GABAA receptor and anti-titin antibody encephalitis in a patient with thymoma.

Autoimmune encephalitis (AE) associated to antibodies against GABA A R is a rare form of encephalitis. On the other hand, thymoma has been linked to antibodies against both muscular and neuronal epitopes, even if concurrent positivity for more than one antibody is exceptional, and their contribution to the clinical course and treatment decision is unclear. We report a case of a 73-year-old male with AE associated with thymoma secreting both anti-GABAaR and anti-titin antibodies. Clinical presentation included status epilepticus, behavioural changes and cognitive decline. While the status was stopped with lacosamide, AE treatment included first- and second-line immunomodulation, in addition to thymoma's removal. Nonetheless, the patient experienced a worsening in cognitive and behavioural status.

Incidence of neuroepithelial primary brain tumors among adult population of Emilia-Romagna Region, Italy.

Incidence of neuroepithelial Primary Brain Tumors (nPBT) varies, ranging from 7.3 to 11.6 cases/100,000/year across Europe. We present incidence and survival of nPBT in the Emilia-Romagna region (ER), Italy. This study is the largest in Southern Europe. Specialists in neurosurgery, neurology, neuroradiology, oncology, radiotherapy, genetics, and pathology of ER notified all suspected nPBT adult cases residing in ER (4,337,966 inhabitants) observed during 2009. Furthermore, through ICD-9 discharge codes, we identified and reviewed all possible cases. Neuroepithelial PBT diagnosis was based on histological or radiological findings. We included 400 incident nPBT cases, of which 102 (25%) were retrospectively identified. These latter were significantly older. The standardized incidence was 10.5/100,000/year (95% CI 9.4-11.5), higher for men. It was 9.2/100,000/year (95% CI 8.3-10.2) for astrocytic tumors, 0.6/100,000/year (95% CI 0.4-0.9) for oligodendroglial tumors, and 7.1 (95% CI 6.3-8.0) for glioblastoma (GBM). Among GBM patients, median survival was 249 days if prospectively identified vs. 132 days when identified through ICD-9 codes (p < 0.0001). The incidence of nPBT in the ER region is among the highest in the literature. Older patients were more likely to escape an active surveillance system. This should be considered when comparing incidence rates across studies, giving the increasing number of elderly people in the general population.

Inhibition of ubiquitin proteasome system rescues the defective sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA1) protein causing Chianina cattle pseudomyotonia.

A missense mutation in ATP2A1 gene, encoding sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA1) protein, causes Chianina cattle congenital pseudomyotonia, an exercise-induced impairment of muscle relaxation. Skeletal muscles of affected cattle are characterized by a selective reduction of SERCA1 in sarcoplasmic reticulum membranes. In this study, we provide evidence that the ubiquitin proteasome system is involved in the reduced density of mutated SERCA1. The treatment with MG132, an inhibitor of ubiquitin proteasome system, rescues the expression level and membrane localization of the SERCA1 mutant in a heterologous cellular model. Cells co-transfected with the Ca(2+)-sensitive probe aequorin show that the rescued SERCA1 mutant exhibits the same ability of wild type to maintain Ca(2+) homeostasis within cells. These data have been confirmed by those obtained ex vivo on adult skeletal muscle fibers from a biopsy from a pseudomyotonia-affected subject. Our data show that the mutation generates a protein most likely corrupted in proper folding but not in catalytic activity. Rescue of mutated SERCA1 to sarcoplasmic reticulum membrane can re-establish resting cytosolic Ca(2+) concentration and prevent the appearance of pathological signs of cattle pseudomyotonia.

Effects of in vivo applications of peripheral blood-derived mesenchymal stromal cells (PB-MSCs) and platlet-rich plasma (PRP) on experimentally injured deep digital flexor tendons of sheep.

Tendon injuries, degenerative tendinopathies, and overuse tendinitis are common in races horses. Novel therapies aim to restore tendon functionality by means of cell-based therapy, growth factor delivery, and tissue engineering approaches. This study examined the use of autologous mesenchymal stromal cells derived from peripheral blood (PB-MSCs), platelet-rich plasma (PRP) and a combination of both for ameliorating experimental lesions on deep digital flexor tendons (DDFT) of Bergamasca sheep. In particular, testing the combination of blood-derived MSCs and PRP in an experimental animal model represents one of the few studies exploring a putative synergistic action of these treatments. Effectiveness of treatments was evaluated at 30 and 120 days comparing clinical, ultrasonographic, and histological features together with immunohistochemical expression of collagen types 1 and 3, and cartilage oligomeric matrix protein (COMP). Significant differences were found between treated groups and their corresponding controls (placebo) regarding tendon morphology and extracellular matrix (ECM) composition. However, our results indicate that the combined use of PRP and MSCs did not produce an additive or synergistic regenerative response and highlighted the predominant effect of MSCs on tendon healing, enhanced tissue remodeling and improved structural organization.

KDM2B is implicated in bovine lethal multi-organic developmental dysplasia.

In the last decade breeders of Romagnola cattle observed an outbreak of a new congenital anomaly. This lethal multi-organ developmental dysplasia is mainly characterized by facial deformities, ascites and hepatic fibrosis. Affected stillborn calves were inbred to a single founder sire suggesting autosomal monogenic recessive inheritance. We localized the causative mutation to a 1.2 Mb interval on BTA 17 by genome-wide association and identical by descent mapping. A solution-based method for targeted DNA capture combined with massively parallel sequencing was used to analyze the entire critical region containing 24 genes. Homozygosity for two non-synonymous coding sequence variants affecting the RNF34 and KDM2B genes was detected by evaluating one affected calf. Here we show that the disease phenotype is associated with a KDM2B missense mutation (c.2503G>A) leading to an amino acid exchange (p.D835N) in an evolutionary strongly conserved domain. In addition, the genetic makeup of three inbred cattle strongly supports the causality of the KDM2B mutation. This report of a naturally-occurring spontaneous mutation of a JmjC domain containing histone demethylase gene provides evidence for their important role in the endo- and mesodermal organ development.

Arachnomelia in Brown Swiss cattle maps to chromosome 5.

Arachnomelia in Brown Swiss cattle is a monogenic autosomal recessive inherited congenital disorder of the skeletal system giving affected calves a spidery look (OMIA ID 000059). Over a period of 20 years 15 cases were sampled in the Swiss and Italian Brown cattle population. Pedigree data revealed that all affected individuals trace back to a single acknowledged carrier founder sire. A genome scan using 240 microsatellites spanning the 29 bovine autosomes showed homozygosity at three adjacent microsatellite markers on bovine Chr 5 in all cases. Linkage analysis confirmed the localization of the arachnomelia mutation in the region of the marker ETH10. Fine-mapping and haplotype analysis using a total of 34 markers in this region refined the critical region of the arachnomelia locus to a 7.19-Mb interval on bovine Chr 5. The disease-associated IBD haplotype was shared by 36 proven carrier animals and allows marker-assisted selection. As the corresponding human and mouse chromosome segments do not contain any clear functional candidate genes for this disorder, the mutation causing arachnomelia in the Brown Swiss cattle might help to identify an unknown gene in bone development.

Familial epilepsy and developmental dysphasia: description of an Italian pedigree with autosomal dominant inheritance and screening of candidate loci.

PURPOSE: To describe a familial epileptic condition combining a peculiar electro-clinical pattern with developmental language dysfunction in a large Italian kindred. METHODS: We studied the clinical and neurophysiological features of a 4-generation family with 10 affected members (3 deceased). We also analysed in 7 affected and 7 healthy members microsatellite markers for 51 candidate loci for epilepsy, including 42 loci containing ion channel genes expressed in the brain, as well as the SPCH1 and SRPX2 loci. RESULTS: Five of the seven living affected members (aged 20-58 years) had the full phenotype (seizures, EEG epileptiform abnormalities and dysphasia). The language dysfunction was the first symptom, becoming evident since the period of language development and mainly consisting of phonemic and syntactic paraphasias, difficulty of expression and reduced verbal fluency. The seizures had their onset between 2 and 23 years and were reported as epileptic falls (4) associated or not with myoclonic features, absences (3), tonic-clonic (1) and complex partial seizures (1). The seizures were easily controlled by antiepileptic treatment in all patients except one. In the five patients with a good response of seizures to treatment, the EEG tracings showed the coexistence of focal and generalized epileptiform abnormalities; in the refractory patient the interictal EEG demonstrated bilateral asynchronous fronto-temporal paroxysms with left predominance and ictal SEEG recording suggested a multifocal origin of the discharges. MRI of the brain was normal in all patients. Linkage analysis provided negative LOD scores for all the investigated loci. CONCLUSION: We have described a novel familial pattern of epilepsy and developmental dysphasia which is not genetically linked to epilepsy or speech disorder loci, as documented by a candidate-gene linkage approach.