Identification of the novel HLA-A*30:221 allele by next-generation sequencing.

The novel HLA-A*30:221 allele differs from HLA-A*30:01:01:01 by one nucleotide substitution in Exon 7.

Identification of the novel HLA-A*30:181 allele by next-generation sequencing.

HLA-A*30:181 differs from HLA-A*30:01:01 by one nucleotide substitution in Exon 4832 G to A.

A new HLA-B allele, HLA-B*07:422.

The novel allele HLA-B*07:422 differs from HLA-B*07:02:01:01 by one nucleotide substitution in exon 4.

A new HLA-DQA1 allele, HLA-DQA1*01:26.

The novel allele HLA-DQA1*01:26 differs from HLA-DQA1*01:01:01:01 by one nucleotide substitution in exon 2.

Characterization of the novel HLA-DQA1*01:27 allele by sequencing-based typing.

HLA-DQA1*01:27 differs from HLA-DQA1*01:01:01:01 by one nucleotide substitution in codon 221 in exon 4.

Automatic detection of cataplexy.

OBJECTIVE: Although being the most specific symptom of narcolepsy type 1 (NT1), cataplexy is currently investigated by clinical interview only, with potential diagnostic pitfalls. Our study aimed at testing the accuracy of an automatic video detection of cataplexy in NT1 patients vs. non-cataplectic subjects undergoing a standardized test with emotional stimulation. METHODS: Fifteen drug-naive NT1 patients and 15 age- and sex-balanced non-cataplectic subjects underwent a standardized video recording procedure including emotional stimulation causing laughter. Video recordings were visually inspected by human scorers to detect three typical cataplexy facial motor patterns (ptosis, mouth opening and head drop), and then analysed by SHIATSU (Semantic-based HIearchical Automatic Tagging of videos by Segmentation using cUts). Expert-based and automatic attack detection was compared in NT1 patients and non-cataplectic subjects. RESULTS: All NT1 patients and none of the non-cataplectic subjects displayed cataplexy during emotional stimulation. Automatic detection correlated well with experts' assessments in NT1 with an overall accuracy of 81%. In non-cataplectic subjects, automatic detection falsely identified cataplexy in two out of 15 (13.3%) subjects who showed active eyes closure during intense laughter as a confounder with ptosis. CONCLUSIONS: Automatic cataplexy detection by applying SHIATSU to a standardized test for video documentation of cataplexy is feasible, with an overall accuracy of 81% compared to human examiners. Further studies are warranted to enlarge the range of elementary motor patterns detected, analyse their temporal/spatial relations and quantify cataplexy for diagnostic purposes.

B vitamin deficiency promotes tau phosphorylation through regulation of GSK3beta and PP2A.

Neurofibrillary tangles (NFTs), composed of intracellular filamentous aggregates of hyperphosphorylated protein tau, are one of the pathological hallmarks of Alzheimer's disease (AD). Tau phosphorylation is regulated by the equilibrium between activities of its protein kinases and phosphatases; unbalance of these activities is proposed to be a reasonable causative factor to the disease process. Glycogen synthase kinase 3beta (GSK3beta) is one of the most important protein kinase in regulating tau phosphorylation; overexpression of active GSK3beta causes ADlike hyperphosphorylation of tau. Protein phosphatase 2A (PP2A) is the major phosphatase that dephosphorylates tau; it was demonstrated that highly conserved carboxyl-terminal sequence of PP2A C-subunit is a focal point for phosphatase regulation. This is the site of a reversible methyl esterification reaction that controls AB_{alpha}C heterotrimers formation. Here we demonstrate that GSK3beta and PP2A genes were upregulated by inhibiting methylation reactions through B vitamin deficiency. In this condition, methylated catalytic subunit PP2Ac was decreased, leading to reduced PP2A activity. By contrast, we observed GSK3beta protein increase and a modulation in phosphorylation sites that regulate GSK3beta activity. Therefore, one-carbon metabolism alteration seems to be a cause of deregulation of the equilibrium between GSK3beta and PP2A, leading to abnormal hyperphosphorylated tau.

Autoantibodies in patients with monoclonal gammopathies.

Although autoantibody activities are rather often associated to monoclonal gammopathies, only monoclonal immunoglobulins of the IgM isotype are really directed against autoantigens that are often polysaccharides or are formed by highly repetitive structures. This strict association is frequently revealed also by clinical manifestations of the autoimmune response generated by the monoclonal macroglobulin. Most monoclonal immunoglobulins of non-IgM isotype are instead totally inactive toward self-antigens, the autoantibody activity being instead associated, if present, to polyclonal immunoglobulins. Although the same BAFF/APRIL system is involved in perpetuation of humoral autoimmunity as well as in stimulation of clonal B-cell expansion, the autoimmune commitment of B cells of a non-IgM isotype is hardly compatible with their possible involvement in an uncontrolled proliferation pathway, whose prerequisite is the homing of these B cells to the bone marrow compartment. The IgM-secreting cells appear instead to possess a much lower tendency, and/or a looser requirement, for their homing in the bone marrow prior to their actual proliferation. This may explain the quite different consequences, in terms of autoimmunity, between IgM and non-IgM paraproteinemias.