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Sequencing of the IL6 gene in a case-control study of cerebral palsy in children.

ABSTRACT: BACKGROUND: Cerebral palsy (CP) is a group of nonprogressive disorders of movement and posture caused by abnormal development of, or damage to, motor control centers of the brain. A single nucleotide polymorphism (SNP), rs1800795, in the promoter region of the interleukin-6 (IL6) gene has been implicated in the pathogenesis of CP by mediating IL-6 protein levels in amniotic fluid and cord plasma and within brain lesions. This SNP has been associated with other neurological, vascular, and malignant processes as well, often as part of a haplotype block. METHODS: To refine the regional genetic association with CP, we sequenced (Sanger) the IL6 gene and part of the promoter region in 250 infants with CP and 305 controls. RESULTS: We identified a haplotype of 7 SNPs that includes rs1800795. In a recessive model of inheritance, the variant haplotype conferred greater risk (OR?=?4.3, CI?=?[2.0-10.1], p?=?0.00007) than did the lone variant at rs1800795 (OR?=?2.5, CI?=?[1.4-4.6], p?=?0.002). The risk haplotype contains one SNP (rs2069845, CI?=?[1.2-4.3], OR?=?2.3, p?=?0.009) that disrupts a methylation site. CONCLUSIONS: The risk haplotype identified in this study overlaps with previously identified haplotypes that include additional promoter SNPs. A risk haplotype at the IL6 gene likely confers risk to CP, and perhaps other diseases, via a multi-factorial mechanism.

SUBMITTER: Khankhanian P

PROVIDER: S-EPMC3881497 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Sequencing of the IL6 gene in a case-control study of cerebral palsy in children.

Khankhanian Pouya P Baranzini Sergio E SE Johnson Britt A BA Madireddy Lohith L Nickles Dorothee D Croen Lisa A LA Wu Yvonne W YW

BMC medical genetics 20131207

<h4>Background</h4>Cerebral palsy (CP) is a group of nonprogressive disorders of movement and posture caused by abnormal development of, or damage to, motor control centers of the brain. A single nucleotide polymorphism (SNP), rs1800795, in the promoter region of the interleukin-6 (IL6) gene has been implicated in the pathogenesis of CP by mediating IL-6 protein levels in amniotic fluid and cord plasma and within brain lesions. This SNP has been associated with other neurological, vascular, and ...[more]

PMID: 24314052

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Project description:BackgroundStochastic Resonance (SR) Stimulation has been used to enhance balance in populations with sensory deficits by improving the detection and transmission of afferent information. Despite the potential promise of SR in improving postural control, its use in individuals with cerebral palsy (CP) is novel. The objective of this study was to investigate the immediate effects of electrical SR stimulation when applied in the ankle muscles and ligaments on postural stability in children with CP and their typically developing (TD) peers.MethodsTen children with spastic diplegia (GMFCS level I- III) and ten age-matched TD children participated in this study. For each participant the SR sensory threshold was determined. Then, five different SR intensity levels (no stimulation, 25, 50, 75, and 90% of sensory threshold) were used to identify the optimal SR intensity for each subject. The optimal SR and no stimulation condition were tested while children stood on top of 2 force plates with their eyes open and closed. To assess balance, the center of pressure velocity (COPV) in anteroposterior (A/P) and medial-lateral (M/L) direction, 95% COP confidence ellipse area (COPA), and A/P and M/L root mean square (RMS) measures were computed and compared.ResultsFor the CP group, SR significantly decreased COPV in A/P direction, and COPA measures compared to the no stimulation condition for the eyes open condition. In the eyes closed condition, SR significantly decreased COPV only in M/L direction. Children with CP demonstrated greater reduction in all the COP measures but the RMS in M/L direction during the eyes open condition compared to their TD peers. The only significant difference between groups in the eyes closed condition was in the COPV in M/L direction.ConclusionsSR electrical stimulation may be an effective stimulation approach for decreasing postural sway and has the potential to be used as a therapeutic tool to improve balance. Applying subject-specific SR stimulation intensities is recommended to maximize balance improvements. Overall, balance rehabilitation interventions in CP might be more effective if sensory facilitation methods, like SR, are utilized by the clinicians.Trial registrationClinicalTrials.gov identifier NCT02456376; 28 May 2015 (Retrospectively registered); https://clinicaltrials.gov/ct2/show/NCT02456376 .

Project description:Cerebral palsy is primarily an upper motor neuron disease that results in a spectrum of progressive movement disorders. Secondary to the neurological lesion, muscles from patients with cerebral palsy are often spastic and form debilitating contractures that limit range of motion and joint function. With no genetic component, the pathology of skeletal muscle in cerebral palsy is a response to aberrant neurological input in ways that are not fully understood. This study was designed to gain further understanding of the skeletal muscle response to cerebral palsy using microarrays and correlating the transcriptional data with functional measures. Hamstring biopsies from gracilis and semitendinosus muscles were obtained from a cohort of patients with cerebral palsy (n=10) and typically developing patients (n=10) undergoing surgery. Affymetrix HG-U133A 2.0 chips (n=40) were used and expression data was verified for 6 transcripts using quantitative real-time PCR, as well as for two genes not on the microarray. Chips were clustered based on their expression and those from patients with cerebral palsy clustered separately. Significant genes were determined conservatively based on the overlap of three summarization algorithms (n=1,398). Significantly altered genes were analyzed for over-representation among gene ontologies, transcription factors, pathways, microRNA and muscle specific networks. These results centered on an increase in extracellular matrix expression in cerebral palsy as well as a decrease in metabolism and ubiquitin ligase activity. The increase in extracellular matrix products was correlated with mechanical measures demonstrating the importance in disability. These data lay a framework for further studies and novel therapies. Skeletal muscle biopsies from both the gracilis and semitendinosus were obtained during surgery for 20 pediatric subjects for affymetrix microarray analysis. We obtained a group of 10 patients undergoing medial hamstring lengthening in the cerebral palsy group and 10 patients undergoing ACL reconstruction with hamstring autograft in the control group. This provided 40 microarrays in 4 groups to analyze the effect of cerebral palsy and also differences between muscles.

Project description:To assess the effects of radial extracorporeal shock wave therapy (rESWT) on plantar flexor muscle spasticity and gross motor function in very young patients with cerebral palsy (CP).The design was case-control study (level of evidence 3).The setting was the Department of Pediatric Neurology and Neurorehabilitation, First Hospital of Jilin University, Changchun, China.Those with a diagnosis of CP and spastic plantar flexor muscles were recruited between April 2014 and April 2015.According to the parents' decision, patients received 1 ESWT session per week for 3 months, with 1500 radial shock waves per ESWT session and leg with positive energy flux density of 0.03 mJ/mm, combined with traditional conservative therapy (rESWT group) or traditional conservative therapy alone (control group).The Modified Ashworth Scale (MAS) (primary outcome measure) and passive range of motion (pROM) measurements were collected at baseline (BL), 1 month (M1), and 3 months (M3) after BL. The Gross Motor Function Measure (GMFM)-88 was collected at BL and M3.Sixty-six patients completed the final review at 3 months and were included in the study. Subjects ranged in age from 12 to 60 months (mean age 27.0 ± 13.6 months; median age 22.0 months; 33.3% female). For the rESWT group (n = 34), mean MAS grades at BL, M1, and M3 were 2.6, 1.9, and 1.5 on the left side and 1.9, 1.7, and 1.2 on the right side. For the control group (n = 32), mean MAS grades at BL, M1, and M3 were 2.5, 2.4, and 2.1 on the left side and 1.8, 1.8, and 1.5 on the right side. The within-subject effects time × side and time × treatment were statistically significant (P < 0.01). Similar results were found for the improvement of mean pROM. GMFM-88 improved from BL to M3, but showed no statistically significant difference between the groups. There were no significant complications.This study demonstrates that the combination of rESWT and traditional conservative therapy is more effective than traditional conservative therapy alone in the treatment of spasticity in very young patients with CP.

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Sequencing of the IL6 gene in a case-control study of cerebral palsy in children.

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Sequencing of the IL6 gene in a case-control study of cerebral palsy in children.

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