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ABSTRACT: Abnormally expanded C9orf72 hexanucleotide repeats are found in up to 7% of patients with sporadic amyotrophic lateral sclerosis (SALS). It is not known whether the sporadic nature of the disease represents incomplete penetrance of the phenotype or expansion of the repeat in the SALS patient. The sizes of C9orf72 hexanucleotide repeats were measured in blood DNA of 43 SALS patients and their parents who had no symptoms of ALS. Two SALS patients (4.7%) had abnormally expanded (>30 repeats) C9orf72 repeats. Both of their fathers (one with dementia) also had abnormally expanded repeats. Nine SALS patients had intermediate-normal repeat sizes (7-30 repeats); in each of these, one parent had a similar repeat size. In the remaining 32 SALS patients, the repeat sizes were low-normal (<7 repeats). There was no evidence of repeat instability leading to abnormal numbers of repeats in any SALS patient in this trio cohort. Our results suggest that a simple monogenic mechanism is not likely to be the cause of C9orf72 repeat-related SALS.
Neuroreport 05/2012; 23(9):556-9. · 1.66 Impact Factor
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ABSTRACT: To determine whether the combination of stochastic resonance (SR) electrical stimulation and a neoprene knee sleeve could improve center of pressure (COP) measures of postural sway during single-leg stance in those with knee osteoarthritis (OA).
Counterbalanced, repeated-measures intervention study of osteoarthritic adults during 6 different testing conditions: a control condition-control 1 (1); a counterbalance sequence of 4 treatment conditions-no stimulation with sleeve (2), 75% stimulation with sleeve (3), 100% stimulation with sleeve (4), and 150% stimulation with sleeve (5); and a second control condition-control 2 (6).
University sports medicine research laboratory.
Subjects (N=52) with radiographically determined, minimal-to-moderate medial knee OA.
Neoprene knee sleeve and SR electrical stimulation.
COP displacement in the medial-lateral and anterior-posterior directions was collected to resolve the mean velocity, SD, range, and total path length.
No significant differences were found in the study measures between the testing conditions. Additionally, no significant differences were found between the 3 stimulation conditions or between the sleeve-alone and stimulation conditions for any of the study measures.
There were no significant improvements in balance with the use of a neoprene knee sleeve. Additionally, there was no added benefit of the SR stimulation as applied in the current configuration in this population.
Archives of physical medicine and rehabilitation 03/2012; 93(7):1123-8. · 2.18 Impact Factor
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ABSTRACT: We have recently discovered that c-Jun executes a non-transcriptional function to stabilize hypoxia inducible factor 1α (HIF-1α) and that pseudolaric acid B (PAB) accelerates HIF-1α degradation and phosphorylates c-Jun at Ser63/73. In this study, PAB was used as a probe to investigate whether and how the Ser63/73 phosphorylation of c-Jun regulates its functions. The PAB-induced reduction of HIF-1α protein was rescued through supplying additional non-phosphorylated c-Jun. However, c-Jun siRNA, which reduced both the PAB-driven phosphorylated c-Jun and the total c-Jun protein, did not prevent the PAB-induced decrease in HIF-1α. HIF-1α was revealed to be co-immunoprecipitated only with the non-phosphorylated c-Jun. PAB increased the phosphorylated c-Jun while reducing the non-phosphorylated c-Jun at Ser63/73, which impaired its function in stabilizing HIF-1α. Consequently, PAB led to the degradation of HIF-1α, thus resulting in the decreased HIF-1α-dependent expression of mdr-1 and VEGF. We accordingly propose a function-converter model of c-Jun: the Ser63/73 phosphorylation serves as a function converter to convert c-Jun from its non-transcriptional function to its transcriptional function.
Journal of Molecular Medicine 03/2012; 90(8):971-81. · 4.67 Impact Factor
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ABSTRACT: Stimulator of interferon (IFN) genes (STING), also known as MPYS/MITA/ERIS/TMEM173, is a recently discovered adaptor protein that functions downstream of RIG-I and upstream of TBK1 and plays an important role in type I interferon (IFN) production. Mammalian STINGs have been isolated from human, mouse, pig, cattle and chimpanzee. In this study, the rat STING cDNA was cloned by degenerate PCR and rapid amplification of 3'-cDNA ends (3'-RACE) strategies. The full-length cDNA of rat STING consists of 1615 bp with a 1140-bp open reading frame (ORF). The predicted protein is composed of 379 amino acids and contains 2 putative transmembrane domains. The amino acid similarities between the STING from rat and other mammals range from 68% to 82%. Real-time quantitative PCR analysis indicated that rat STING mRNA was most abundant in the spleen, pancreas and lymph node. Overexpression of rat STING led to upregulation of IFN-β mRNA expression in IEC-6 cells. Rat STING mRNA was up-regulated when IEC-6 cells were transfected with poly (I:C). In addition, a miR-24 binding site in the 3'UTR of rat STING was identified. We also found that endogenous STING could be regulated post-transcriptionally by miR-24 in IEC-6 cells. These results are of importance to reveal the biological function of STING in rat animal model.
Developmental and comparative immunology 02/2012; 37(3-4):414-20. · 3.29 Impact Factor
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ABSTRACT: Eupolyphaga sinensis Walker popularly known as "preferred drug to regulate blood flow" are traditionally used in folk medicine in the treatment of ecchymoma, posttraumatic wound, hepatic fibrosis and tumor.
To characterize chemical compositions and to evaluate the antitumor and immunomodulatory of Eupolyphaga sinensis Walker ethanol extract (ESEE) in hepatocarcinoma H(22) bearing mice.
ESEE was obtained by ethanol reflux extraction and analyzed by gas chromatography-mass spectrometry (GC-MS) after methylation. ICR mice were treated with ESEE for 14 consecutive days at doses of 31mg/kg (low-dose), 62mg/kg (mid-dose) and 124mg/kg (high-dose) after H(22) tumor cells were implanted. At the end of the experiments, the tumor weight of each mouse was measured. Levels of serum TNF-α and IFN-γ was assayed by ELISA. Protein expressions of Bax, Bcl-2 and caspases-3 were detected by immunohistochemistry.
Chemical analysis revealed the presence of 6 components that account for 97.55% of fatty acids, indicating the occurrence of saturated and polyunsaturated fatty acids. Oral administration of ESEE could inhibit tumor growth, promote Th1 type cytokine productions (TNF-α and IFN-γ) and induce apoptosis of hepatocarcinoma via increase of Bax/Bcl-2 ratio and activation of caspases-3. Oral administration of ESEE in a dosage of 6.2g/kg did not lead to toxic effects in mice.
ESEE was effective in inhibiting tumor growth in vivo and could also serve as immunoadjuvant for tumor therapy.
Journal of ethnopharmacology 02/2012; 141(1):178-82. · 2.32 Impact Factor
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ABSTRACT: IFN-β promoter stimulator 1 (IPS-1) is an important adaptor protein linking RIG-I/MDA5 to the downstream signaling molecules and plays the pivotal role in type I interferons induction. In this study, we cloned and characterized Tibetan porcine IPS-1, investigated the tissue distribution, compared different messenger RNA expression for IPS-1 between Tibetan and Crossbred (Duroc × Yorkshire × Landrace) pigs (DLY). The Tibetan porcine IPS-1 gene was first cloned from spleen. The entire open reading frame (ORF) of the IPS-1 is 1,575 bp and encodes for 524 amino acid residues, has 1 putative transmembrane domains, with a higher degree of sequence similarity with common pig (99.37%) and cattle (81.23%) than with human (70.20%) or mouse (63.44%). Real-time quantitative PCR analysis indicated that Tibetan porcine IPS-1 mRNA was most abundant in the liver and kidney. The expression of IPS-1 of Tibetan pigs in most tissues was higher than DLY pigs.
Molecular Biology Reports 02/2012; 39(6):7011-7. · 2.93 Impact Factor
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ABSTRACT: Tibetan pig is well known for its strong disease resistance. However, little is known about the molecular basis of its strong resistance to disease. Stimulator of interferon (IFN) genes (STING), also known as MPYS/MITA/ERIS/TMEM173, is an adaptor that functions downstream of RIG-I and MAVS and upstream of TBK1 and plays a critical role in type I IFN induction. Here we report the first cloning and characterization of STING gene from Tibetan pig. The entire open reading frame (ORF) of the Tibetan porcine STING is 1137 bp, with a higher degree of sequence similarity with Landrace pig (98%) and cattle (88%) than with chimpanzee (84%), human (83%) or mouse (77%). The predicted protein is composed of 378 amino acids and has 4 putative transmembrane domains. Real-time quantitative PCR analysis indicated that Tibetan pig STING mRNA was most abundant in the lung and heart. Overexpression of Tibetan porcine STING led to upregulation of IFN-β and IFN-stimulated gene 15 (ISG15) in porcine jejunal epithelial cell line IPEC-J2 cells. This is the first study investigating the biological role of STING in intestinal epithelial cells, which lays a foundation for the further study of STING in intestinal innate immunity.
International Journal of Molecular Sciences 01/2012; 13(1):506-15. · 2.60 Impact Factor
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ABSTRACT: Distraction osteogenesis (DO) has been popular to improve hypoplastic mandible in patients with hemifacial microsomia in craniofacial surgery. However, changes in width of the lower face after DO still lack in literatures. The aim of this pilot study was to evaluate cephalometric changes in width of the lower face at different time points after DO and to give an insight into the influence on facial contour. A total of 10 patients (8 males and 2 females) with hemifacial microsomia received DO of the mandibular body measured by posteroanterior cephalograms. Five landmarks (crista galli, latero-orbitale, gonion of the unaffected side, incisor point superior of the unaffected maxilla, incisor point inferior of the unaffected side of the mandible) were chosen for cephalometric analysis. Six distances from the soft tissue contour perpendicularly to the vertical reference line (through crista galli) were calculated through the incisor point superior of the unaffected maxilla, gonion of the unaffected side, incisor point inferior of the unaffected side of the mandible. Measurements were taken preoperatively and postoperatively on the day distraction started (time 1), at the end of distraction (time 2), and at the end of the consolidation period (time 3). Calculations for statistical significance were done for all patients. Mean differences between 3 periods were measured by repeated-measures analysis with significance determined at the 0.05 level of confidence. The results suggested that the values of 6 distances at times 2 and 3 had no significant differences when compared with the values at time 1 (P>0.05). In conclusion, DO of the unilateral mandibular body in patients with hemifacial microsomia should not be beneficial to improve the width of the lower face at a short-term follow-up.
The Journal of craniofacial surgery 01/2012; 23(1):94-7. · 0.81 Impact Factor
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ABSTRACT: To evaluate the frequency of sensitization to Aspergillus antigens and the prevalence of allergic bronchopulmonary aspergillosis (ABPA) in asthmatic patients.
Two hundred consecutive non-smoking outpatients with asthma (≥ 18 years) underwent skin testing with aeroallergens, peripheral eosinophil counting, measurements of total serum IgE level and specific IgE against Aspergillus fumigatus, radiologic investigations and pulmonary function tests.
Eleven patients (5.5%) had a positive skin reactivity to Aspergillus antigens. Five of these 11 patients (45.5%) met the diagnostic criteria of ABPA, an overall prevalence of 2.5% (5/200). There were 2 males and 3 females, aging from 19 to 62 years, with a disease duration from 15 to 40 years. All of the patients had asthmatic symptoms such as cough and wheeze. Moderate to severe obstructive ventilatory defect was found in 4 patients. Total serum IgE levels and specific IgE against Aspergillus fumigates were elevated significantly in all the patients, and elevated eosinophil count was found in 3 patients. Three cases were diagnosed as ABPA-CB because of the presence of central bronchiectasis on HRCT.
The prevalence of ABPA in Chinese patients with asthma was underestimated. Clinical features of ABPA were similar to asthma alone, but with longer duration and more severe lung function defect. Sensitization to Aspergillus, increased eosinophils and total serum IgE levels were important indicators for the diagnosis of ABPA.
Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases 12/2011; 34(12):909-13.
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ABSTRACT: Sporadic Parkinson's disease (PD) is thought to have a major genetic component, but the variants involved remain mostly unknown. One possible reason for the difficulty in finding mutations underlying PD is that rare predominantly brain-situated somatic mutations underlie the disease; these mutations would be missed by analysing blood DNA only. To test the feasibility of looking for somatic mutations in PD brain tissue, we compared copy number variants (CNVs) between 8 PD and 26 control brains using Affymetrix 6.0 arrays. The median number of CNVs per brain, and the overall proportion of amplifications and deletions, were similar in PD and control brains. In 7 of the 8 PD brains, however, a total of 45 CNVs were found that were not present in control brains. Twelve of these CNVs overlapped with one or more genes, some of which are involved in pathways suspected in the pathogenesis of PD, or are rare. This study shows that PD brain CNVs can be detected, and raises the possibility that brain-situated mutations could underlie some cases of PD. A method of undertaking a definitive study of brain somatic mutations in PD, using massively parallel sequencing and multiple tissues, is suggested.
Parkinsonism & Related Disorders 09/2011; 18(1):82-5. · 3.80 Impact Factor
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ABSTRACT: Most analyses of blood DNA in sporadic neuromuscular disorders have been inconclusive. This may be because some genetic variants occur only in brain tissue. We therefore looked for copy number variants (CNVs) in both blood and brain in patients with sporadic amyotrophic lateral sclerosis (SALS).
Genome-wide CNVs were compared in blood and brain from 32 SALS patients and from 26 normal (control) brains, using Affymetrix 6.0 arrays.
There were 410 CNVs present in brain but not blood (somatic CNVs) in 94% of the patients (median 8 CNVs per patient). Twenty-four of the somatic CNVs were rare, were not found in control brains, and overlapped with genes.
Brain-specific CNVs may be common and appear to be present in a proportion of patients with SALS. The more detailed copy number analysis that is becoming available with massively parallel sequencing may uncover brain-specific CNVs that underlie some cases of SALS.
Muscle & Nerve 03/2011; 44(4):492-8. · 2.37 Impact Factor
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ABSTRACT: Rare de novo genetic variants have been detected in a number of diseases using case-parent trios. So far, trio studies have largely been confined to early-onset diseases where parent DNA samples are readily available. To test the feasibility of finding rare de novo variants in a typical late-onset neurodegenerative disease, we compared genome-wide copy number variants (CNVs) between patients with sporadic amyotrophic lateral sclerosis (SALS) and their unaffected parents. DNA from 12 SALS patients and their 24 parents was analysed for CNVs using AffyMetrix SNP 6.0 microarrays and Partek software. De novo CNVs (present in patients but not their parents) considered likely candidates for SALS were those that overlapped with CNS-related genes, were rare, or were found in multiple patients. All SALS patients had de novo CNVs. In 11 patients, 37 de novo CNVs fulfilled one or more criteria for a candidate region. Eleven de novo CNVs overlapped with genes, some of which are in pathways suspected in the pathogenesis of SALS. In conclusion, this pilot study shows that trios can be used to look for rare de novo genetic variants in patients with late adult-onset neurodegenerative disease. The results suggest that further studies of this nature with larger numbers of trios are warranted, but it is unusual to find surviving parents of offspring who have a late-onset neurodegenerative disease. An international collaborative effort will therefore be needed to collect sufficient numbers of such trios to reliably detect de novo mutations underlying these diseases.
Journal of neuroscience methods 03/2011; 197(2):297-301. · 2.30 Impact Factor
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06/2010; , ISBN: 9780470015902
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ABSTRACT: Somatic mutations have been suggested as a cause of sporadic amyotrophic lateral sclerosis (SALS). These mutations can be difficult to detect since they may involve only a small percentage of cells within the tissue, so we devised a method to detect low mutation levels in brain DNA. Different proportions of a known SOD1 mutation were prepared to determine the sensitivity of DHPLC. The fraction containing the mutant signal was collected and re-amplified ('enriched') to increase sensitivity and to dideoxy sequence the mutation. The combined technique was used to screen all exons and the promoter of SOD1 in 23 SALS brains. DHPLC could detect a known SOD1 mutation in 5% of a sample of brain tissue. Using our enrichment technique doubled the height of the mutant sequencing signal, which allowed identification of an unknown mutation in 10% of brain tissue. No SOD1 mutations were found in the SALS brains using this technique. In conclusion, combining DHPLC and sequencing doubles the sensitivity of sequencing alone and can detect low levels of known and unknown mutations in brain DNA. No SALS SOD1 somatic mutations were detected, but DHPLC would be useful in looking for somatic mutations in other SALS candidate genes.
Amyotrophic Lateral Sclerosis 01/2010; 11(1-2):76-82. · 3.40 Impact Factor
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ABSTRACT: All patients with sporadic amyotrophic lateral sclerosis (SALS) have TDP-43 inclusions in their motor neurons, suggesting this protein plays a major role in the disease. Coding mutations in the gene for TDP-43, TARDBP, have been found in only a few patients with SALS. However, the non-coding regulatory regions of TARDBP have not yet been examined in SALS. We therefore sequenced both coding and non-coding regions of TARDBP in 46 tissue-banked SALS brains (brain DNA was used to detect somatic mutations). Non-coding variants (in the promoter or intron 1) were detected in 16 patients (35%) and coding variants in 4 (9%). Two known promoter variants were found more frequently in SALS patients than in controls. Two other variants, found in one patient each but not in controls, have potential regulatory functions. In addition, a novel exon 2 change with predicted functional effects was found in one patient. In summary, variants in the promoter and other non-coding regions of TARDBP may disturb the regulation of this gene in some patients with SALS.
Neuromuscular Disorders 09/2009; 19(10):696-700. · 2.80 Impact Factor
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ABSTRACT: Genetic research is used to identify the relative contributions made by inherent abilities (nature) versus environmental effects (nurture) in human performance. The same approach allows a better understanding of how injuries or illnesses can result from sport or physical activity. Having identified the genes involved in athletic performance, there are the intriguing possibilities of using this information for talent search, developing individualized training programs and prevention of sports-related injuries.
There are many interacting genes involved in athletic performance. This class of genes is often described as 'complex' and the mode of inheritance is called 'multifactorial'. Discovery of these genes is difficult using the conventional case control (association) studies. Recent genomic-based developments allowing high throughput SNP analysis are very promising. Potentially more exciting is the availability in the near future of cheaper and faster whole-genome sequencing technologies.
Genetic research in exercise science has produced a lot of data including the ability to draw a human exercise gene map. However, progress at the genetic level has been slow because gene-based association studies are not powerful enough to detect multiple small but cumulative gene effects. In future, the more efficient genomic-based research approaches will accelerate the finding of 'sports genes'. Data generated will be enormous, making it essential to have a direct link between the laboratory researcher and bioinformatics expertise.
Genetics research has moved to the genomics era, i.e. the simultaneous testing of multiple genes is now possible.
Medicine and sport science 02/2009; 54:187-95.
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ABSTRACT: Genetic variants may underlie sporadic amyotrophic lateral sclerosis (SALS), but in only a few percent of patients have causative mutations been found. This is possibly because SALS is more often due to a variation in DNA methylation, an epigenetic phenomenon involved in gene silencing. Methylation across the whole genome was examined in brain DNA of 10 SALS patients and 10 neurologically-normal controls. Methylated DNA was immunoprecipitated and interrogated by Affymetrix GeneChip Human Tiling 2.0R Arrays. Methylation levels were compared between SALS patients and controls at each region of methylation across the genome. SALS patients had either hypo- or hyper-methylation at 38 methylation sites (p </=0.01). Of these, 23 were associated with genes and three with CpG islands. Pathway analysis showed that genes with different methylation in SALS were particularly involved in calcium homeostasis, neurotransmission and oxidative stress. In conclusion, a number of genes, either unsuspected in SALS or in potential cell death pathways, showed altered methylation in SALS brains. The possibility of epigenetic therapy for SALS should encourage confirmation of these initial results in a future larger whole-genome DNA methylation study.
Amyotrophic Lateral Sclerosis 01/2009; · 3.40 Impact Factor
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ABSTRACT: Genetic variants may underlie sporadic amyotrophic lateral sclerosis (SALS), but in only a few percent of patients have causative mutations been found. This is possibly because SALS is more often due to a variation in DNA methylation, an epigenetic phenomenon involved in gene silencing. Methylation across the whole genome was examined in brain DNA of 10 SALS patients and 10 neurologically-normal controls. Methylated DNA was immunoprecipitated and interrogated by Affymetrix GeneChip Human Tiling 2.0R Arrays. Methylation levels were compared between SALS patients and controls at each region of methylation across the genome. SALS patients had either hypo- or hyper-methylation at 38 methylation sites (p </= 0.01). Of these, 23 were associated with genes and three with CpG islands. Pathway analysis showed that genes with different methylation in SALS were particularly involved in calcium homeostasis, neurotransmission and oxidative stress. In conclusion, a number of genes, either unsuspected in SALS or in potential cell death pathways, showed altered methylation in SALS brains. The possibility of epigenetic therapy for SALS should encourage confirmation of these initial results in a future larger whole-genome DNA methylation study.
Amyotrophic Lateral Sclerosis 01/2009; 10(5-6):418-29. · 3.40 Impact Factor
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ABSTRACT: Mutations in the superoxide dismutase 1 gene (SOD1) are associated with familial ALS but the role of SOD1 in sporadic ALS (SALS) is unclear. We therefore sequenced the entire SOD1 gene in 23 patients with SALS. DNA was extracted from frozen pre-frontal cerebral cortex and from blood. The 5 exons, 4 introns and 1 kb upstream and downstream of SOD1 were sequenced. Novel genetic variants were found in 30% (7 of 23) brains and known variants in 91% (21 of 23) brains from patients with SALS. Two novel variants found in SALS patients and not controls were located in the SOD1 promoter and intron 1, with the promoter variant having potential functional implications. A previously described silent variant in exon 5 in one SALS patient appears to abolish an exonic splicing enhancer. All changes found in brain DNA were also found in blood DNA. In conclusion, sequencing the entire SOD1 gene revealed 3 variants in SALS patients that were not detected in controls. Although no unequivocal mutations were found, some of these variants have potential consequences for SALS pathogenesis.
Neuromuscular Disorders 08/2008; 18(7):545-52. · 2.80 Impact Factor
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ABSTRACT: Expansions of triplet repeats are found in a number of neurodegenerative conditions, and different tissues in the same person can have varying repeat lengths. In Kennedy disease, motor neuron loss is due to expansion of the CAG repeat length in the androgen receptor gene (AR). We hypothesised that patients with other sporadic motor neuron diseases could have AR expansions that were restricted to CNS tissue.
We measured the AR triplet repeat length in DNA extracted from the brains of 23 patients with sporadic amyotrophic lateral sclerosis (SALS) and 3 with sporadic progressive muscular atrophy (SPMA). Paired blood samples were available in 15 patients to look for blood-brain differences in CAG repeat length.
No CAG expansions in the Kennedy disease range were found in the SALS or SPMA brains. Furthermore, no brain-blood differences were found in the lengths of AR triplet repeats. Brain AR repeat length was not associated with the duration, or age or site of onset, of disease.
The findings indicate that a brain-specific expansion of AR triplet repeats is unlikely to underlie motor neuron loss in SALS or SPMA.
Journal of the Neurological Sciences 05/2008; 267(1-2):125-8. · 2.35 Impact Factor
