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Biomedical subjects

E Hirsch

Publications and source records attributed to E Hirsch.

At least 55 records · Page 3Linked to original sources
PubMed2001

[The autopsy exception].

It does not seem a priori easy to implement the usual values and milestones of biomedicalethics with explorations performed on a corpse. This is true, at least, when it is considered that the concepts of welfare and benefit concern only the human being himself. This necessarily precludes any practice conducted with another aim. Thus, autopsy cannot be ethically justified unless its usefulness is expressly demonstrated. Furthermore, some conventions should be respected, otherwise the reprobation induced by characterised deviations would anihilate even this usefulness. To overcome ambiguities, and conceive, despite everything, a moral procedure which would be reconcilable with some medico-scientific necessities, the exemption principle may be proposed for autopsy. Because explorations performed on a corpse impose definitely irreproachable behaviours, learned societies and authorities should build up means and methods to unquestionably guarantee the relevance and soundness of practice.

Autopsy↗
PubMed2001

[From historical EEG to signal treatment: applications in childhood epilepsy].

Electroencephalography is a fundamental investigation for the characterization of an epilepsy. It remains a unique way for the evaluation of a cortical activity in real time. The classification of epileptic syndromes is based on electroclinical correlations. The characterization of EEG abnormalities is essential for establishing a specific syndromic diagnosis. Discussing the historical evolution of EEG techniques we show how the recent development of numerized EEG provided the medical community with very useful and simple tools for the treatment of EEG signals. These tools are now integrated in everyday clinical practice. Several methods are presented, illustrating potential applications in childhood epilepsies.

Animals↗
PubMed2001

[Cognitive consequences of Rolandic Epilepsy].

Idiopathic focal epilepsies and particularly rolandic epilepsy are considered to have an excellent outcome with spontaneous recovery during adolescence. The characterization of this syndrome in 1959 by Beaussart and Nayrac was a great progress for childhood epileptology: the existence of a focal epilepsy with a good prognosis and no underlying brain lesion, so-called "benign" epilepsy, was recognized. Since the first descriptions, numerous neuropsychological studies were performed showing variable results. All the studies agree with the fact that children with rolandic epilepsy keep a normal global intellectual efficiency and a good long-term outcome. Nevertheless, some children may suffer transiently during the active phase of the epilepsy from oromotor dysfunction, neuropsychological deficits, or attention deficits with learning disorders. The analysis of cognitive and neurophysiological correlations evidenced a significant correlation between the epileptic focus localization and few specific dysfunctions. We evidenced mainly a significant effect of the persistence of a prolonged slow focus and a strong activation of night EEG spike and waves on cognitive decline and attention disorders. These abnormalities are mainly observed during severe or atypical evolutions of rolandic epilepsy. Preliminary longitudinal studies show that these cognitive deficits are transient. Thus, the presence of an active epileptic focus, without underlying brain lesion, could interfere with normal maturation of cognitive function.

Adolescent↗
PubMed2001

Semiology of typical and atypical Rolandic epilepsy: a video-EEG analysis.

Since the first descriptions of Rolandic Epilepsy or benign epilepsy with centrotemporal spikes (BECTS), typical and atypical forms have been reported. Indeed, classical focal seizures are sometimes associated with various atypical ictal symptoms and cognitive or behavioural disorders. In an effort to define early clinical and EEG criteria allowing early distinction between typical and atypical forms, we recently conducted a prospective study in a cohort of children with Rolandic Epilepsy. The results of this study have been reported elsewhere. We now discuss the semiological characteristics, and comment on the video-EEG data collected during this study. Symptoms were classified into three major categories: "classical focal seizures"; "spike and wave related symptoms"; and "paraictal symptoms". Classical focal seizures constitute the electroclinical expression of the development and the propagation of a focal cortical neuronal discharge. "Spike and wave related symptoms" are brief neurological or neuropsychological phenomena having a relatively strict temporal relation with individual components of isolated focal or generalized spikes and waves. "Paraictal symptoms" consist of acquired progressive and fluctuating motor or cognitive deficits and are not directly correlated with Todd paralysis. We present detailed video-EEG material of selected cases and discuss the usefulness of such distinctions in terminology. We suggest that variability in clinical expression probably reflects the implication of different pathophysiological mechanisms, which in turn could explain differences in sensitivity to treatment. (Published with videosequences.)

Arm↗
PubMed2000

Distinct roles of the adaptor protein Shc and focal adhesion kinase in integrin signaling to ERK.

It has been proposed that integrins activate ERK through the adaptor protein Shc independently of focal adhesion kinase (FAK) or through FAK acting on multiple target effectors, including Shc. We show that disruption of the actin cytoskeleton by cytochalasin D causes a complete inhibition of FAK but does not inhibit Shc signaling and activation of ERK. We have then generated primary fibroblasts carrying a targeted deletion of the segment of beta(1) subunit cytoplasmic domain required for activation of FAK. Analysis of these cells indicates that FAK is not necessary for efficient tyrosine phosphorylation of Shc, association of Shc with Grb2, and activation of ERK in response to matrix adhesion. In addition, integrin-mediated activation of FAK does not appear to be required for signaling to ERK following growth factor stimulation. To examine if FAK could contribute to the activation of ERK in a cell type-specific manner through the Rap1/B-Raf pathway, we have used Swiss-3T3 cells, which in contrast to primary fibroblasts express B-Raf. Dominant negative studies indicate that Shc mediates the early phase and peak, whereas FAK, p130(CAS), Crk, and Rap1 contribute to the late phase of integrin-dependent activation of ERK in these cells. In addition, introduction of B-Raf enhances and sustains integrin-mediated activation of ERK in wild-type primary fibroblasts but not in those carrying the targeted deletion of the beta(1) cytoplasmic domain. Thus, the Shc and FAK pathways are activated independently and function in a parallel fashion. Although not necessary for signaling to ERK in primary fibroblasts, FAK may enhance and prolong integrin-mediated activation of ERK through p130(CAS), Crk, and Rap1 in cells expressing B-Raf.

3T3 Cells↗
PubMed2000

Analysis of the murine phosphoinositide 3-kinase gamma gene.

Phosphoinositide 3-kinase gamma is preferentially expressed in leukocytes. PI3Kgamma is activated by betagamma subunits of heterotrimeric G-proteins, which thus link seven transmembrane helix receptor activation to phosphatidylinositol (3,4,5)-trisphosphate production. Here we describe the molecular cloning of the murine PI3Kgamma cDNA, the PI3Kgamma gene structure, its chromosomal assignment and the analysis of promoter activity. The mouse cDNA shares 86% identity to its pig and human orthologues at the nucleotide level. The MmPI3Kgamma gene spans approximately 30kb and comprises 11 exons. RACE-PCR indicated the presence of multiple start sites generating 5' UTRs with different lengths, the longest being 874bp. The putative promoter region contains no TATA box but several putative binding sites for hematopoietic specific transcription factors. A 1200bp long sequence upstream the first transcription start site was found to possess tissue specific promoter activity. Deletion constructs revealed two contiguous regions, with activator function, ranging from positions -139 to -557, and with inhibitory function, ranging from positions -557 to -892. FISH analysis revealed that the MmPI3Kgamma is located on chromosome 12 band B and that the human orthologue is positioned on chromosome 7q22.2-22.3. In spite of some differences in the ATP-binding site, recombinant murine PI3Kgamma protein is equally sensitive to wortmannin as its human counterpart. This suggests that mouse models will provide reliable results in the assessments of novel PI3Kgamma inhibitors.

Amino Acid Sequence↗
PubMed2000

Acute systemic inflammation up-regulates secretory sphingomyelinase in vivo: a possible link between inflammatory cytokines and atherogenesis.

Inflammation plays a critical role in atherogenesis, yet the mediators linking inflammation to specific atherogenic processes remain to be elucidated. One such mediator may be secretory sphingomyelinase (S-SMase), a product of the acid sphingomyelinase gene. The secretion of S-SMase by cultured endothelial cells is induced by inflammatory cytokines, and in vivo data have implicated S-SMase in subendothelial lipoprotein aggregation, macrophage foam cell formation, and possibly other atherogenic processes. Thus, the goal of this study was to seek evidence for S-SMase regulation in vivo during a physiologically relevant inflammatory response. First, wild-type mice were injected with saline or lipopolysaccharide (LPS) as a model of acute systemic inflammation. Serum S-SMase activity 3 h postinjection was increased 2- to 2.5-fold by LPS (P < 0.01). To determine the role of IL-1 in the LPS response, we used IL-1 converting enzyme knockout mice, which exhibit deficient IL-1 bioactivity. The level of serum S-SMase activity in LPS-injected IL-1 converting enzyme knockout mice was approximately 35% less than that in identically treated wild-type mice (P < 0.01). In LPS-injected IL-1-receptor antagonist knockout mice, which have an enhanced response to IL-1, serum S-SMase activity was increased 1. 8-fold compared with LPS-injected wild-type mice (P < 0.01). Finally, when wild-type mice were injected directly with IL-1beta, tumor necrosis factor alpha, or both, serum S-SMase activity increased 1. 6-, 2.3-, and 2.9-fold, respectively (P < 0.01). These data show regulation of S-SMase activity in vivo and they raise the possibility that local stimulation of S-SMase may contribute to the effects of inflammatory cytokines in atherosclerosis.

Acute Disease↗
PubMed2000

Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation.

Phosphoinositide 3-kinase (PI3K) activity is crucial for leukocyte function, but the roles of the four receptor-activated isoforms are unclear. Mice lacking heterotrimeric guanine nucleotide-binding protein (G protein)-coupled PI3Kgamma were viable and had fully differentiated neutrophils and macrophages. Chemoattractant-stimulated PI3Kgamma-/- neutrophils did not produce phosphatidylinositol 3,4,5-trisphosphate, did not activate protein kinase B, and displayed impaired respiratory burst and motility. Peritoneal PI3Kgamma-null macrophages showed a reduced migration toward a wide range of chemotactic stimuli and a severely defective accumulation in a septic peritonitis model. These results demonstrate that PI3Kgamma is a crucial signaling molecule required for macrophage accumulation in inflammation.

Animals↗
PubMed2000

Two-year clinical performance of two primer adhesives on class V restorations.

The prime purpose of this clinical trial was to examine the clinical quality and retention rate of resin composite in connection with two recently developed acetone-based primer adhesives in Class V lesions according to ADA Clinical Protocol Guidelines for Dentin and Enamel Adhesive Materials. All cavities were nonretentive and predominantly in dentin (mixed Class V lesions). Total bonding was not limited either by sub-base or by base materials. All the trial restorations were placed under rubber dam. Group 1 (Version 16-135-1) and group 2 (Version 17-17-1) consisted of 42 patients with 46 trials and 38 patients with 43 fillings, respectively. The mean follow-up period and the recall response at the end of the study of group 1 were 22.8 months and 92.9% and of group 2 were 22.4 months and 94.7%. The trial restorations of both groups maintained their predominantly rated USPHS-Code Alpha level within the follow-up period. The cumulative failure rate of two trials in group 1 and four in group 2 determined a failure percentage of 4.4% and 9.3%, respectively, which is within the ADA-18 month limit of <10% Charlie. The Version KL 16-135-1 came into the market as Prime & Bond(R) 2.1, and the other one turned out to be Dyract Adhesive(R) PSA, which was primarily introduced as a single-component adhesive for compomer restorative Dyract(R) (Dentsply DeTrey, Germany).

Acetone↗
PubMed2000

Preterm delivery in mice with renal abscess.

OBJECTIVE: Our purpose was to develop a mouse model of renal abscess to study the effect of extrauterine infection on preterm delivery. METHODS: Escherichia coli or sterile medium was injected into the left kidney of 70 pregnant mice that had completed approximately 75% of gestation. Preterm delivery rates were recorded for various inocula. Kidney specimens were obtained and examined grossly and histologically for abscess formation. RESULTS: Thirty-one of 51 animals (60.8%) infected with 1 x 10(5)-9 x 10(6) bacteria and none of 19 uninfected animals delivered prematurely (P < .001). Renal abscess was induced in 100% of mice receiving bacterial inoculation but in none receiving sterile medium. CONCLUSION: Kidney injection provides a reliable method for inducing renal abscess in pregnant mice. Renal abscess induces preterm delivery at a stable rate across a wide range of bacterial inocula. This model of extrauterine infection may be particularly useful in investigations of infection-induced preterm delivery.

Abscess↗
PubMed2000

The indirect basal ganglia pathway in dopamine D(2) receptor-deficient mice.

Recent pathophysiological models of basal ganglia function in Parkinson's disease predict that specific neurochemical changes in the indirect pathway would follow the lack of stimulation of D(2) dopamine receptors. Post mortem studies of the basal ganglia in genetically modified mice lacking functional copies of the D(2) dopamine receptor gene allowed us to test these predictions. When compared with their congenic N(5) wild-type siblings, mice lacking D(2) receptors show an increased expression of enkephalin messenger RNA in the striatum, and an increased activity and expression of cytochrome oxidase I in the subthalamic nucleus, as expected. In addition, D(2) receptor-deficient mice display a reduced expression of glutamate decarboxylase-67 messenger RNA in the globus pallidus, as the basal ganglia model predicts. This reduction contrasts with the lack of change or increase in glutamate decarboxylase-67 messenger RNA expression found in animals depleted of dopamine after lesions of the mesostriatal dopaminergic system. Furthermore, D(2) receptor-deficient mice show a significant decrease in substance P messenger RNA expression in the striatonigral neurons which form the direct pathway. Finally, glutamate decarboxylase-67 messenger RNA expression in the basal ganglia output nuclei was not affected by mutations in the D(2) receptor gene, a fact that could probably be related to the absence of a parkinsonian locomotor phenotype in D(2) receptor-deficient mice. In summary, these findings provide compelling evidence demonstrating that the lack of endogenous stimulation of D(2) receptors is sufficient to produce subthalamic nucleus hyperactivity, as assessed by cytochrome oxidase I histochemistry and messenger RNA expression, and strongly suggest the existence of interactions between the basal ganglia direct and indirect pathways.

Animals↗
PubMed2000

Crosslinking of alpha-synuclein by advanced glycation endproducts--an early pathophysiological step in Lewy body formation?

An excess of reactive carbonyl compounds (carbonyl stress) and their reaction products, advanced glycation endproducts (AGEs), are thought to play a decisive role in the pathogenesis of neurodegenerative disorders and Parkinson's disease (PD) in particular. Accumulation of AGEs in various intracellular pathological hallmarks of PD, such as Lewy bodies, densely crosslinked intracellular protein deposits formed from neurofilament components and alpha-synuclein, have already been described in patients in advanced stages of the disease. There is, however, no indication of the involvement of AGE-induced crosslinking of alpha-synuclein in very early stages of the disease. In this study, we observed that AGEs and alpha-synuclein are similarly distributed in very early Lewy bodies in the human brain in cases with incidental Lewy body disease. These cases might be viewed as pre-Parkinson patients, i.e. patients who came for autopsy before the possible development of clinical signs of PD. AGEs are both markers of transition metal induced oxidative stress as well as, inducers of protein crosslinking and free radical formation by chemical and cellular processes. Thus, it is likely that AGE promoted formation of Lewy bodies reflects very early causative changes rather than late epiphenomenons of PD.

Aged↗
PubMed2000

Defective neurogenesis in citron kinase knockout mice by altered cytokinesis and massive apoptosis.

Citron-kinase (Citron-K) has been proposed by in vitro studies as a crucial effector of Rho in regulation of cytokinesis. To further investigate in vivo its biologic functions, we have inactivated Citron-K gene in mice by homologous recombination. Citron-K-/- mice grow at slower rates, are severely ataxic, and die before adulthood as a consequence of fatal seizures. Their brains display defective neurogenesis, with depletion of specific neuronal populations. These abnormalities arise during development of the central nervous system due to altered cytokinesis and massive apoptosis. Our results indicate that Citron-K is essential for cytokinesis in vivo but only in specific neuronal precursors. Moreover, they suggest a novel molecular mechanism for a subset of human malformative syndromes of the CNS.

Animals↗