Functional Variant in Complement C3 Gene Promoter and Genetic Susceptibility to Temporal Lobe Epilepsy and Febrile Seizures

BACKGROUND: Human mesial temporal lobe epilepsies (MTLE) represent the most frequent form of partial epilepsies and are frequently preceded by febrile seizures (FS) in infancy and early childhood. Genetic associations of several complement genes including its central component C3 with disorders of the central nervous system, and the existence of C3 dysregulation in the epilepsies and in the MTLE particularly, make it the C3 gene a good candidate for human MTLE. METHODOLOGY/PRINCIPAL FINDINGS: A case-control association study of the C3 gene was performed in a first series of 122 patients with MTLE and 196 controls. Four haplotypes (HAP1 to 4) comprising GF100472, a newly discovered dinucleotide repeat polymorphism [(CA)8 to (CA)15] in the C3 promoter region showed significant association after Bonferroni correction, in the subgroup of MTLE patients having a personal history of FS (MTLE-FS+). Replication analysis in independent patients and controls confirmed that the rare HAP4 haplotype comprising the minimal length allele of GF100472 [(CA)8], protected against MTLE-FS+. A fifth haplotype (HAP5) with medium-size (CA)11 allele of GF100472 displayed four times higher frequency in controls than in the first cohort of MTLE-FS+ and showed a protective effect against FS through a high statistical significance in an independent population of 97 pure FS. Consistently, (CA)11 allele by its own protected against pure FS in a second group of 148 FS patients. Reporter gene assays showed that GF100472 significantly influenced C3 promoter activity (the higher the number of repeats, the lower the transcriptional activity). Taken together, the consistent genetic data and the functional analysis presented here indicate that a newly-identified and functional polymorphism in the promoter of the complement C3 gene might participate in the genetic susceptibility to human MTLE with a history of FS, and to pure FS. CONCLUSIONS/SIGNIFICANCE: The present study provides important data suggesting for the first time the involvement of the complement system in the genetic susceptibility to epileptic seizures and to epilepsy

Migrants in Chains: On the Enslavement of Muslims in Renaissance and Enlightenment Europe

religion

An Ancien régime revisited : “Privatization” and political economy in the Eighteenth-Century Ottoman Empire

Donated by Klaus Kreise

The locations of stroke lesions next to the posterior internal capsule may predict the recovery of the related proprioceptive deficits

Background: Somatosensory deficits after stroke correlate with functional disabilities and impact everyday-life. In particular, the interaction of proprioception and motor dysfunctions affects the recovery. While corticospinal tract (CST) damage is linked to poor motor outcome, much less is known on proprioceptive recovery. Identifying a predictor for such a recovery could help to gain insights in the complex functional recovery processes thereby reshaping rehabilitation strategies. Methods: 50 patients with subacute stroke were tested before and after neurological rehabilitation. Proprioceptive and motor impairments were quantified with three clinical assessments and four hand movement and proprioception measures using a robotic device. Somatosensory evoked potentials (SSEP) to median nerve stimulation and structural imaging data (MRI) were also collected. Voxel-based lesion-symptom mapping (VLSM) along with a region of interest (ROI) analysis were performed for the corticospinal tract (CST) and for cortical areas. Results: Before rehabilitation, the VLSM revealed lesion correlates for all clinical and three robotic measures. The identified voxels were located in the white matter within or near the CST. These regions associated with proprioception were located posterior compared to those associated with motor performance. After rehabilitation the patients showed an improvement of all clinical and three robotic assessments. Improvement in the box and block test was associated with an area in anterior CST. Poor recovery of proprioception was correlated with a high lesion load in fibers towards primary sensorymotor cortex (S1 and M1 tract). Patients with loss of SSEP showed higher lesion loads in these tracts and somewhat poorer recovery of proprioception. The VSLM analysis for SSEP loss revealed a region within and dorsal of internal capsule next to the posterior part of CST, the posterior part of insula and the rolandic operculum. Conclusions: Lesions dorsal to internal capsule next to the posterior CST were associated with proprioceptive deficits and may have predictive value. Higher lesion load was correlated with poorer restoration of proprioceptive function. Furthermore, patients with SSEP loss trended towards poor recovery of proprioception, the corresponding lesions were also located in the same location. These findings suggest that structural imaging of the internal capsule and CST could serve as a recovery predictor of proprioceptive function.ISSN:1662-453XISSN:1662-454

The locations of stroke lesions next to the posterior internal capsule may predict the recovery of the related proprioceptive deficits

BACKGROUND: Somatosensory deficits after stroke correlate with functional disabilities and impact everyday-life. In particular, the interaction of proprioception and motor dysfunctions affects the recovery. While corticospinal tract (CST) damage is linked to poor motor outcome, much less is known on proprioceptive recovery. Identifying a predictor for such a recovery could help to gain insights in the complex functional recovery processes thereby reshaping rehabilitation strategies. METHODS: 50 patients with subacute stroke were tested before and after neurological rehabilitation. Proprioceptive and motor impairments were quantified with three clinical assessments and four hand movement and proprioception measures using a robotic device. Somatosensory evoked potentials (SSEP) to median nerve stimulation and structural imaging data (MRI) were also collected. Voxel-based lesion-symptom mapping (VLSM) along with a region of interest (ROI) analysis were performed for the corticospinal tract (CST) and for cortical areas. RESULTS: Before rehabilitation, the VLSM revealed lesion correlates for all clinical and three robotic measures. The identified voxels were located in the white matter within or near the CST. These regions associated with proprioception were located posterior compared to those associated with motor performance. After rehabilitation the patients showed an improvement of all clinical and three robotic assessments. Improvement in the box and block test was associated with an area in anterior CST. Poor recovery of proprioception was correlated with a high lesion load in fibers towards primary sensorymotor cortex (S1 and M1 tract). Patients with loss of SSEP showed higher lesion loads in these tracts and somewhat poorer recovery of proprioception. The VSLM analysis for SSEP loss revealed a region within and dorsal of internal capsule next to the posterior part of CST, the posterior part of insula and the rolandic operculum. CONCLUSION: Lesions dorsal to internal capsule next to the posterior CST were associated with proprioceptive deficits and may have predictive value. Higher lesion load was correlated with poorer restoration of proprioceptive function. Furthermore, patients with SSEP loss trended towards poor recovery of proprioception, the corresponding lesions were also located in the same location. These findings suggest that structural imaging of the internal capsule and CST could serve as a recovery predictor of proprioceptive function