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Biomedical subjects

Jean-François Pellissier

Publications and source records attributed to Jean-François Pellissier.

At least 19 recordsLinked to original sources
PubMed2006

Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple deletions or depletion of mitochondrial DNA by a dHPLC-based assay.

ANT1, TWINKLE and POLG genes affect mtDNA stability and are involved in autosomal dominant PEO, while mutations in POLG are responsible for numerous clinical presentations, including autosomal recessive PEO, sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO), spino-cerebellar ataxia and epilepsy (SCAE) or Alpers syndrome. In this study, we report on the mutational analysis of ANT1, TWINKLE and POLG genes in 15 unrelated patients, using a dHPLC-based protocol. This series of patients illustrates the large array of clinical presentations associated with mtDNA stability defects, ranging from isolated benign PEO to fatal Alpers syndrome. A total of seven different mutations were identified in six of 15 patients (40%). Six different recessive mutations were found in POLG, one in TWINKLE while no mutation was identified in ANT1. Among the POLG mutations, three are novel and include two missense and one frameshift changes. Seventeen neutral changes and polymorphisms were also identified, including four novel neutral polymorphisms. Overall, this study illustrates the variability of phenotypes associated with mtDNA stability defects, increases the mutational spectrum of POLG variants and provides an efficient and reliable detection protocol for ANT1, TWINKLE and POLG mutational screening.

Adenine Nucleotide Translocator 1↗
PubMed2006

Block of neural Kv1.1 potassium channels for neuroinflammatory disease therapy.

OBJECTIVE: We asked whether blockade of voltage-gated K+ channel Kv1.1, whose altered axonal localization during myelin insult and remyelination may disturb nerve conduction, treats experimental autoimmune encephalomyelitis (EAE). METHODS: Electrophysiological, cell proliferation, cytokine secretion, immunohistochemical, clinical, brain magnetic resonance imaging, and spectroscopy studies assessed the effects of a selective blocker of Kv1.1, BgK-F6A, on neurons and immune cells in vitro and on EAE-induced neurological deficits and brain lesions in Lewis rats. RESULTS: BgK-F6A increased the frequency of miniature excitatory postsynaptic currents in neurons and did not affect T-cell activation. EAE was characterized by ventriculomegaly, decreased apparent diffusion coefficient, and decreased (phosphocreatine + beta-adenosine triphosphate)/inorganic phosphate ratio. Reduced apparent diffusion coefficient and impaired energy metabolism indicate astrocytic edema. Intracerebroventricularly BgK-F6A-treated rats showed attenuated clinical EAE with unexpectedly reduced ventriculomegaly and preserved apparent diffusion coefficient values and (phosphocreatine + beta-adenosine triphosphate)/inorganic phosphate ratio. Thus, under BgK-F6A treatment, brain damage was dramatically reduced and energy metabolism maintained. INTERPRETATION: Kv1.1 blockade may target neurons and astrocytes, and modulate neuronal activity and neural cell volume, which may partly account for the attenuation of the neurological deficits. We propose that Kv1.1 blockade has a broad therapeutic potential in neuroinflammatory diseases (multiple sclerosis, stroke, and trauma).

Animals↗
PubMed2006

Biological effects of four PSEN1 gene mutations causing Alzheimer disease with spastic paraparesis and cotton wool plaques.

We describe the biological consequences on PSEN1 exons 8 or 9 splicing and Abeta peptides production of four PSEN1 mutations associated with a phenotypic variant of Alzheimer disease, which includes cotton wool plaques and spastic paraparesis (CWP/SP). Two of these mutations (c.869-22_869-23ins18 and c.871A > C, p.T291P) are novel mutations located in intron 8 and exon 9, respectively. The c.869-22_869-23ins18 mutation caused exon 9 skipping whereas the c.871A > C (p.T291P) mutation showed only a modest effect on exon 9 skipping. The previously reported E280G and P264L mutations, located in exon 8, had no effect on mRNA splicing. Infection of cells with mutant T291P, E280G, or P264L cDNAs caused a variable increase in secreted Abeta42. We conclude that none of the previously proposed mechanisms, i.e. exceptionally large increases in secreted Abeta42 levels or loss of PSEN1 exons 8 or 9, provides complete explanation of the CWP/SP phenotype.

Alzheimer Disease↗
PubMed2006

Metabosensitive afferent fiber responses after peripheral nerve injury and transplantation of an acellular muscle graft in association with schwann cells.

Studies dedicated to the repair of peripheral nerve focused almost exclusively on motor or mechanosensitive fiber regeneration. Poor attention has been paid to the metabosensitive fibers from group III and IV (also called ergoreceptor). Previously, we demonstrated that the metabosensitive response from the tibialis anterior muscle was partially restored when the transected nerve was immediately sutured. In the present study, we assessed motor and metabosensitive responses of the regenerated axons in a rat model in which 1 cm segment of the peroneal nerve was removed and immediately replaced by an autologous nerve graft or an acellular muscle graft. Four groups of animals were included: control animals (C, no graft), transected animals grafted with either an autologous nerve graft (Gold Standard-GS) or an acellular muscle filled with Schwann Cells (MSC) or Culture Medium (MCM). We observed that (1) the tibialis anterior muscle was atrophied in GS, M(SC) and M(CM) groups, with no significant difference between grafted groups; (2) the contractile properties of the reinnervated muscles after nerve stimulation were similar in all groups; (3) the metabosensitive afferent responses to electrically induced fatigue was smaller in M(SC) and MCM groups; and (4) the metabosensitive afferent responses to two chemical agents (KCl and lactic acid) was decreased in GS, M(SC) and M(CM) groups. Altogether, these data indicate a motor axonal regeneration and an immature metabosensitive afferent fiber regrowth through acellular muscle grafts. Similarities between the two groups grafted with acellular muscles suggest that, in our conditions, implanted Schwann cells do not improve nerve regeneration. Future studies could include engineered conduits that mimic as closely as possible the internal organization of uninjured nerve.

Afferent Pathways↗
PubMed2006

Platelet-endothelial cell adhesion molecule-1 and CD146: soluble levels and in situ expression of cellular adhesion molecules implicated in the cohesion of endothelial cells in idiopathic inflammatory myopathies.

OBJECTIVE: Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of diseases characterized by chronic inflammation of muscles. We investigated the role of cellular adhesion molecules implicated in the cohesion of endothelial cells in IIM. METHODS: In 22 patients with IIM we investigated plasma concentrations of soluble junctional adhesion molecules [platelet-endothelial cell adhesion molecule (sPECAM-1) and sCD146] and cellular adhesion molecules [sP-selectin, sE-selectin, intercellular adhesion molecule (sICAM-1), and vascular cell adhesion molecule (sVCAM-1)] implicated in leukocyte/endothelial cell interactions. Results were compared to a control group. Muscle biopsy samples from 8 out of 22 IIM patients were studied by immunohistochemistry for tissue expression of these molecules and compared to normal muscle samples. PECAM-1 and CD146 expression was also studied using immunoblots from muscle biopsies from 5 patients and 2 controls. RESULTS: We observed distinct patterns of soluble levels and in situ expression between dermatomyositis (DM), polymyositis (PM), and sporadic inclusion body myositis (s-IBM). PM samples showed significantly increased levels of sCD146, sPECAM-1, and s-ICAM1 and increased expression of CD146, CD31, and ICAM-1 in endothelial cells, whereas CD146 and ICAM-1 were also recorded in some muscle fibers. In DM, sE-selectin, sP-selectin, and sPECAM-1 were significantly increased, with abnormal expression of ICAM-1 in endothelial cells and perifascicular muscle fibers. In the small group of s-IBM samples, results were similar to PM, but the only significant increase was the level of sPECAM-1. Immunoblots confirmed increased expression of PECAM-1 and CD146 in all IIM muscles in comparison to controls, with the highest expression in PM and IBM samples. CONCLUSION: We observed abnormal increases of soluble levels of adhesion molecules implicated in endothelial cell junctions in PM (sCD146, sPECAM-1) and to a lesser extent in DM and s-IBM (sPECAM-1). We conclude that the distinctly different profiles between PM/s-IBM and DM reflect differences in the pathophysiological background of these diseases.

CD146 Antigen↗
PubMed2004

Combination of histopathological and electromyographic patterns can help to evaluate functional outcome of critical ill patients with neuromuscular weakness syndromes.

INTRODUCTION: The aim of the study was to describe patterns of neuromuscular weakness using a combination of electromyography and histology, and to evaluate functional outcome in patients following complicated cardiovascular surgery. METHODS: Fifteen adults requiring long-term mechanical ventilation (>15 days) following cardiovascular surgery associated with postoperative complications were prospectively included. Electrophysiological and histological analyses (muscle and nerve) were performed when failure to wean from mechanical ventilation associated with peripheral neuromuscular weakness was noticed. Functional disability was evaluated 12 months after surgery. RESULTS: Six patients had a predominantly axonal neuropathy, six presented with myopathy, and three patients had a combination of axonal neuropathy and myopathy. All of them presented with acute tetraparesis and failure to wean from mechanical ventilation. All of the study patients who received corticosteroids exhibited a myopathic pattern (with or without axonopathic changes) but never an axonopathic pattern only. Only two of the eight survivors at 12 months were not ambulatory. These two patients had no detectable compound muscle action potential on electrophysiological examination. CONCLUSION: The combination of electromyographic evaluation and neuromuscular histological abnormalities could help to identify the type and severity of neuromuscular weakness, in turn helping to evaluate the patient's potential functional prognosis.

Adult↗
PubMed2004

Multiminicore disease in a family susceptible to malignant hyperthermia: histology, in vitro contracture tests, and genetic characterization.

BACKGROUND: Histological anomalies associated with malignant hyperthermia (MH) have been scarcely reported. In some patients susceptible to MH (MHS), central cores have been identified and a genetic association has been proposed, but multiminicore lesions have not been systematically reported. OBJECTIVE: To analyze the association between multiminicores and MHS in a large family with MH with an approach combining histology, in vitro contracture tests, and genetic analysis. PATIENTS AND METHODS: Twenty-nine members of an MH family (147 members) were investigated. MAIN OUTCOME MEASURES: Muscle biopsy specimens were analyzed histologically and with in vitro contracture tests. Genetic analyses were performed to determine the presence of mutations in the ryanodine receptor (RYR1) gene. RESULTS: According to the gold standard in vitro contracture tests, 17 patients were diagnosed as having MHS and 10 as not being susceptible. Multiminicores were found in 16 of the 17 MHS patients and in a single nonsusceptible participant. A linkage between the MH trait and the RYR1 locus in chromosome 19 was demonstrated, whereas no already known mutations were found. Two missense heterozygous mutations (R2676W and T2787S) were identified from sequencing of the entire coding complementary DNA. Overall, we found a significant association between MHS and the presence of multiminicores (chi(2) = 26.5, P<.001) on the one hand and the presence of new mutations in the RYR1 gene (chi(2) = 19.0, P<.001) on the other hand. This remarkably high occurrence of multiminicores in an MHS family is uncommon, and genetic analyses indicate that the association between multiminicores and MHS is linked to a novel R2656W and T2787S substitution present on the same allele of the RYR1 gene. CONCLUSIONS: These results indicate that multiminicore lesions are observed in MHS patients with neither clinical signs related to multiminicore disease nor histological features of congenital myopathies. These multiminicore lesions may be secondary to mutations in the RYR1 gene. As a consequence, these patients must be distinguished from patients with multiminicore disease and from other MHS patients for whom multiminicores are not observed.

DNA Mutational Analysis↗
PubMed2004

Focal myositis associated with S-1 radiculopathy: report of two cases.

Two cases are described of pseudotumoral calf hypertrophy after laminectomy for a compressive S-1 radiculopathy. The serum creatine kinase (CK) level was normal or mildly elevated. T2-weighted magnetic resonance imaging (MRI) showed calf enlargement, with an increased signal of the medial head of the gastrocnemius muscle. Electromyography revealed fibrillation potentials and positive sharp waves, but no complex repetitive discharges in the affected gastrocnemius muscle, with motor unit potentials having mixed neurogenic and myopathic features. Muscle biopsy revealed a focal myositis associated with some features of denervation. A brief course of corticosteroids was followed by remission clinically and improvement in the MRI findings.

Adult↗
PubMed2004

Pellagra: a rare disease observed in a victim of mental and physical abuse.

Lesions of the brain stem and cerebellum due to nutritional deficiencies are mostly seen in chronic alcohol abuse and more rarely in severe malnutrition. We report the case of a 27-year-old woman, found dead in the family flat. She presented cachexia (167 cm, 25 kg) and multiple hematomas of the limbs. Postmortem examination revealed lesions due to peritonitis. Neuropathological examination showed severe atrophy of the corpus callosum and central neuronal chromatolysis, which are observed in pellagra. Inflammatory colitis or celiac disease was not found. Toxicological analysis was negative, in particular no alcohol absorption. Pellagra, which is due to nicotinamide deficiency, is a disease rarely seen in this country. In this case, nutritional deficiency was the consequence of failure to eat in a context of abuse. The woman was born of an incestuous relationship and presented intellectual retardation due to poor affective relations with her mother.

Adult↗
PubMed2003

Cytokines, chemokines, and cell adhesion molecules in inflammatory myopathies.

The inflammatory myopathies include dermatomyositis (DM), polymyositis (PM), and sporadic inclusion-body myositis (s-IBM). In DM, the main immune effector response appears to be humoral and directed against the microvasculature, whereas in both PM and s-IBM, cytotoxic CD8+ T cells and macrophages invade and eventually destroy nonnecrotic muscle fibers expressing major histocompatibility complex class I. The need for more specific and safer therapies in inflammatory myopathies has prompted researchers to better decipher the molecular events associated with inflammation and muscle fiber loss in these diseases. The complex specific migration of leukocyte subsets to target tissues requires a coordinated series of events, namely activation of leukocytes, adhesion to the vascular endothelium, and migration. Cell adhesion molecules (CAM) and chemokines play a major role in this multistep process. In addition, cytokines by stimulating CAM expression and orchestrating T-cell differentiation also influence the immune response. This review focuses on recent advances in defining the molecular events involved in leukocyte trafficking in inflammatory myopathies. Specific topics include a concise summary of clinical features, pathological findings and immunopathology observed in inflammatory myopathies, background information about cytokines, chemokines and cell adhesion molecules, and the expression of these molecules in inflammatory myopathies.

Cell Adhesion Molecules↗
PubMed2003

[BK virus-induced tubulo-interstitial nephritis in a renal transplant recipient].

We present a case of renal BK virus infection with renal allograft dysfunction. Renal allograft biopsy showed mononuclear infiltrates in the interstitium and viral inclusions in the tubular epithelial cells. Infected cells were stained with an anti-polyomavirus antibody. The polymerase chain reaction (PCR) performed on blood, urine, and on the DNA extracted from renal tissue showed the presence of the BK virus DNA sequence. The immunosuppressive therapy including tacrolimus, prednisone, and mycophenolate mofetil was reduced leading to an improvement of the renal function. BK virus infection is now recognized as a cause of renal allograft dysfunction, and has been observed with increasing frequency in recent years. Reactivation of the latent virus occurs in immunocompromised hosts such as organ recipients with immunosuppressive treatment. Histologically, renal BK virus infection is characterized by a lymphocytic interstitial infiltrate, and could mimic acute rejection. The pathologist should diagnose the viral infection and may be helped by urine cytology and immunohistochemistry. An accurate diagnosis is important because antirejection therapy favors the decline of the renal function. Enhanced new immunotherapy protocols seem to be the main risk factor for this infection. The response to reduced immunosuppression is variable with reports of an end stage renal failure in 70% of the patients after 18 months.

Adult↗
PubMed2002

Intracranial meningeal melanocytoma associated with ipsilateral nevus of Ota. Case report.

In this report, the authors review the case of a man with a neurocutaneous syndrome. He presented with an intracerebral melanocytoma associated with a blue nevus of the scalp; its location and its appearance during childhood supported the diagnosis of a nevus of Ota. Meningeal melanocytomas are increasingly being diagnosed, but remain rare. Primary meningeal malignant melanoma is the first differential diagnosis to eliminate. Despite their common embryonic origin. the association of a melanocytoma with a nevus of Ota is rare. A nevus of Ota exhibits the same melanocytic proliferation and affects the trigeminal nerve territory. An ocular effect is not always observed. In contrast to an ocular lesion, a nevus of Ota rarely transforms into a malignant melanoma. It is found only among caucasians. During 4 years of follow-up review after surgery, the patient remained asymptomatic. Other than antiepileptic therapy, he received no complementary treatment and cerebral imaging revealed no evidence of recurrence.

Adult↗
PubMed2002

[Dysferlinopathy. Example of a new myopathy].

Over the past 10 years, the impact of modern microscopic pathology and molecular genetics on the knowledge of myopathies has been enormous. Dysferlinopathy is a good example. Dysferlin is a surface membrane protein without homology with known mammalian protein excepted otoferlin. It is encoded by a gene on chromosome 2. Miyoshi myopathy and limb girdle muscular dystrophy 2B have been reported to arise from defects in the same genetic locus (chromosome 2p 13). Some personal different examples are presented with typical features, high level of creatine kinase. Gene mutations, immunoblot and immunohistochemistry allow the diagnosis. Three clinical phenotypes are separated: distal myopathy, proximal myopathy, entire lower limbs posterior compartment amyotrophy. Structural changes are mild. Inflammation is not unusual and leads to the diagnosis of polymyositis. There are no correlation genotype-phenotype.

Dysferlin↗