic findings in the ventral horn. In both humans and animals, loss of synaptic afferents is found in chromatolytic cells but not in normally-appearing motorneurons, thus suggesting that loss of synapses is a later event in motor neuron disease. These morphological features, together with the lack of c-Jun/AP-1 immunostaining and lack of staining with the method of in situ labelling of nuclear DNA fragmentation of dying cells, are different from those found during the process of naturally occurring (programmed) cell death in normal development. Although deletions in the SMN and NAIP genes located in 5q are found in patients with SMA, the cell death programme in SMA should not be considered as a mere persistence or reactivation of naturally occurring (programmed) cell death during normal development.

Amyotrophic Lateral Sclerosis↗

PubMed1995

Ionizing radiation-induced apoptosis is associated with c-Jun expression and c-Jun/AP-1 activation in the developing cerebellum of the rat.

Previous studies have shown that ionizing radiation-induced cell death in the developing brain has morphological characteristics of apoptosis and is associated with internucleosomal DNA fragmentation. In the present study, we have observed c-Jun induction in cells sensitive to ionizing radiation during the whole process of radiation-induced cell death, and that this expression is accompanied by modifications in the composition of AP-1 complexes: c-Jun/AP-1 activity is highly increased whereas Jun D/AP-1 is slightly decreased. These results show that c-Jun expression and c-Jun/AP-1 activity are induced in the developing brain following ionizing radiation.

Animals↗

PubMed1995

NMDA receptors mediate heat shock protein induction in the mouse brain following administration of the ibotenic acid analogue AMAA.

Expression of inducible heat shock protein-70 (HSP-70) and hsp-70 mRNA were studied in the adult mouse brain following systemic administration of the ibotenic acid analogue (+/-)-2-amino-3-hydroxy-5-methyl-4-isoxazoleacetic acid (AMAA), which is a potent N-methyl-D-aspartate (NMDA) agonist. At the dose of 20 mg/kg, AMAA produced excitatory behaviours in adult mice but overt convulsions were not seen. This treatment did not result in any detectable morphological brain damage at 4 days following administration. At 2.5 h and 5 h following treatment induction of hsp-70 mRNA expression was found in the pyramidal cell layers of CA1 and, to a lesser extent, CA3 fields of hippocampal Ammon's horn, amygdala, olfactory lobes, tenia tecta, hypothalamic nuclei and a superficial layer of cingulate, frontal and retrosplenial cortices. The presence of HSP-70 was detected by immunochemistry at 24 h following drug administration in those regions previously showing hsp-70 mRNA induction. AMAA-induced hsp-70 mRNA expression was prevented by pre-treatment with the non-competitive NMDA antagonist MK-801. These results suggest that NMDA receptors are involved in the stress response induced by AMAA.

Animals↗

PubMed1995

Induction of cyclooxygenase-2 mRNA and protein following transient focal ischemia in the rat brain.

Expression of cyclooxygenase-2 (cox-2) mRNA and inducible heat-shock protein-70 (hsp-70) mRNA was studied with in situ hybridization techniques at 30 min and 4 h following 1 h transient middle cerebral artery (MCA) occlusion in the rat brain. In addition, immunoreactivity for cox-2 was studied after 8 h of reperfusion. Induction of hsp-70 and cox-2 mRNA was found in the brain side ipsilateral to MCA occlusion. Hsp-70 mRNA was induced in the parietal cortex and striatum within the territory of the occluded MCA. Induction of cox-2 mRNA was particularly seen in cortical layer II in the brain side ipsilateral to MCA occlusion. At 30 min of reperfusion, areas showing cox-2 mRNA induction included the cingulate and frontal cortices located perifocally to the areas showing hsp-70 mRNA induction, and the piriform cortex. At 4 h of reperfusion, induction of cox-2 mRNA was seen within the parietal cortex. At 8 h of reperfusion, immunoreactivity for cox-2 was mainly seen in the ipsilateral cortex. These results demonstrate that transient focal ischemia induces the expression of cox-2 mRNA and protein in discrete areas of the rat brain during reperfusion, which might lead to local increases of arachidonic acid metabolism.

Animals↗

PubMed1995

Chronic effects of single intrastriatal injections of 6-hydroxydopamine or 1-methyl-4-phenylpyridinium studied by microdialysis in freely moving rats.

Extracellular dopamine (DA) and its main cerebral metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were measured by bilateral striatal microdialysis in rats at different times (2, 7, 15 and 60 days) after unilateral administration into the right striatum of 1-methyl-4-phenylpyridinium ion (MPP+) or 6-hydroxydopamine (6-OHDA). In both cases the decrease in extracellular dopamine did not exceed 40% of control values. The response of DOPAC and HVA depended on the treatment: MPP+ caused a marked acute decrease in the dopamine metabolites but allowed a progressive recovery that was very evident after 60 days; 6-OHDA caused a progressive decrease in the dopamine metabolites throughout the two months of the study. Tyrosine hydroxylase immunostaining revealed severe neuronal loss in substantia nigra two months after striatal administration of 6-OHDA, whereas no significant neuronal loss was found at the same time after MPP+ administration. A bilateral challenge infusion of MPP+ through the microdialysis probe was used to assess the dopaminergic capacity of both striata: at all the times studied there was a sharp depletion of DA on the non-lesioned side; both MPP(+)- and 6-OHDA-treated striata were unresponsive after a short time (2 days); after 2 months the response in MPP(+)-lesioned rats was similar on both sides, whereas 6-OHDA-lesioned striata were still unresponsive to MPP+. In rats, then, the effects of MPP+ could be partly reversed whereas the effects of 6-OHDA were not. These results suggest that neurotoxins causing striatal dopamine loss may act through different mechanisms, which could be significant for the etiopathogenic development of Parkinson's disease.

1-Methyl-4-phenylpyridinium↗

PubMed1995

Survival of parvalbumin-immunoreactive neurons in the gerbil hippocampus following transient forebrain ischemia does not depend on HSP-70 protein induction.

HSP-70 was induced in the gerbil following 20 min of forebrain ischemia. The induction, as revealed with immunohistochemistry, is stronger and longer-lasting in CA3 and dentate gyrus than in CA1. Most neurons in this region, except GABAergic interneurons containing the calcium-binding protein parvalbumin, eventually cease to live as a result of delayed cell death. Double-labeling of inducible HSP-70 and parvalbumin has shown that no co-localization occurs in the hippocampus and neocortex of the gerbil in this model of transient forebrain ischemia. These results show that different thresholds of sensitivity and vulnerability exist for different subpopulations of neurons in the ischemic hippocampus, and suggest that HSP-70 protein induction is probably not essential for the survival of particular neuronal subpopulations subjected to transient ischemia.

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

[Lipoprotein(a): its concentrations in children with insulin-dependent diabetes mellitus].

BACKGROUND: Insulin-dependent diabetes mellitus (IDDM) is characterized by an increased risk of having cardiovascular diseases which have been associated to, among other factors, an increase in lipoprotein (a) [Lp(a)] levels. METHODS: With the aim of analyzing the relationship between Lp(a) plasma levels and the degree of metabolic control in infantile diabetes mellitus their levels have been evaluated in children with IDDM and correlated with the degree of metabolic control and the length of disease evolution. The study was performed in a sample of 41 children diagnosed with IDDM and ages ranging from 2 to 9 years, and 82 normolipemic healthy children corresponding to the same ages and an equal proportion by sex. Cholesterol and total triglycerides, HDL, LDL and VLDL cholesterol, apolipoproteins AI and B were determined in all. Fasting glycemia, glycohemoglobin, serum fructosamine and creatinine clearance were used as markers of metabolic disease control. RESULTS: No significant differences were observed in the Lp(a) values among sexes or age in the control group. Upon comparison of the Lp(a) values of the diabetic patients with the control group, no significant differences were observed. In the diabetic children, no differences were found between the Lp(a) values according to the glycohemoglobin values (X +/- SD g/l) (< 8% 0.16 +/- 0.13); (> or = 8% 0.21 +/- 0.26). The Lp(a) values were only increased in diabetic children with more than 5 years of evolution (control: 0.12 +/- 0.14, IDDM < or = 5 years; 0.16 +/- 0.16 and IDDM > 5 years: 0.34 +/- 0.31 [p < 0.01]). CONCLUSIONS: The plasma levels of Lp(a) in diabetic children are significantly related to the length of disease evolution and are independent of the degree of metabolic control.

Blood Glucose↗

PubMed1995

Increased beta-amyloid precursor protein expression in astrocytes in the gerbil hippocampus following ischaemia: association with proliferation of astrocytes.

Increases in beta-amyloid precursor proteins (APP), which include the beta-amyloid senile plaque protein present in patients with Alzheimer's disease, have been shown to occur in models of neuronal damage and neurotoxic cell injury. This observation led us to examine the expression of these proteins after transient ischaemic episodes in the gerbil. Animals were killed 2-28 days after ischaemia and APP were detected by immunocytochemistry at the light and electron microscopic levels with an antibody raised against the C-terminal region of these proteins. The gliotic reaction was also examined using glial fibrillary acid protein (GFAP) immunoreactivity. Two days after ischaemia, neuronal cell death was observed in the hippocampal CA1 region accompanied by astrocyte hypertrophy. These hypertrophic astrocytes were found to be GFAP positive but stained weakly for APP. Seven days after ischaemia both astrocyte hypertrophia and hyperplasia, with identified mitotic figures, were observed. These hyperplasic astrocytes were intensely stained by the APP antibody, and were observed up to 28 days after ischaemia. This shows that neuronal cell death produced by transient ischaemia is followed by an increased APP expression which appears to be associated with the hyperplasic astrocytes but not with the initial hypertrophy of this cell population. These results, when taken together with those obtained in other models of neuronal damage or death, clearly suggest that APP expression follows neuronal death and is associated with astrocyte proliferation.

Amyloid beta-Protein Precursor↗

PubMed1995

Kainic acid-induced heat shock protein-70, mRNA and protein expression is inhibited by MK-801 in certain rat brain regions.

The regional expression of inducible 72 kDa heat shock protein (HSP-70), HSP-70 mRNA and the neuropathological outcome of their expression were examined in the rat brain following systemic administration of kainic acid (9 mg/kg), and also after pretreatment with the non-competitive N-methyl-D-aspartate antagonist MK-801 (1 mg/kg). Five hours after administration of kainic acid alone, dense expression of HSP-70 mRNA was found within the limbic system, mainly in the hippocampus, piriform and entorhinal cortices, amygdaloid complex, thalamic nuclei, subiculum and in other cortical areas in rats that had shown convulsive behaviour. At 24 h, HSP-70 immunoreactivity was seen in most areas previously expressing HSP-70 mRNA, except the piriform and entorhinal cortices and several ventral nuclei of the amygdaloid complex. Histopathological examination at 24 h revealed marked cell loss in these latter regions and less severe histopathological changes in other areas of the limbic system in brains of convulsive rats. No alterations were apparent in non-convulsive rats. The percentage of rats showing convulsive behaviour with kainic acid was reduced from 74 to 4% following pretreatment with MK-801. In addition, MK-801 inhibited the kainic acid-induced expression of HSP-70 mRNA and protein in certain brain regions, notably the cortex, the pyramidal cell layer of CA1, and discrete thalamic nuclei. However, HSP-70 mRNA induction was sustained in the pyramidal cell layer of CA3, the amygdaloid complex and the subiculum, despite the fact that none of these rats convulsed. MK-801 prevented necrosis in all rats examined except the single rat that had shown convulsive behaviour. These results show that early regional expression of inducible HSP-70 mRNA allows the visualization of regions affected by kainic acid and maps regions inhibited by MK-801. In addition, the results identify brain regions putatively involved in the manifestation of limbic convulsions. Furthermore, these data illustrate that the induction of HSP-70 mRNA is not predictive of cell death or survival.

Animals↗

PubMed1995

Expression of c-fos and inducible hsp-70 mRNA following a transient episode of focal ischemia that had non-lethal effects on the rat brain.

Expression of c-fos and inducible hsp-70 mRNA was studied with in situ hybridization techniques at different times following an episode of middle cerebral artery (MCA) occlusion not resulting in any apparent lethal effect on the rat brain. hsp-70 and c-fos mRNA were found in the ipsilateral striatum and adjacent cortex. In the striatum, levels of hsp-70 mRNA increased from 1 to 2 and 4 h of reperfusion, whereas levels of c-fos mRNA decreased from 1 to 4 h of reperfusion. These results demonstrate that following non-lethal focal ischemia the brain areas within the MCA territory show high c-fos and hsp-70 mRNA expression response, illustrating the concomitant induction of these mRNAs in cells that survive the ischemic insult.

Animals↗

PubMed1995

Both apoptosis and necrosis occur following intrastriatal administration of excitotoxins.

To learn about the mechanisms of excitotoxic cell death in vivo, three different excitatory amino acid receptor agonists (kainic acid, quinolinic acid or quisqualic acid) were injected in the left striatum of adult rats. Brains were examined at 24 and 48 h after injection. Morphological and biochemical studies were performed using conventional stains, histochemistry, in situ labelling of nuclear DNA fragmentation, and agarose gel electrophoresis of extracted DNA. Large numbers of cells with cytoplasmic shrinkage and nuclear condensation or granular degeneration of the chromatin, and fewer cells with apoptotic morphology were distributed at random in the injured areas of the three groups of treated animals but not in rats injected with vehicle alone. A ladder pattern, typical of internucleosomal DNA fragmentation, was observed 24 h after treatment. This was replaced by a smear pattern, consistent with random DNA breakdown, at 48 h. These morphological and biochemical results suggest that prevailing necrosis together with apoptosis occur following intrastriatal injection of different excitotoxins.

Animals↗

PubMed1995

Postnatal development of calbindin-D28k immunoreactivity in the cerebral cortex of the cat.

To learn about maturational patterns of nonpyramidal neurons in the cerebral cortex, calbindin-D28k immunoreactivity was studied in the kitten cortex. Immunoreactive neurons first appear in the cortical and subcortical areas related to the limbic system, including the cingulate and retrosplenial cortices, and in the secondary motor areas. These are followed by the primary motor and sensory association areas and, finally, by the primary sensory areas. In all cortical areas, calbindin-D28k immunoreactivity first develops in layer V pyramidal neurons and later in nonpyramidal neurons, except in the primary sensory areas, where immunoreactive pyramidal neurons are not found at any age. Transient calbindin-D28k immunoreactivity occurs in pyramidal neurons that are mainly localized in the cingulate and retrosplenial cortices and in the secondary motor area, as well as in nonpyramidal neurons localized in the subplate and layer I, and in a subset of large multipolar and bitufted neurons in layer VI. Nonpyramidal neurons localized in layers II to IV, and some neurons in layer VI, develop permanent calbindin-D28k immunoreactivity. Calbindin-D28k immunoreactivity labels subsets of GABAergic interneurons that form vertical axonal tufts, so that temporal and regional patterns of calbindin-D28k immunoreactivity during development may be implicated in the maturation of columnar (vertical) inhibition in the cerebral cortex. In addition to neurons, corticofugal and afferent fibres of subcortical origin exhibit calbindin-D28k immunoreactivity. Transient calbindin-D28k immunoreactivity occurs in corticofugal fibres arising from the cingulate and prefrontal cortices, which are probably corticostriatal projection fibres. In contrast, permanent immunoreactivity occurs in what are probably thalamocortical fibres ending in layer IV, and in punctate terminals located in the upper third of layer I.

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

Induction of heat-shock protein-70 messenger RNA and protein following systemic kainate injection in the rat: evidence of protein axonal transport.

Induction of heat-shock protein-70 was studied using in situ hybridization and immunohistochemistry in the adult rat at different times following intraperitoneal injection of kainate. Marked expression of heat-shock protein-70 messenger RNA was observed during the first 24 h, followed by residual signal at 48 h. Inducible heat-shock protein-70 protein was found in sensitive areas not subjected to early cell death, including the lateral, dorsal and cingular cortices, lateral amygdala, thalamus and hippocampus at 12, 24 and 48 h after injection. In the hippocampus, inducible heat-shock protein-70 immunoreactivity was contained in the soma and proximal dendritic region of neurons of CA3, hilus and CA1 at 12 h, and within the entire dendritic arbor at 24 h. Heat-shock protein-70 immunoreactivity decreased in the cell bodies at four days, but delicate immunostaining appeared in the dorsal fornix, fimbria, and ventral and dorsal hippocampal commissures, as well as in the strata oriens and radiatum of CA3, and part of the stratum radiatum of CA1. Inducible heat-shock protein-70 immunoreactivity at day 7 was mainly localized in the strata oriens and radiatum of CA1 and CA3, and inner one-third of the molecular layer of the dentate gyrus, in which the ipsilateral and commissural hippocampal pathways terminate. These findings show that, in the hippocampus, inducible heat-shock protein-70 is synthesized in the cytoplasm of neurons and subsequently transported at slow rates (about 2-5 mm/day) through the axons to appropriate terminals in the ipsilateral and contralateral hippocampus. A similar pattern is observed for sensitive neurons (heat-shock protein-70 immunoreactive) in the neocortex and thalamus, and labelling of corticocortical, corticostriatal and intrathalamic (between the dorsal and the reticular nuclei) fibres. Since inducible heat-shock protein-70 keeps native proteins unfolded to prevent abnormal configuration following diverse insults, heat-shock protein-70 is proposed as a marker of transient impaired assembly of native proteins in sensitive neurons and axons following intraperitoneal kainate injection.

Animals↗

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↗

PubMed1995

A new human gene from the Down syndrome critical region encodes a proline-rich protein highly expressed in fetal brain and heart.

Down syndrome is a major cause of mental retardation and congenital heart defects. While most of the affected individuals have three copies of chromosome 21, patients with partial trisomy 21 have also been described. These rare cases define a minimal region for the Down syndrome phenotype encompassing about 3 Mb around D21S55. By using a new method for the identification of coding sequences (Alu-splice PCR) we have identified a new gene, DSCR1, from region 21q22.1-q22.2. DSCR1 encodes a novel protein which has an acidic domain, a serine-proline motif, a putative DNA binding domain and a proline-rich region with the characteristics of a SH3 domain ligand. These features suggest that DSCR1 could be involved in transcriptional regulation and/or signal transduction. DSCR1 is highly expressed in human brain and heart, and increased expression in the brains of young rats compared with adults suggests a role for DSCR1 during central nervous system development. Structural characteristics, together with its particular expression in brain and heart, encourage us to suggest that the overexpression of DSCR1 may be involved in the pathogenesis of Down syndrome, in particular mental retardation and/or cardiac defects.

Aging↗