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Biomedical subjects

M Nicolle

Publications and source records attributed to M Nicolle.

At least 19 recordsLinked to original sources
PubMed2004

Improvement of Shack-Hartmann wave-front sensor measurement for extreme adaptive optics.

The development of high-performance adaptive optics systems requires the optimization of wave-front sensors (WFSs) working in the high-order correction regime. We propose a new method to improve the wave-front slope estimation of a Shack-Hartmann WFS in such a regime. Based on a detailed analysis of the different errors in the slope estimation with a classical centroid and with the new method, the gain in terms of wave-front-sensing accuracy in both the detector and the photon noise regimes is stressed. This improvement is proposed without major system disruption.

Journal Article↗
PubMed2004

Distinct phenotypes of congenital acetylcholine receptor deficiency.

We contrast the phenotypes associated with hereditary acetylcholine receptor deficiency arising from mutations in either the acetylcholine receptor epsilon subunit or the endplate acetylcholine receptor clustering protein rapsyn. Mutational screening was performed by amplification of promoter and coding regions by PCR and direct DNA sequencing. We identified mutations in 37 acetylcholine receptor deficiency patients; 18 had acetylcholine receptor-epsilon mutations, 19 had rapsyn mutations. Mutated acetylcholine receptor-epsilon associated with bulbar symptoms, ptosis and ophthalmoplegia at birth, and generalized weakness. Mutated rapsyn caused either an early onset (rapsyn-EO) or late onset (rapsyn-LO) phenotype. Rapsyn-EO associated with arthrogryposis and life-threatening exacerbations during early childhood. Rapsyn-LO presented with limb weakness in adolescence or adulthood resembling seronegative myasthenia gravis. Awareness of distinct phenotypic features of acetylcholine receptor deficiency resulting from acetylcholine receptor-epsilon or rapsyn mutations should facilitate targeted genetic diagnosis, avoid inappropriate immunological therapy and, in some infants, prompt the rapid introduction of treatment that could be life saving.

4-Aminopyridine↗
PubMed2003

Rapsyn mutations in hereditary myasthenia: distinct early- and late-onset phenotypes.

Rapsyn mutations in 16 unrelated patients with a congenital/hereditary myasthenic syndrome were identified, and a mutation (N88K) common to each of them was found. Two distinct phenotypes were noted: early and late onset. The former is frequently associated with arthrogryposis multiplex congenita and life-threatening crises. The late-onset phenotype developed in adolescence or adulthood and was initially mistaken for seronegative myasthenia gravis. Recognition of this late-onset phenotype should prevent inappropriate immunotherapy.

Adolescent↗
PubMed2000

Increasing the number of hepatitis B vaccine injections augments anti-HBs response rate in HIV-infected patients. Effects on HIV-1 viral load.

Preventing hepatitis B by vaccination is essential in HIV-infected patients (higher progression rate of HBV infection to chronicity, lower rate of serum HBe Ag loss). However, it has been shown a decreased anti-HBs response in these individuals after a standard vaccination (3 doses of 20 micrograms). Thus, we tested the hypothesis that doubling the number of hepatitis B vaccine injections might increase anti-HBs response rate. HIV-infected patients with CD4 > 200/microliter, who were on stable antiretroviral treatment, as well as seronegative for HBV markers, and who have never been vaccinated against HBV, were given 3 intramuscular injections of Genhevac B 20 micrograms at 1 month intervals. Initial non responders were given 3 additional monthly injections. Anti-HBs titer was followed. We also evaluated the effects on HIV-1 viral load. Twenty patients with a median CD4 cell count of 470/microliter were enrolled. The response rate after three 20 micrograms injections was 55% (11/20), lower in individuals with CD4 between 200 and 500/microliter (4/12 = 33.3%), compared to patients with CD4 above 500/microliter (7/8 = 87.5%, P = 0.02). Among 9 initial non-responders, only 2 did not respond to 3 additional doses; thus, the overall response rate was 90% (18/20). Geometric mean titers of anti-HBs were 133 IU/l and 77.5 IU/l, after 3 and 6 Genhevac doses, respectively (P = 0.38). One year later, only 10/17 (58.8%) patients had protective anti-HBs. Five patients experienced a significant viral load increase, transient in 3 cases. These preliminary results suggest that doubling the number of hepatitis B vaccinations in HIV-infected patients might significantly improve anti-HBs response rate; however, close monitoring of anti-HBs is necessary because of its short-lived persistence. The effects on HIV-1 viral load are limited.

Adult↗
PubMed2000

[Emergence of resistant hepatitis B virus strains during long-term lamivudine therapy in human immunodeficiency virus co-infected patients].

Seven patients co-infected with hepatitis B virus (HBsAg and HBeAg carriers, quantifiable HBV DNA with the bDNA technic) and human immunodeficiency virus received a triple antiretroviral combination therapy, including lamivudine (150 mg twice a day). Hepatitis B viral load rapidly became undetectable in 6/7 patients. It remained below the level of detection in 2 subjects, after 20 and 22 months of treatment, with one of them achieving HBeAg/anti-HBe seroconversion. However, in the other 4 individuals, hepatitis B viremia increased again after 8 to 16 months of lamivudine-containing regimen. The last patient was a non-responder. The 4 relapsers developed a double mutation Leu(528) for Met(528) and Met(552) for Val(552), on hepatitis B virus polymerase, either concomitant (M8 and M16) with a hepatitis B virus DNA increase, or 2 months earlier (M10 and M12). The high frequency of hepatitis B virus resistance to lamivudine emphasizes the necessity of identifying more effective strategies, such as double combination therapies.

Adult↗
PubMed1999

Cross-restriction of a T cell clone to HLA-DR alleles associated with rheumatoid arthritis: clues to arthritogenic peptide motifs.

OBJECTIVE: To identify distinctive sequence motifs required for productive peptide presentation by those HLA-DR alleles/DR4 subtypes that predispose to rheumatoid arthritis (RA). METHODS: We tested 10 different HLA-DR4 subtypes for presentation of acetylcholine receptor peptides to 8 different DR4-restricted T cell lines/clones in proliferation assays. RESULTS: Seven of the 8 T cells depended absolutely on either the autologous Lys71 (in Dw4) or Arg71 (e.g., Dw14), despite these alleles' similar charge and RA associations. In contrast, the PM-A T cell was only mildly affected by this interchange. Moreover, after minor modifications, peptides were presented to this unusual T cell preferentially by all the RA-associated subtypes of DR4 as well as by 2 other DR alleles (DR1 and DR1402) that predispose to RA. CONCLUSION: This coincident cross-restriction to all the RA-associated HLA-DR alleles except DR10 shows that there could even be a single arthritogenic peptide; we now suggest a possible consensus motif.

Alleles↗
PubMed1999

Distant interactions between dimorphisms in HLA-DR4 radically affect recognition of defined peptides by a specific T cell clone.

Several isolated dimorphisms recur in many HLA class II alleles, but it is not clear whether they merely influence the binding of peptides locally or have more general effects on their recognition by T cells. For example, interchanges in HLA-DRbeta include 86Gly <--> Val and 57Asp <--> Ser at either end of its alpha helix, and 71Arg <--> Lys in the middle. In DR4, the existence of six subtypes differing by single substitutions at these sites enabled us to assess their functional effects--both in isolation and in their natural context--on peptide presentation to a specific T cell clone with unusually broad cross-restrictions. Unexpectedly, the restriction imposed by 86Val was much more severe in the context of 71Arg than 71Lys, but was also more readily overcome by reducing the bulk of the 'p1' peptide 'anchor' residue (149Trp --> Phe). Moreover, when there was also a distant 57Asp-->Ser substitution, compensating similarly for 86Val proved much more difficult. Thus 86Val and 57Ser in combination had far more drastic effects on peptide presentation than they did separately, when peptide binding was also largely unchanged. These and other interactions with position 71 together provide strong evidence that the configuration of the peptide-DR4 complex is critical for T cell recognition, which could be affected by subtle conformational influences on the p1-9 core of the peptide or on the alpha helix of DR4beta (between positions 86 and 57). Ideally, therefore, the effects of individual class II substitutions should be considered in their natural context rather than in isolation.

Alleles↗
PubMed1996

Alterations in opiate receptor binding in the hippocampus of aged Long-Evans rats.

Quantitative in vitro autoradiography was used to examine [3H]D-Ala2, MePhe4, Gly-015 enkephalin (DAGO) (mu-agonist) and [3H]diprenorphine (general opiate antagonist) binding sites in the hippocampal formation of young (6-8 months) and aged (25-28 months) Long-Evans rats. Age-related changes in these binding sites were restricted to specific regions but were not generally dependent on the ligand used. No reliable age-related changes in opiate binding were observed in the CA1 field or subicular region. In contrast, a decrease in the density of binding was found in both dorsal and ventral hippocampus within the CA3 field of aged brains. An age-related decrease in opiate binding within the dentate gyrus differed in its topography at dorsal and ventral levels of the hippocampus. A uniform decrease of opiate receptor binding was found throughout the dorsal dentate gyrus, while a more localized decrease of these sites occurred in hilar and granular layers of the ventral dentate gyrus. These results indicate that a decrease of opiate binding in the hippocampal formation is largely localized to the CA3 region and dentate gyrus of aged rats. These findings are discussed with reference to age-related changes in hippocampal pathways containing opioid peptides. The implications for hippocampal opioid function in learning and age-related cognitive decline are also considered.

Age Factors↗
PubMed1995

Peptide-selected T cell lines from myasthenia gravis patients and controls recognize epitopes that are not processed from whole acetylcholine receptor.

To study pathogenic T helper cells in myasthenia gravis (MG) reacting against the acetylcholine receptor (AChR), we have previously selected five CD4+ T cell lines/clones from MG patients (or healthy controls) against full-length recombinant human AChR alpha subunit (alpha 1-437); these can all recognize AChR solubilized from human muscle. Recently, T cells selected with pooled AChR subunit synthetic peptides have shown greater heterogeneity than above. Hoping to validate that, we have characterized three MG and six control T cell lines selected with pooled peptides (averaging 33 residues long) covering the alpha subunit sequence; recurring responses to three particular peptides each showed preferred HLA class II restrictions--p75-115/DR4, p138-167/DR4, and p309-344/DR3 (or DR52a). However, none of three lines from MG patients recognized p138-167--even one from a previous responder to this epitope in full-length alpha 1-437; otherwise they resembled those from controls. Moreover, no peptide-selected line responded significantly to whole AChR, alpha 1-437, or even to shorter polypeptides sharing one terminus with the peptide, suggesting specificity for epitopes not naturally processed by APCs from blood. Of 20 sublines maintained with individual peptides, at least 10 responded to independently synthesized overlapping sequences, but four others depended on contaminants in the original peptides. A single line did recognize one longer polypeptide, but only after tryptic digestion; the processing of this cryptic epitope was evidently the limiting factor here rather than its concentration or the T cell sensitivity. Therefore, while synthetic peptides are essential for mapping epitopes, assessment of the pathogenic MG T cell repertoire requires full-length Ag processed naturally.

Amino Acid Sequence↗
PubMed1993

Presentation of endogenous acetylcholine receptor epitope by an MHC class II-transfected human muscle cell line to a specific CD4+ T cell clone from a myasthenia gravis patient.

Muscle or thymic myoid cells, if induced to express MHC class II in addition to endogenous acetylcholine receptor (AChR), might present epitopes derived from the AChR to specific CD4+ T cells. These T cells could in turn initiate or maintain the anti-AChR response that is responsible for AChR loss in myasthenia gravis (MG). We transfected the AChR+ TE671 (rhabdomyosarcoma) cells with HLA-DR4 and co-cultured them with the DR4-restricted, CD4+ T cell clone (PM-A1; raised from a hyperplastic thymus of an MG patient and previously shown to recognise all forms of the AChR that contain the sequence alpha 144-156). Significant T cell activation, demonstrated both by 3H-thymidine incorporation and by lysis of the TE671 cells, was found in the presence of added alpha 144-156 and, more importantly, in the absence of exogenous antigen. These results show that MHC class II-expressing muscle or other AChR-expressing cells could present endogenous AChR to pathogenic T cells. This process may be important in the aetiology of MG.

Antigen-Presenting Cells↗