Biomedical subjects
Laurent Magy
Publications and source records attributed to Laurent Magy.
IgG neuropathy: an immunoelectron microscopic study.
There are many potential mechanisms of peripheral nerve impairment by a monoclonal IgG dysglobulinemia. In this study, using electron microscopy, we observed widening of the myelin lamellae comparable to that commonly described in IgM neuropathies with antimyelin-associated glycoprotein activity. Such features have yet to be described in IgG neuropathies. In addition, we observed deposits of a granular material in the interstitial tissue of the nerve. By immunoelectron microscopy, we demonstrated the presence of the IgG in the lesions of myelin and the endoneurial space. A direct link between monoclonal dysglobulinemia (regardless of type) and polyneuropathy should be confirmed by nerve biopsy, because the result may influence treatment.
Fatigue as the main presenting symptom of chronic inflammatory demyelinating polyradiculoneuropathy: a study of 11 cases.
Fatigue has been shown to be more frequent than previously thought in immune-mediated polyneuropathies. However, fatigue has not been reported as the main cause of referral in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients. Between January 2001 and December 2003, we investigated 11 patients referred for fatigue, for which we established a final diagnosis of CIDP. All patients had at least two clinical examinations including assessment of the fatigue severity scale (FSS) and one electrophysiological and laboratory work up. Additionally, 10 of the 11 patients had a nerve biopsy. There were 11 male patients. Mean age at onset was 53 +/- 11 years. Main cause of referral was fatigue in all patients. Additional symptoms included cramps (one case), distal paresthesias (six cases), limb pain (seven cases) and vasomotor disturbances (one case). Cerebrospinal fluid (CSF) analysis displayed a moderate increase in protein content in four patients. Electrophysiological analysis showed abnormalities in all patients. Among 11 patients, one fulfilled the American Academy of Neurology electrodiagnostic criteria for CIDP and three fulfilled the inflammatory neuropathy cause and treatment group or the Nicolas et al. criteria. In the eight remaining patients, a nerve biopsy confirmed the diagnosis of CIDP. Ten patients were treated, among which seven showed a significant improvement based on the FSS scale. This study shows that fatigue is a possible cause of referral for patients with CIDP and, like previous reports, emphasizes the lack of sensitivity of widely accepted electrophysiological criteria of CIDP. Long-term follow up of these patients is warranted to determine the prognosis of these minimal forms of CIDP and establish the best therapeutic strategy in such cases.
Stem cells, progenitors and myelin repair.
Remyelination, the process by which new myelin sheaths are restored to demyelinated axons, represents one of the most compelling examples of adult multipotent progenitor cells contributing to regeneration of the injured central nervous system (CNS). This process can occur with remarkable efficiency in both clinical disease, such as multiple sclerosis, and in experimental models, revealing an impressive ability of the adult CNS to repair itself. However, the inconsistency of remyelination in multiple sclerosis, and the loss of axonal integrity that results from its failure, makes enhancement of remyelination an important therapeutic objective. Identifying potential targets will depend on a detailed understanding of the cellular and molecular mechanisms of remyelination. In this article we address two important issues. First, we consider the nature of the cell or cells that respond to demyelination and generate new oligodendrocytes, identifying current areas of uncertainty and addressing the role of adult CNS stem and progenitor cells. Second, we discuss the concept of adult progenitor activation following demyelination, focusing on the increased expression of (1) olig transcription factors, (2) bone morphogenetic proteins and (3) fyn, a member of the src-family of tyrosine kinases.
The renin-angiotensin systems: evolving pharmacological perspectives for cerebroprotection.
During the last 20 years, the renin-angiotensin system (RAS) has become an increasingly important focus of basic and clinical cardiovascular research. One main conceptual step forward was made with the discovery of a tissue RAS and the understanding of its critical pathophysiological role in atherogenesis and plaque destabilisation. Major effort to find new strategies for blocking the RAS has produced new classes of drugs which were expected to be clinically important in the management of hypertension and heart failure. As landmark clinical studies have demonstrated that inhibition of the RAS significantly reduces morbidity and mortality from coronary heart disease, myocardial infarction and heart failure, the concept has rapidly emerged that blocking the RAS was the strategy of choice for preventing cardiovascular diseases. More recently, basic research has however continuously extended our understanding of the complexity of the systemic and tissue RASs, that can no longer be viewed as one-way streets in which one single effector, angiotensin II acts solely through its major (AT1) receptor. Meanwhile, clinical trials have challenged the concept that blocking the RAS is the most effective preventive strategy for all patients and all target organs. Consistent with the recent understanding that the RAS encompasses a number of distinct effectors acting through different receptors to promote opposite effects, a growing body of basic and clinical evidence suggests that blunting the RAS is a double-edge sword, with beneficial effects counterbalanced by deleterious ones, resulting in a net effect that critically depends on the experimental conditions, or the clinical characteristics of the study population. Of particular clinical relevance, a number of clinical trials point to the somewhat provocative conclusion that beyond their blood pressure lowering effect antihypertensive drugs that decrease angiotensin II formation are less stroke protective than the ones that increase angiotensin levels. This review focuses on the recent experimental evidence demonstrating that angiotensin II and its derivatives acting through the non-AT1 receptors are involved in protective mechanisms against cerebral ischaemia and discusses in the light of the recent large cardiovascular prevention trials the clinical relevance of this new concept. The perspective of a renewal of therapeutical strategies to optimise the prevention of target organ damage and perhaps even some of the diseases of ageing, such as loss of cognitive function is emphasised.
Successful treatment of human herpesvirus 6 encephalomyelitis in immunocompetent patient.
We report a case of human herpesvirus 6 (HHV-6) encephalomyelitis in an immunocompetent patient, which was confirmed by viral amplification from cerebrospinal fluid. Cidofovir was used, followed by ganciclovir, because of an adverse effect to probenecid. The patient recovered. HHV-6 should be recognized as one of the causes of encephalomyelitis.
Diagnostic value of nerve biopsy for atypical chronic inflammatory demyelinating polyneuropathy: evaluation of eight cases.
The diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) relies primarily on clinical and electrophysiologic examination, but the nerve biopsy findings may be supportive, especially in atypical cases. In order to define the usefulness of nerve biopsy in this disease, we retrospectively studied 44 consecutive patients whom we classified as having CIDP on pathological grounds. We found that 8 of these 44 patients had pathological findings indicative of CIDP but did not meet any of the usually accepted electrophysiological criteria for its diagnosis. Among these eight patients, five responded favorably to conventional therapy. All of these eight patients had an electrophysiological pattern of generalized axonopathy with additional subtle findings suggestive of demyelination that prompted us to perform a nerve biopsy. Our data suggest that a significant number of patients with unrecognized CIDP are erroneously classified as having chronic idiopathic axonal polyneuropathy. CIDP should be suspected if the electrophysiological examination displays subtle abnormalities suggestive of demyelination, even in the presence of a prominent axonal pattern. Nerve biopsy in these patients may reveal abnormalities suggestive of CIDP and guide therapeutic options.
Inducible expression of FGF2 by a rat oligodendrocyte precursor cell line promotes CNS myelination in vitro.
Transplantation of glial cells into the central nervous system (CNS) may be a promising approach for the treatment of myelin disorders such as multiple sclerosis (MS). Myelination by transplantation of oligodendrocyte precursors has been obtained in different animal models of demyelination. A strategy to favor CNS remyelination is to enrich the lesioned areas in growth factors to stimulate the quiescent population of oligodendrocyte precursors. In this context, we have developed a genetically modified CG4 cell line (CG4-FGF2), which are able to release significant amounts of fibroblast growth factor 2 (FGF2) in a controlable fashion in vitro. The data presented here demonstrate that upon induction with Dox, CG4-FGF2 cells retain their capacity to differentiate in vitro. Additionally, we provide evidence that FGF2 release by engineered cells enhance proliferation and migration of cells of the oligodendrocyte lineage without preventing them to differentiate and myelinate axons in vitro.
Transient exposure to FGF2 enhances myelination in embryonic brain cell cocultures.
The amount of myelination in vivo and in vitro depends on the number of oligodendrocyte progenitors, their differentiation, and on the neuron function. It has been shown that continuous administration of FGF2, a mitotic and neuroprotective factor, allows oligodendrocyte progenitors to proliferate, but prevents them from differentiating and myelinating. This study was designed to test the effect of transient exposure to FGF2 on myelination in an oligodendrocyte/neuron coculture system. At 2 days in vitro, cultures were treated with a single dose of 20 ng/ml FGF2. Cell proliferation was determined by BrdU uptake. The number of cells of the oligodendrocyte lineage was determined by immunocytology of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase). The maturation of oligodendrocytes and myelination was followed by immunocytological analysis of MBP (myelin basic protein). Electron microscopy was used to study the ultrastructure of myelin. BrdU uptake procedure showed an increase in cell proliferation in FGF2-treated cultures after 48 h of treatment. At 15-18 days in vitro, CNPase(+) and MBP(+) cells were much more abundant in cultures treated with FGF2 than in control cultures. We observed differentiation and maturation of oligodendrocytes and a higher degree of myelination in FGF2-treated cultures compared to controls. Electron microscopy showed the presence of myelin structures in FGF2-treated cultures that did not differ morphologically from those observed in control cultures. Transient exposure of cultured brain cells to FGF2 increased myelination in vitro. Administration of FGF2 over a short period might thus enhance remyelination in demyelinating diseases in vivo.
[Importance of the nerve biopsy for the diagnosis of atypical forms of chronic inflammatory demyelinating polyradiculoneuritis: 8 cases].
The objective of the study was to define how could be helpful a nerve biopsy for identification of atypical cases of chronic inflammatory demyelinating polyneuropathy (CIDP). An ad hoc committee in 1991 defined the clinical, electrophysiological and pathological criteria for diagnosis of CIDP. In common with other authors, we regard the rather specific electrophysiological criteria as being too restrictive, and we think that a significant number of patients may therefore not benefit from effective treatment or be excluded from therapeutic trials. The Inflammatory Neuropathy Cause and Treatment (INCAT) group (2001) has proposed new electrophysiological criteria of CIDP, which are more sensitive and do not loose any specificity. Over a period of three years (January 1999 to December 2001), we classified 44 patients into two categories: those presenting the strict criteria of the ad hoc committee and those who we regarded as cases of CIDP who did not meet these strict criteria. All these patients benefited from one or more clinical and electrophysiological examinations; extensive biological workup and genetic study when appropriate excluded other causes of neuropathy. Nerve biopsies were taken from all patients and samples were included in paraffin and epon for systematic light and electron microscopic examination. Out of 44 patients, 24 fulfilled the INCAT electrophysiological criteria with only 12 of these cases fulfilling the criteria of the ad hoc committee. Eight patients did not fulfill any of the widely accepted electrophysiological criteria of CIDP. However, study of nerve biopsies of these eight patients revealed histological features characteristic of CIDP according to histological criteria (AAN-1991). Among these patients, six have been treated and five responded favorably to conventional treatments for CIDP. Without information from the nerve biopsy, these patients would not have been treated effectively because their electrophysiological profile was indicative of axonal impairment interpreted erroneously as primary.
LR white post-embedding colloidal gold method to immunostain MBP, P0, NF and S100 in glutaraldehyde fixed peripheral nerve tissue.
A variety of immunocytochemical techniques are now widely used for the electron and light microscopic examination of biological samples. They are employed routinely for investigating the role of certain proteins in nervous tissue. Immunoelectron microscopic studies require the tissue to be fixed and embedded in a solid support, which may disrupt cellular structures and destroy crucial antigens. A technique of post-embedding with LR white resin has been developed, and it has been shown that certain antigens tolerate fixation with glutaraldehyde. In this study, we optimized a previous post-embedding method using low-water-miscible low-temperature embedding resin (LR white) to immunostain MBP, P0, NF and S100 proteins in peripheral nerves fixed with a relatively high concentration of glutaraldehyde found to be compatible with the morphology of normally compacted nerve fibers from humans and adult animals. The main difference in the procedures described here from previous ones is the elimination of vibratome sectioning, rendering this immunostaining technique more accessible to neuropathological laboratories using standard equipment for the ultrastructural study of peripheral nerves. It may prove of value for localization and quantification of these proteins in normal and pathological conditions.
Immunocytological studies of L-MAG expression regulation during myelination of embryonic brain cell cocultures.
The myelin-associated glycoprotein (MAG) possesses two isoforms, known as S-MAG and L-MAG. We followed the expression and localization of L-MAG in comparison to myelin basic protein (MBP) during myelination in dissociated embryonic rat brain cell cocultures. Using immunofluorescence microscopy, we observed L-MAG and MBP in oligodendrocyte (OL) cell bodies and processes before and at the onset of myelination. At advanced stages of myelination, L-MAG immunostaining decreased, and subsequently disappeared from OL soma and myelinated internodes, whereas MBP immunoreactivity decreased only in the OL soma. These results are consistent with biochemical studies and provide the first clear demonstration of a transient expression of L-MAG during the early stages of myelination in vitro, providing further evidence that L-MAG plays a role during this period.