Publisher Correction: Anti-AMPA GluA3 antibodies in Frontotemporal dementia: a new molecular target.

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Anti-AMPA GluA3 antibodies in Frontotemporal dementia: a new molecular target.

Frontotemporal Dementia (FTD) is a neurodegenerative disorder mainly characterised by Tau or TDP43 inclusions. A co-autoimmune aetiology has been hypothesised. In this study, we aimed at defining the pathogenetic role of anti-AMPA GluA3 antibodies in FTD. Serum and cerebrospinal fluid (CSF) anti-GluA3 antibody dosage was carried out and the effect of CSF with and without anti-GluA3 antibodies was tested in rat hippocampal neuronal primary cultures and in differentiated neurons from human induced pluripotent stem cells (hiPSCs). TDP43 and Tau expression in hiPSCs exposed to CSF was assayed. Forty-one out of 175 screened FTD sera were positive for the presence of anti-GluA3 antibodies (23.4%). FTD patients with anti-GluA3 antibodies more often presented presenile onset, behavioural variant FTD with bitemporal atrophy. Incubation of rat hippocampal neuronal primary cultures with CSF with anti-GluA3 antibodies led to a decrease of GluA3 subunit synaptic localization of the AMPA receptor (AMPAR) and loss of dendritic spines. These results were confirmed in differentiated neurons from hiPSCs, with a significant reduction of the GluA3 subunit in the postsynaptic fraction along with increased levels of neuronal Tau. In conclusion, autoimmune mechanism might represent a new potentially treatable target in FTD and might open new lights in the disease underpinnings.

Intrafamilial phenotypic variability in Andersen-Tawil syndrome: A diagnostic challenge in a potentially treatable condition.

Andersen-Tawil syndrome (ATS) is a rare autosomal dominant channelopathy characterized by periodic paralysis, cardiac dysrhythmias, and distinct facial and skeletal characteristics, that may be variably present in the affected members. Mutations in the KCNJ2 and KCNJ5 gene have been associated with this disorder. We describe a family in which several members presented with different ATS phenotypes. The proband, a 4-year-old boy, presented with recurrent episodes of muscle weakness from an early age; two siblings suffered cardiac arrhythmia but had never experienced episodes of paralysis; their mother reported occasional muscle pain after exercise and unspecified cardiac arrhythmias. The analysis of KCNJ2 gene in the proband disclosed the presence of a pathogenic mutation (p.R218W), that was subsequently confirmed in the other affected subjects. Our results underline the possible intrafamilial phenotypic variability, ranging from full clinical triad to exclusive cardiac or muscular involvement, representing a diagnostic challenge that may also delay adequate management. There are still limited data on the treatment of ATS; in our patient there was clinical improvement with dichlorphenamide.

ClC-1 mutations in myotonia congenita patients: insights into molecular gating mechanisms and genotype-phenotype correlation.

KEY POINTS: Loss-of-function mutations of the skeletal muscle ClC-1 channel cause myotonia congenita with variable phenotypes. Using patch clamp we show that F484L, located in the conducting pore, probably induces mild dominant myotonia by right-shifting the slow gating of ClC-1 channel, without exerting a dominant-negative effect on the wild-type (WT) subunit. Molecular dynamics simulations suggest that F484L affects the slow gate by increasing the frequency and the stability of H-bond formation between E232 in helix F and Y578 in helix R. Three other myotonic ClC-1 mutations are shown to produce distinct effects on channel function: L198P shifts the slow gate to positive potentials, V640G reduces channel activity, while L628P displays a WT-like behaviour (electrophysiology data only). Our results provide novel insight into the molecular mechanisms underlying normal and altered ClC-1 function. ABSTRACT: Myotonia congenita is an inherited disease caused by loss-of-function mutations of the skeletal muscle ClC-1 chloride channel, characterized by impaired muscle relaxation after contraction and stiffness. In the present study, we provided an in-depth characterization of F484L, a mutation previously identified in dominant myotonia, in order to define the genotype-phenotype correlation, and to elucidate the contribution of this pore residue to the mechanisms of ClC-1 gating. Patch-clamp recordings showed that F484L reduced chloride currents at every tested potential and dramatically right-shifted the voltage dependence of slow gating, thus contributing to the mild clinical phenotype of affected heterozygote carriers. Unlike dominant mutations located at the dimer interface, no dominant-negative effect was observed when F484L mutant subunits were co-expressed with wild type. Molecular dynamics simulations further revealed that F484L affected the slow gate by increasing the frequency and stability of the H-bond formation between the pore residue E232 and the R helix residue Y578. In addition, using patch-clamp electrophysiology, we characterized three other myotonic ClC-1 mutations. We proved that the dominant L198P mutation in the channel pore also right-shifted the voltage dependence of slow gating, recapitulating mild myotonia. The recessive V640G mutant drastically reduced channel function, which probably accounts for myotonia. In contrast, the recessive L628P mutant produced currents very similar to wild type, suggesting that the occurrence of the compound truncating mutation (Q812X) or other muscle-specific mechanisms accounted for the severe symptoms observed in this family. Our results provide novel insight into the molecular mechanisms underlying normal and altered ClC-1 function.

Exposure to a low dose of bisphenol A impairs pituitary-ovarian axis in prepubertal rats: effects on early folliculogenesis.

The research work studies the effect of providing a low dose of bisphenol A (BPA), on the reproductive axis of prepubertal female rats. Wistar mated rats were treated with either 0.1% ethanol or BPA in their drinking water until their offspring were weaned on the 21 day of birth. The estimated average dose of exposure to dams was approximately 3µg/kg/day. The pups were sacrificed at the 30th day of life. Body weight at the moment of the sacrifice was significantly higher in the group exposed to BPA; ovarian weight and its relative weight were not modified. LH and estradiol levels increased significantly, meanwhile FSH ones showed no significant changes. The number of primary, secondary and atretic follicles increased and antral ones was decreased. Our results demonstrated that early exposure to a low dose of BPA disrupts the normal function of the reproductive axis in prepubertal female rats.

Long-term follow-up in infantile-onset lambert-eaton myasthenic syndrome.

Lambert-Eaton myasthenic syndrome is a neuromuscular junction disorder characterized by proximal limb muscle weakness, fatigability, decreased deep-tendon reflexes, and autonomic symptoms. There are 2 forms of Lambert-Eaton myasthenic syndrome: one most frequently associated with small-cell lung cancer (P-Lambert-Eaton myasthenic syndrome) and the other that is a pure autoimmune form (NP-Lambert-Eaton myasthenic syndrome). Lambert-Eaton myasthenic syndrome is a very rare disorder in children younger than age 12 years. Herein, we report a 25-year-old man with NP-Lambert-Eaton myasthenic syndrome, which onset was at the age of 10 years. To date, this is the most long-term follow-up of NP-Lambert-Eaton myasthenic syndrome in childhood. In our patient, the only symptomatic treatment with 3,4-diaminopyridine phosphate has been sufficient to guarantee him a good quality of life. Our data remind physicians to keep in mind the diagnosis of Lambert-Eaton myasthenic syndrome in children with a proximal myopathic pattern and they confirm the specificity of compound muscle action potential incremental pattern after brief maximal effort in Lambert-Eaton myasthenic syndrome.

Type I interferon and Toll-like receptor expression characterizes inflammatory myopathies.

OBJECTIVES: Juvenile dermatomyositis (JDM), adult dermatomyositis, and polymyositis (PM) are idiopathic inflammatory myopathies (IIMs) characterized by muscle infiltration and specific muscle fiber alterations. They are thought to have an autoimmune etiology, but triggering factors, and how immunologic attack induces muscle weakness, remain unknown. Recent evidence suggests a key role for type I interferon (IFN)-mediated innate immunity in dermatomyositis, which we explored in JDM, dermatomyositis, and PM by gene expression profiling, and other methods. METHODS: Ten IIM and 5 control muscle biopsies were assessed for expression of approximately 16,000 genes by microarray; 37 additional IIM, 10 dystrophinopathic, and 14 nonmyopathic control muscles were studied for type I IFN-dependent genes, and Toll-like receptor (TLR) expression by immunochemistry and PCR. RESULTS: Type I IFN-dependent transcripts were significantly upregulated in IIM muscles compared to controls; in JDM the most expressed were ISG15 (408-fold), IFIT3 (261-fold), MX1 (99-fold), and IRF7 (37-fold). IFN-ß (but not IFN-α) transcripts were upregulated in PM as well as dermatomyositis/JDM. TLR3 was upregulated particularly in JDM, being localized on vascular endothelial cells, muscle infiltrating cells (mainly myeloid dendritic cells), and regenerating myofibers; TLR7 and TLR9 proteins were present in IIM (prominently in PM), mainly on cell infiltrates, particularly plasma cells, and on some injured myofibers. CONCLUSIONS: IFN-ß and type I IFN-induced molecules are involved in PM as well as JDM/dermatomyositis. Endosomal TLRs (effectors of innate immunity) are also involved (but differently) in the 3 conditions, further suggesting viral involvement, although TLR activation could be secondary to tissue damage.

Detection of poliovirus-infected macrophages in thymus of patients with myasthenia gravis.

BACKGROUND: Genetic and environmental factors are thought to contribute to the etiology of the autoimmune disease myasthenia gravis (MG). Viral involvement has long been suspected, but direct evidence of involvement has not been found. We recently reported that Toll-like receptor 4 (TLR4)-a key activator of innate immunity-was overexpressed in the thymus of some patients with MG, suggesting that thymic infection by pathogens might be involved in MG pathogenesis. We searched for evidence of intrathymic infection in patients with MG. METHODS: Twenty-seven MG thymuses (6 involuted, 7 hyperplastic, 5 thymitis, and 9 thymoma) previously tested for TLR4 expression, 18 nonpathologic control thymuses, and 10 pathologic control thymuses from patients without MG (8 thymoma and 2 hyperplastic) were analyzed for cytomegalovirus, varicella-zoster virus, herpes simplex virus types 1 and 2, eubacteria, respiratory syncytial virus, and enteroviruses using PCR techniques. Immunohistochemistry and double immunofluorescence were used to detect enterovirus capsid protein VP1 in thymic specimens and analyze TLR4 expression in VP1-positive cells. RESULTS: Poliovirus was detected in 4 MG thymuses (14.8%; 2 thymitis and 2 thymoma). No virus was detected in any control thymus. A linear correlation between plus and minus strand poliovirus RNA levels was observed in all 4 thymuses, suggesting persistent thymic infection. VP1 protein was detected in the cytoplasm of CD68-positive macrophages scattered through thymic medulla in all PV-positive thymuses. VP1 and TLR4 colocalized in infected cells. CONCLUSIONS: Poliovirus-infected macrophages are present in thymus of some patients with myasthenia gravis, suggesting a viral contribution to the intrathymic alterations leading to the disease.

Risk of arrhythmia in type I myotonic dystrophy: the role of clinical and genetic variables.

OBJECTIVE: To examine the association between the presence of arrhythmia in type 1 myotonic dystrophy (DM1) and clinical-genetic variables, evaluating their role as predictors of the risk of arrhythmia. METHODS: 245 patients with genetically proven DM1 underwent clinical and non-invasive cardiological evaluation. Severity of muscular involvement was assessed according to the 5 point Muscular Disability Rating Score (MDRS). Data were analysed by univariate and multivariate models. RESULTS: 245 patients were examined and cardiac arrhythmias were found in 63 subjects, 40 of whom required a device implant. Statistical analyses revealed that men had more than double the risk of developing arrhythmias compared with women (p = 0.018). Addition of each year of age caused an increased risk of arrhythmia equal to 3% (p = 0.030). Subjects with MDRS 5 had a risk of arrhythmia 12 times higher than patients with MDRS 1-2 (p<0.001). Although all of these variables were significantly associated with cardiac rhythm dysfunction, they had a low sensitivity for the prediction of arrhythmic risk CONCLUSION: Male sex, age and muscular disability were strongly associated with the development of arrhythmia in DM1. However, all of these variables were weak predictors of arrhythmic risk. These results suggest that other factors may be involved in the development of cardiac conduction abnormalities in DM1.

A hybrid electroabsorption modulator device for generation of high spectral-efficiency optical modulation formats.

We report a novel hybrid integrated optic device consisting of AlGaInAs/InP electroabsorption modulators and a four-arm silica-on-silicon planar lightwave circuit optical interferometer. The device is designed for generation of high spectral efficiency optical modulation formats. We demonstrate generation of 21.4 Gb/s quadrature phase shift keyed optical signals with electrical data drives of 2V(pp) amplitudes, achieving a bit error rate of 10(-9) with the required optical signal to noise ratio of ~18 dB in a 0.1 nm resolution bandwidth.

[Visual acuity and magnification requirement after ranibizumab in patients with wet age-related macular degeneration]. / Fernvisus und Vergrösserungsbedarf nach Ranibizumab bei Patienten mit feuchter altersbedingter Makuladegeneration.

BACKGROUND: The purpose of this study was to examine the visual outcome by measuring visual acuity (VA) and magnification requirement (MR) in patients with wet AMD after repeated intravitreal injections of ranibizumab. PATIENTS AND METHODS: A total of 195 eyes were treated with repeated intravitreal injections of ranibizumab "as needed". VA (Snellen chart) and MR (SZB reading chart) at baseline of 114 eyes with occult or minimally classic lesions, 42 eyes with predominantly classic lesions and 39 with retinal angiomatous proliferations (RAP) were compared at 3 and 6 months after beginning of treatment. RESULTS: The whole group of 195 patients with wet AMD (688 intravitreal injections within 6 months) demonstrated a mean improvement of VA of 0.72 lines after 3 months (p < 0.001) and 1.54 lines after 6 months (p < 0.001) and a mean improvement of MR of 0.59 log units after 3 months (p < 0.001) and 0.73 log units after 6 months (p < 0.001). Mean change in VA after 3 and 6 months demonstrated a significant improvement (p < 0.001 to p < 0.05) for eyes with occult CNV (+ 0.8 /+ 1.6 lines) and RAP (+ 1.2 /+ 1.9 lines) whereas mean improvement in VA for classic CNV (+ 0.02 /+ 0.87 lines) did not reach significance compared to baseline. Comparable results were obtained for the mean change of MR after 3 and 6 months for eyes with occult CNV (+ 0.75 log units/+ 0.92 log units). For eyes with RAP mean improvement of MR was + 0.74 log units after 3 months (p < 0.05) and it was not significant with + 0.8 log units after 6 months (p > 0.05). MR did not show a significant change during follow-up for classic CNV. Apart from eyes with classic CNV, in more than 90 % of the eyes both VA and MR remained stable or improved (loss < 3 lines in VA or deterioration of MR of < 3 log units). Although 45 % of the eyes with predominantly classic CNV had received photodynamic therapies with Verteporfin prior to the intravitreal injections with ranibizumab, MR remained stable in 80 % over 6 months. CONCLUSION: With repeated injections of ranibizumab "as needed", VA could be improved as well as MR could be lowered in a majority of patients with wet AMD and therefore reading ability could be optimized. Over 6 months the treatment frequency was lower compared to the monthly administration.

Immunochemotherapy with in vivo purging and autotransplant induces long clinical and molecular remission in advanced relapsed and refractory follicular lymphoma.

BACKGROUND: To evaluate the clinical outcome of patients with relapsed or refractory follicular lymphoma treated with immunochemotherapy, in vivo purging and high-dose therapy with autotransplant. PATIENTS AND METHODS: Sixty-four patients were enrolled in the trial. Primary end point was progression-free survival (PFS). Secondary end points were the in vivo purging effect on stem-cell harvest and the impact of molecular response on the outcome. RESULTS: At enrollment, 59% of patients were PCR+ for bcl-2 rearrangement in bone marrow (PCR-informative). After the immunochemotherapy, before mobilization, 97% obtained complete response or partial response and 87% of patients informative for bcl-2 were molecularly negative. Sixty-one patients proceeded to in vivo purging and peripheral blood stem cell (PBSC) mobilization with rituximab and high-dose AraC. The median number of CD34+ cells collected was 16.6 x 10(6)/kg. Of 33 PCR-informative patients, the harvests resulted in PCR- in all. Fifty-eight patients received high-dose therapy and autotransplant of in vivo purged PBSC. After a median follow-up of 3.5 years, 41 patients are in complete remission. Five-year PFS is 59%. CONCLUSION: This study demonstrates that patients with advanced relapsed or refractory follicular lymphoma treated with immunochemotherapy, in vivo purging and autotransplant may obtain long-lasting PFS. In bcl-2-positive patients, in vivo purging allows the harvest of lymphoma-free PBSC. Absence of the bcl-2 rearrangement after autotransplant is associated with persistent clinical remission.

First experience with the 2005 modified Gore Helex ASD occluder system.

We report about our initial experience for the in 2005 modified Helex (Gore) device for closure of atrial septal defects (ASD) and persistent foramen ovale (PFO). Major changes were made at the delivery system for simplifying the Helex implantation procedure. We treated 11 patients, 8 children and 3 adults, with ages between 3 and 62 years. In 10 patients the diagnosis was a relevant ASD with volume overload of the right heart (Left to right shunts between 30 and 50%). One adult (age 58 years) have had a small left to right shunt with a PFO-like defect and the history of 2 neurologic embolic events. In 3 patients we found 2 defects. In all patients a Helex occluder was implanted successfully. The mean fluoroscopy time was 8,4 minutes. The immediate occlusion rate after 24 hours was 91%. In all cases there was a very good adaptation of the device to the anatomical structures. In this small series, the Helex occluder appears to offer a reliable system of occlusion for small and moderate ASDs and for PFO with minimal risk of major complications.