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Biomedical subjects

E Fransen

Publications and source records attributed to E Fransen.

31 records · Page 2Linked to original sources
PubMed1998

L1 knockout mice show dilated ventricles, vermis hypoplasia and impaired exploration patterns.

L1 is a neural cell adhesion molecule mainly involved in axon guidance and neuronal migration during brain development. Mutations in the human L1 gene give rise to a complex clinical picture, with mental retardation, neurologic abnormalities and a variable degree of hydrocephalus. Recently, a transgenic mouse model with a targeted null mutation in the L1 gene was generated. These knockout (KO) mice show hypoplasia of the corticospinal tract. Here we have performed further studies of these KO mice including magnetic resonance imaging of the brain, neuropathological analysis and behavioral testing. The ventricular system was shown to be abnormal with dilatation of the lateral ventricles and the 4th ventricle, and an altered shape of the Sylvius aqueduct. Additionally, the cerebellar vermis of the KO mice is hypoplastic. Their exploratory behavior is characterized by stereotype peripheral circling reminiscent of that of rodents with induced cerebellar lesions.

Animals↗
PubMed1998

Genotype-phenotype correlation in L1 associated diseases.

The neural cell adhesion molecule L1 (L1CAM) plays a key role during embryonic development of the nervous system and is involved in memory and learning. Mutations in the L1 gene are responsible for four X linked neurological conditions: X linked hydrocephalus (HSAS), MASA syndrome, complicated spastic paraplegia type 1 (SP-1), and X linked agenesis of the corpus callosum. As the clinical picture of these four L1 associated diseases shows considerable overlap and is characterised by Corpus callosum hypoplasia, mental Retardation, Adducted thumbs, Spastic paraplegia, and Hydrocephalus, these conditions have recently been lumped together into the CRASH syndrome. We investigate here whether a genotype-phenotype correlation exists in CRASH syndrome since its clinical spectrum is highly variable and numerous L1 mutations have been described. We found that (1) mutations in the extracellular part of L1 leading to truncation or absence of L1 cause a severe phenotype, (2) mutations in the cytoplasmic domain of L1 give rise to a milder phenotype than extracellular mutations, and (3) extracellular missense mutations affecting amino acids situated on the surface of a domain cause a milder phenotype than those affecting amino acids buried in the core of the domain.

Abnormalities, Multiple↗
PubMed1998

Systemic inflammation present in patients undergoing CABG without extracorporeal circulation.

STUDY OBJECTIVES: This study was conducted to evaluate to what extent the cardiopulmonary bypass (CPB) procedure in patients undergoing coronary artery bypass grafting (CABG) contributes to the systemic inflammatory response. Therefore, we measured bactericidal permeability increasing protein (BPI) as an indicator of neutrophil activation, interleukin 6 as inducer of the acute phase response, and lipopolysaccharide binding protein and C-reactive protein as parameters of the acute phase response in patients undergoing CABG either with or without the use of CPB. DESIGN: Prospective study. SETTING: Cardiopulmonary surgery department in a university hospital. PATIENTS: Sixteen patients undergoing elective CABG were included. Eight patients underwent surgery with CPB, and eight patients underwent surgery without CPB (non-CPB). INTERVENTIONS: In the CPB group, blood samples were taken upon induction of anesthesia, at the start of aortic cross-clamping, at aortic unclamping, and 0.5, 4, 8, and 18 h thereafter. In the non-CPB group, blood samples were taken upon induction of anesthesia, and 0.5, 4, 8, and 18 h after completion of the bypass graft anastomoses. MEASUREMENTS AND RESULTS: BPI release from neutrophil granules markedly increased during surgery in CPB patients but not in non-CPB patients. The increase in acute phase reactants, however, was the same in both patient groups. CONCLUSIONS: These data indicate that the acute phase response in CABG patients, which has historically been ascribed to the CPB procedure, is predominantly caused by the surgical procedure per se. Early neutrophil activation, however, is seen only when extracorporeal circulation is used.

Acute-Phase Proteins↗
PubMed1997

L1-associated diseases: clinical geneticists divide, molecular geneticists unite.

The neuronal cell adhesion molecule L1 (L1CAM) is a transmembrane glycoprotein belonging to the immunoglobulin superfamily and is essential in the development of the nervous system. It is mainly expressed on neurons and Schwann cells, and plays a key role in axon outgrowth and pathfinding through interactions with various extracellular ligands and intracellular second messenger systems. Mutations in L1 are responsible for a wide spectrum of neurologic abnormalities and mental retardation. This spectrum includes X-linked hydrocephalus, MASA syndrome, X-linked complicated spastic paraplegia type 1 and X-linked agenesis of the corpus callosum. These four diseases were initially described as distinct clinical entities with an overlapping clinical spectrum, but can now be lumped into one syndrome caused by mutations in the L1 gene. The main clinical features of this spectrum are Corpus callosum hypoplasia, mental Retardation, Adducted thumbs, Spastic paraplegia and Hydrocephalus, which has led to the acronym CRASH syndrome.

Agenesis of Corpus Callosum↗
PubMed1997

Release of lipopolysaccharide toxicity-modulating proteins in patients undergoing cardiopulmonary bypass using noncoated and heparin-coated extracorporeal circuits. A clinical pilot study.

STUDY OBJECTIVE: Cardiopulmonary bypass (CPB) induces a generalized inflammatory response, including activation of leukocytes, contributing to postoperative morbidity. The inflammatory pathways leading to this systemic inflammatory response syndrome are considered identical to those involved in septic shock. Therefore, we studied the release of bactericidal/permeability-increasing protein (BPI), lipopolysaccharide binding protein (LBP), and soluble CD14 (sCD14)-all proteins that modulate the effects of lipopolysaccharide (LPS)-in patients undergoing CPB. In addition, the effect of heparin coating of the extracorporeal bypass circuit on the release of these parameters was assessed. DESIGN: Prospective, randomized clinical pilot study. SETTING: Cardiothoracic Surgery Department in a university hospital. PATIENTS: Fourteen patients undergoing elective coronary artery bypass grafting were included. Seven patients underwent CPB using a standard, noncoated extracorporeal circuit, and seven patients had CPB using a heparin-coated extracorporeal circuit (Duraflo II). INTERVENTIONS: Blood samples were taken after induction of anesthesia, just before aortic crossclamping, and 0, 0.5, 1.5, 3, 6, 12, and 24 h after declamping. MEASUREMENTS AND RESULTS: CPB with a noncoated extracorporeal circuit induced a sharp increase in neutrophil-derived BPI, manifest directly after release of the aortic crossclamp, which was significantly attenuated using a heparin-coated system. Also, CPB induced a gradual increase of the acute-phase reactant LBP, which was identical in the noncoated and heparin-coated groups. Systemic release of sCD14 after crossclamp release was significantly higher in the noncoated group compared with the heparin-coated group, but did not rise above baseline levels. CONCLUSIONS: These data confirm that CPB-induced leukocyte activation is attenuated using a heparin-treated extracorporeal circuit and point to the possible role of LPS toxicity-modulating proteins in the systemic inflammatory response after bypass surgery.

Acute-Phase Proteins↗
PubMed1996

The clinical spectrum of mutations in L1, a neuronal cell adhesion molecule.

Mutations in the gene encoding the neuronal cell adhesion molecule L1 are responsible for several syndromes with clinical overlap, including X-linked hydrocephalus (XLH, HSAS), MASA (mental retardation, aphasias, shuffling gait, adducted thumbs) syndrome, complicated X-linked spastic paraplegia (SP 1), X-linked mental retardation-clasped thumb (MR-CT) syndrome, and some forms of X-linked agenesis of the corpus callosum (ACC). We review 34 L1 mutations in patients with these phenotypes.

Cell Adhesion Molecules, Neuronal↗
PubMed1996

Positional cloning of a gene involved in hereditary multiple exostoses.

Hereditary multiple exostosis (EXT) is an autosomal dominant condition mainly characterized by the presence of multiple exostoses on the long bones. These exostoses are benign cartilaginous tumors (enchondromata). Three different EXT loci on chromosomes 8q (EXT1), 11p (EXT2) and 19p (EXT3) have been reported, and recently the EXT1 gene was identified by positional cloning. To isolate the EXT2 gene, we constructed a contig of yeast artificial chromosomes (YAC) and P1 clones covering the complete EXT2 candidate region on chromosome 11p11-p12. One of the transcribed sequences isolated from this region corresponds to a novel gene with homology to the EXT1 gene, and harbours inactivating mutations in different patients with hereditary multiple exostoses. This indicates that this gene is the EXT2 gene. EXT2 has an open reading frame encoding 718 amino acids with an overall homology of 30.9% with EXT1, suggesting that a family of related genes might be responsible for the development of EXT.

Amino Acid Sequence↗
PubMed1995

CRASH syndrome: clinical spectrum of corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraparesis and hydrocephalus due to mutations in one single gene, L1.

L1 is a neuronal cell adhesion molecule with important functions in the development of the nervous system. The gene encoding L1 is located near the telomere of the long arm of the X chromosome in Xq28. We review here the evidence that several X-linked mental retardation syndromes including X-linked hydrocephalus (HSAS), MASA syndrome, X-linked complicated spastic paraparesis (SP1) and X-linked corpus callosum agenesis (ACC) are all due to mutations in the L1 gene. The inter- and intrafamilial variability in families with an L1 mutation is very wide, and patients with HSAS, MASA, SP1 and ACC can be present within the same family. Therefore, we propose here to refer to this clinical syndrome with the acronym CRASH, for Corpus callosum hypoplasia, Retardation, Adducted thumbs, Spastic paraplegia and Hydrocephalus.

Abnormalities, Multiple↗
PubMed1995

Overtraining following intensified training with normal muscle glycogen.

The purpose of this study was to determine if consumption of appropriate amounts of carbohydrate during a period of increased exercise training would protect the athletes from becoming overtrained. Eight male competitive cyclists were monitored and tested during three training periods: a) normal training (moderate intensity, long duration, 7 d, NORM); b) overtraining (high intensity training, 15 d, OVER); and c) recovery (minimal training, 6 d, REC). Throughout the training 160 g of liquid carbohydrate were consumed within the first 2 h after the daily exercise bout. Mean dietary intake (NORM = 13.7 +/- 1.6, OVER = 14.1 +/- 1.0 MJ.d-1) and carbohydrate percent (NORM = 64.0 +/- 2.1, OVER = 67.4 +/- 2.5%) were not different during the different training periods. Similarly, resting muscle glycogen levels were not different (NORM = 530.9 +/- 42.5, OVER = 571.2 +/- 27.5 mumol.g-1 dry weight). Five criteria were used to determine if overtraining occurred in a subject (decreased maximal workload, maximal heart rate, ratio of maximal lactate to rating of perceived exertion (HLa:RPE), and resting plasma cortisol levels, increased affirmative response to a daily questionnaire). All subjects met at least three of the five criteria and thus were classified as overtrained. Therefore, short-term overtraining may occur even when resting muscle glycogen levels are maintained.

Adult↗
PubMed1994

MASA syndrome is due to mutations in the neural cell adhesion gene L1CAM.

MASA syndrome is a recessive X-linked disorder characterized by mental retardation, adducted thumbs, shuffling gait, aphasia and, in some cases, hydrocephalus. Since it has been shown that X-linked hydrocephalus can be caused by mutations in L1CAM, a neuronal cell adhesion molecule, we performed an L1CAM mutation analysis in eight unrelated patients with MASA syndrome. Three different L1CAM mutations were identified: a deletion removing part of the open reading frame and two point mutations resulting in amino acid substitutions. L1CAM, therefore, harbours mutations leading to either MASA syndrome or HSAS, and might be frequently implicated in X-linked mental retardation with or without hydrocephalus.

Aphasia↗
PubMedDate not supplied

Long-term potentiation in mice lacking the neural cell adhesion molecule L1.

Genetic evidence indicates that cell adhesion molecules of the immunoglobulin superfamily (IgCAMs) are critical for activity-dependent synapse formation at the neuromuscular junction in Drosophila and have also been implicated in synaptic remodelling during learning in Aplysia (see [1] for review). In mammals, a widely adopted model for the process of learning at the cellular level is long-term potentiation (LTP) in the hippocampal formation. Studies in vitro have shown that antibodies to the IgCAMs L1 and NCAM reduce LTP in CA1 neurons of rat hippocampus, suggesting a role for these molecules in the modulation of synaptic efficacy, perhaps by regulating synaptic remodelling [2]. A role for NCAM in LTP has been confirmed in mice lacking NCAM [3] (but see [4]), but similar studies have not been reported for L1. Here we examine LTP in the hippocampus of mice lacking L1 [5,6], using different experimental protocols in three different laboratories. In tests of LTP in vitro and in vivo we found no significant differences between mutant animals and controls. Thus, contrary to expectation, our data suggest that L1 function is not necessary for the establishment or maintenance of LTP in the hippocampus. Impaired performance in spatial learning exhibited by L1 mutants may therefore not be due to hippocampal dysfunction [6].

Animals↗