Autoantibodies directed against the amino-terminal domain I of human calpastatin (ACAST-DI Ab) in connective tissue diseases. High levels of ACAST-DI Ab are associated with vasculitis in lupus

To identify new autoantibody populations in patients with rheumatic diseases, a cDNA expression library was immunoscreened with a rheumatoid arthritis (RA) patient's serum which contains autoantibodies binding to uncharacterized polypeptides by Western-blotting. One clone encoding the amino-terminal region (Nt) [domain L and half of domain I] of human calpastatin was selected. Different fragments of the selected cDNA were prepared and the corresponding recombinant polypeptides were produced by in vitro translation and analysed by Western blotting. Most RA sera bound to recombinant amino-terminal region and domain I but not to domain L. This prompted us to use a recombinant polypeptide corresponding to the domain I of calpastatin as the antigen in a solid-phase ELISA to test sera from patients with various systemic rheumatic diseases and healthy controls.Anti-calpastatin domain I antibodies (ACAST-DI Ab), were detected by ELISA in RA, systemic lupus erythematosus (SLE), Sj?gren's syndrome and control sera at respective frequencies of 10, 9, 0 and 1%. These Ab did not have prognostic value in early RA; high levels were significantly associated with vasculitis in SLE. Antibodies reacting with the calpastatin amino-terminal region are produced during systemic rheumatic diseases and are predominantly directed against domain I. High levels of these Ab may constitute a marker of vasculitis in SLE.     

A polymorphic variant of the gene coding desmoglein 1, the target autoantigen of pemphigus foliaceus, is associated with the disease

Two polymorphic markers were identified on the desmoglein 1 gene which encodes the autoantigen targeted by pathogenic antibodies in pemphigus foliaceus (PF), a cutaneous autoimmune blistering disease. The first marker, made of a variant haplotype of five mis-sense mutations located on the part of the gene encoding the fourth and fifth extracellular domains of the protein, is not associated with the disease. The second marker consists of a single silent T to C transition at position 809 and was found to be significantly more frequent (P = 0.015) in Caucasian PF patients (n = 36) than in controls (n = 98). Thus, pemphigus foliaceus constitutes another example of autoimmune disease in which the autoantigen polymorphism contributes to disease susceptibility.     

Expanding the clinical spectrum of STIP1 homology and U-box containing protein 1-associated ataxia

Journal of Neurology - STUB1 has been first associated with autosomal recessive (SCAR16, MIM# 615768) and later with dominant forms of ataxia (SCA48, MIM# 618093). Pathogenic variations in STUB1...     

Automatic analysis of single-channel sleep EEG: validation in healthy individuals

STUDY OBJECTIVE: To assess the performance of automatic sleep scoring software (ASEEGA) based on a single EEG channel comparatively with manual scoring (2 experts) of conventional full polysomnograms. DESIGN: Polysomnograms from 15 healthy individuals were scored by 2 independent experts using conventional R&K rules. The results were compared to those of ASEEGA scoring on an epoch-by-epoch basis. SETTING: Sleep laboratory in the physiology department of a teaching hospital. PARTICIPANTS: Fifteen healthy volunteers. MEASUREMENTS AND RESULTS: The epoch-by-epoch comparison was based on classifying into 2 states (wake/sleep), 3 states (wake/REM/ NREM), 4 states (wake/REM/stages 1-2/SWS), or 5 states (wake/REM/ stage 1/stage 2/SWS). The obtained overall agreements, as quantified by the kappa coefficient, were 0.82, 0.81, 0.75, and 0.72, respectively. Furthermore, obtained agreements between ASEEGA and the expert consensual scoring were 96.0%, 92.1%, 84.9%, and 82.9%, respectively. Finally, when classifying into 5 states, the sensitivity and positive predictive value of ASEEGA regarding wakefulness were 82.5% and 89.7%, respectively. Similarly, sensitivity and positive predictive value regarding REM state were 83.0% and 89.1%. CONCLUSIONS: Our results establish the face validity and convergent validity of ASEEGA for single-channel sleep analysis in healthy individuals. ASEEGA appears as a good candidate for diagnostic aid and automatic ambulant scoring.     

Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive death of cortical and spinal motor neurons, for which there is no effective treatment. Using a cell-based assay for compounds capable of preventing motor neuron cell death in vitro, a collection of approximately 40,000 low-molecular-weight compounds was screened to identify potential small-molecule therapeutics. We report the identification of cholest-4-en-3-one, oxime (TRO19622) as a potential drug candidate for the treatment of ALS. In vitro, TRO19622 promoted motor neuron survival in the absence of trophic support in a dose-dependent manner. In vivo, TRO19622 rescued motor neurons from axotomy-induced cell death in neonatal rats and promoted nerve regeneration following sciatic nerve crush in mice. In SOD1(G93A) transgenic mice, a model of familial ALS, TRO19622 treatment improved motor performance, delayed the onset of the clinical disease, and extended survival. TRO19622 bound directly to two components of the mitochondrial permeability transition pore: the voltage-dependent anion channel and the translocator protein 18 kDa (or peripheral benzodiazepine receptor), suggesting a potential mechanism for its neuroprotective activity. TRO19622 may have therapeutic potential for ALS and other motor neuron and neurodegenerative diseases.     

The serotonin-N-acetylserotonin–melatonin pathway as a biomarker for autism spectrum disorders

Elevated whole-blood serotonin and decreased plasma melatonin (a circadian synchronizer hormone that derives from serotonin) have been reported independently in patients with autism spectrum disorders (ASDs). Here, we explored, in parallel, serotonin, melatonin and the intermediate N-acetylserotonin (NAS) in a large cohort of patients with ASD and their relatives. We then investigated the clinical correlates of these biochemical parameters. Whole-blood serotonin, platelet NAS and plasma melatonin were assessed in 278 patients with ASD, their 506 first-degree relatives (129 unaffected siblings, 199 mothers and 178 fathers) and 416 sex- and age-matched controls. We confirmed the previously reported hyperserotonemia in ASD (40% (35–46%) of patients), as well as the deficit in melatonin (51% (45–57%)), taking as a threshold the 95th or 5th percentile of the control group, respectively. In addition, this study reveals an increase of NAS (47% (41–54%) of patients) in platelets, pointing to a disruption of the serotonin-NAS–melatonin pathway in ASD. Biochemical impairments were also observed in the first-degree relatives of patients. A score combining impairments of serotonin, NAS and melatonin distinguished between patients and controls with a sensitivity of 80% and a specificity of 85%. In patients the melatonin deficit was only significantly associated with insomnia. Impairments of melatonin synthesis in ASD may be linked with decreased 14-3-3 proteins. Although ASDs are highly heterogeneous, disruption of the serotonin-NAS–melatonin pathway is a very frequent trait in patients and may represent a useful biomarker for a large subgroup of individuals with ASD.     

Neurogenic pain relief by repetitive transcranial magnetic cortical stimulation depends on the origin and the site of pain

OBJECTIVE: Drug resistant neurogenic pain can be relieved by repetitive transcranial magnetic stimulation (rTMS) of the motor cortex. This study was designed to assess the influence of pain origin, pain site, and sensory loss on rTMS efficacy. PATIENTS AND METHODS: Sixty right handed patients were included, suffering from intractable pain secondary to one of the following types of lesion: thalamic stroke, brainstem stroke, spinal cord lesion, brachial plexus lesion, or trigeminal nerve lesion. The pain predominated unilaterally in the face, the upper limb, or the lower limb. The thermal sensory thresholds were measured within the painful zone and were found to be highly or moderately elevated. Finally, the pain level was scored on a visual analogue scale before and after a 20 minute session of "real" or "sham" 10 Hz rTMS over the side of the motor cortex corresponding to the hand on the painful side, even if the pain was not experienced in the hand itself. RESULTS: and discussion: The percentage pain reduction was significantly greater following real than sham rTMS (-22.9% v -7.8%, p = 0.0002), confirming that motor cortex rTMS was able to induce antalgic effects. These effects were significantly influenced by the origin and the site of pain. For pain origin, results were worse in patients with brainstem stroke, whatever the site of pain. This was consistent with a descending modulation within the brainstem, triggered by the motor corticothalamic output. For pain site, better results were obtained for facial pain, although stimulation was targeted on the hand cortical area. Thus, in contrast to implanted stimulation, the target for rTMS procedure in pain control may not be the area corresponding to the painful zone but an adjacent one. Across representation plasticity of cortical areas resulting from deafferentation could explain this discrepancy. Finally, the degree of sensory loss did not interfere with pain origin or pain site regarding rTMS effects. CONCLUSION: Motor cortex rTMS was found to result in a significant but transient relief of chronic pain, influenced by pain origin and pain site. These parameters should be taken into account in any further study of rTMS application in chronic pain control.