Showing papers by "Martin R Turner published in 2009"
TL;DR: Potential biomarkers that are sensitive to the progression of disease, which might enhance the diagnostic algorithm and provide new drug targets, are now being identified from analysis of the blood and cerebrospinal fluid, as well as from neuroimaging and neurophysiology studies.
Abstract: Amyotrophic lateral sclerosis (ALS; motor neuron disease) is a relentlessly progressive disorder. After half a century of trials, only one drug with modest disease-modifying potency--riluzole--has been developed. The diagnosis of this disorder is still clinical and there is a pronounced delay between the onset of symptoms and diagnosis, possibly beyond the therapeutic window. Bedside quantification of the involvement of the corticospinal tract and extramotor areas is inadequate and functional rating scales, forced vital capacity, and patient survival have been the measures of therapeutic response so far. Potential biomarkers that are sensitive to the progression of disease, which might enhance the diagnostic algorithm and provide new drug targets, are now being identified from analysis of the blood and cerebrospinal fluid, as well as from neuroimaging and neurophysiology studies. In combination, these biomarkers might be sensitive to early therapeutic effects and would reduce our reliance on animal models, which have uncertain relevance to sporadic ALS in human beings. Such biomarkers might also resolve complexities of phenotypic heterogeneity in clinical trials. In this Review, we discuss the development of biomarkers in ALS and consider potential future directions for research.
406 citations
TL;DR: It is reported that miR-155-deficient mice have reduced numbers of Tregs, both in the thymus and periphery, due to impaired development, and that additional miRNAs control Treg function.
Abstract: Foxp3 is a transcription factor that is essential for the normal development of regulatory T cells (Tregs). In the absence of microRNAs (miRNAs), Foxp3 + Tregs develop but fail to maintain immune homeostasis, leading to a scurfy-like disease. Global analysis of the network of genes regulated by Foxp3 has identified the miRNA miR-155, which is highly expressed in Tregs, as a direct target of Foxp3. In this study we report that miR-155-deficient mice have reduced numbers of Tregs, both in the thymus and periphery, due to impaired development. However, we found no evidence for defective suppressor activity of miR-155-deficient Tregs, either in vitro or in vivo. Our results indicate that miR-155 contributes to Treg development, but that additional miRNAs control Treg function.
371 citations
TL;DR: In this article, the RNA polymerase II component, ELP3, was found to be associated with ALS in three human populations comprising 1483 people (P=1.96 x 10(-9)).
Abstract: Amyotrophic lateral sclerosis (ALS) is a spontaneous, relentlessly progressive motor neuron disease, usually resulting in death from respiratory failure within 3 years. Variation in the genes SOD1 and TARDBP accounts for a small percentage of cases, and other genes have shown association in both candidate gene and genome-wide studies, but the genetic causes remain largely unknown. We have performed two independent parallel studies, both implicating the RNA polymerase II component, ELP3, in axonal biology and neuronal degeneration. In the first, an association study of 1884 microsatellite markers, allelic variants of ELP3 were associated with ALS in three human populations comprising 1483 people (P=1.96 x 10(-9)). In the second, an independent mutagenesis screen in Drosophila for genes important in neuronal communication and survival identified two different loss of function mutations, both in ELP3 (R475K and R456K). Furthermore, knock down of ELP3 protein levels using antisense morpholinos in zebrafish embryos resulted in dose-dependent motor axonal abnormalities [Pearson correlation: -0.49, P=1.83 x 10(-12) (start codon morpholino) and -0.46, P=4.05 x 10(-9) (splice-site morpholino), and in humans, risk-associated ELP3 genotypes correlated with reduced brain ELP3 expression (P=0.01). These findings add to the growing body of evidence implicating the RNA processing pathway in neurodegeneration and suggest a critical role for ELP3 in neuron biology and of ELP3 variants in ALS.
274 citations
TL;DR: It is shown that a pathway containing Vav and Rac proteins may negatively regulate Notch signaling during early thymic development and a similar novel phenotype is found in the absence of Vav1, Vav2, and Vav3, which function as guanine nucleotide exchange factors for Rac1 and Rac2.
69 citations
TL;DR: In vivo diffusion tensor imaging measures demonstrate differences in white matter degeneration between sporadic ALS and a unique familial form of the disease, indicating that genotype influences the distribution of cerebral pathologic features in ALS.
Abstract: BACKGROUND
The basis of heterogeneity in the clinical presentation and rate of progression of amyotrophic lateral sclerosis (ALS) is poorly understood.
OBJECTIVES
To use diffusion tensor imaging as a measure of axonal pathologic features in vivo in ALS and to compare a homogeneous form of familial ALS (homozygous D90A SOD1 [superoxide dismutase 1]) with sporadic ALS.
DESIGN
Cross-sectional diffusion tensor imaging study.
SETTING
Tertiary referral neurology clinic.
PATIENTS
Twenty patients with sporadic ALS, 6 patients with homozygous D90A SOD1 ALS, and 21 healthy control subjects.
MAIN OUTCOME MEASURE
Fractional anisotropy in cerebral white matter.
RESULTS
Patients with homozygous D90A SOD1 ALS showed less extensive pathologic white matter in motor and extramotor pathways compared with patients with sporadic ALS, despite similar disease severity assessed clinically using a standard functional rating scale. Fractional anisotropy correlated with clinical measures of severity and upper motor neuron involvement.
CONCLUSION
In vivo diffusion tensor imaging measures demonstrate differences in white matter degeneration between sporadic ALS and a unique familial form of the disease, indicating that genotype influences the distribution of cerebral pathologic features in ALS
45 citations
TL;DR: It is proposed that Vav proteins affect macrophage morphology and motile behaviour by coupling adhesion receptors to Rac1 and RhoA activity and regulating adhesion signalling events such as paxillin and ERK1/2 phosphorylation by acting as adapters.
44 citations
TL;DR: A case of functional vitamin B12 deficiency where the repeated measurement of a serum B12 level within the normal range led to delay in the diagnosis of subacute combined degeneration of the spinal cord, and possibly permanent neurological damage as a result.
Abstract: We describe a case of functional vitamin B12 deficiency where the repeated measurement of a serum B12 level within the normal range led to delay in the diagnosis of subacute combined degeneration of the spinal cord, and possibly permanent neurological damage as a result. Failure of intracellular transport of B12 by transcobalamin-2 can lead to functional B12 deficiency but with apparently normal serum levels, and is suggested by raised levels of either serum methylmalonic acid or homocysteine, associated with low levels of transcobalamin-2. Such patients may respond to repeated high-dose injections of B12.
43 citations
TL;DR: An excess of ALS cases in some postcode districts in south-east England is suggested, suggesting environmental factors that trigger ALS might result in a pattern of geographical clustering of cases.
Abstract: Background: Amyotrophic lateral sclerosis (ALS) is a degenerative disease of motor neurons that causes progressive paralysis and eventually results in death from respiratory failure
42 citations
TL;DR: This is a symptom-based review where the evidence (or lack of it) for the association of various neurological problems with thyroid dysfunction, and also the pitfalls in interpretation of the biochemical tests are considered.
Abstract: There are many neurological manifestations of thyroid disease, and thyroid function has taken its place in the "routine bloods" of neurology practice. However, although conditions such as carpal tunnel syndrome prompt thyroid testing despite any clear evidence for this approach, other symptoms of potential significance in terms of thyroid disease may be overlooked in the busy general neurology clinic, or abnormal thyroid tests may be assumed to be incidental. Psychiatric disorders, loss of consciousness, movement disorders and weakness may all be manifestations of primary thyroid disease. This is a symptom-based review where we will consider the evidence (or lack of it) for the association of various neurological problems with thyroid dysfunction, and also the pitfalls in interpretation of the biochemical tests.
27 citations
TL;DR: The PI3K activity has been shown to be inhibitory to CSR and the effects on immunoglobulin production and ASC differentiation are harder to disentangle from the developmental effects on cell populations and at present remain uncertain.
Abstract: The PI3K signalling pathway is crucial to normal B cell development and response to antigen. The p1108 catalytic subunit plays an important and non-redundant role within this pathway although other catalytic isoforms may also contribute. Although CD40, TLR and cytokines all activate PI3K the BCR seems especially dependent upon PI3K signalling. The downstream effects of PI3K may be mediated to a large extent by activation of PKB. In B cell development PI3K promotes development of MZ and Bl cells. In the response to antigen PI3K is crucial to BCR-mediated proliferation. PI3K activity has been shown to be inhibitory to CSR. The effects on immunoglobulin production and ASC differentiation are harder to disentangle from the developmental effects on cell populations and at present remain uncertain.
TL;DR: It is become clear that there is a borderland where there are patients with optic neuritis-only and myelitis- only forms of the disease, and these may be seronegative in the early phase.
Abstract: Neuromyelitis optica (NMO), also known as Devic’s disease, is an emerging clinical and pathological entity originally thought to be a variant of multiple sclerosis. Characterised by episodes of demyelination confined to the optic nerve and spinal cord, the discovery in such patients of antibodies to the aquaporin-4 channel has been largely responsible for defining the phenotype to date. Recently it has become clear that there is a borderland where there are patients with optic neuritis-only and myelitis-only forms of the disease, and these may be seronegative in the early phase. We describe two cases of optic neuritis-only NMO, and explore the current understanding of the diagnosis and spectrum of NMO disorders.
TL;DR: A method for identification of protein-protein interactions by combining two cell-free protein technologies, namely ribosome display and protein in situ immobilisation, which has promise for library screening of pairwise protein interactions, down to the analytical level of individual domain or motif mapping.
TL;DR: An 18-year-old woman had a partial seizure affecting the left arm with secondary generalization, and her mother recalled that the patient sustained a head injury as a 3-week-old neonate, falling from the sofa onto …
Abstract: An 18-year-old woman had a partial seizure affecting the left arm with secondary generalization. There was no history of seizures. Her mother recalled that the patient sustained a head injury as a 3-week-old neonate, falling from the sofa onto …
TL;DR: A 64-year-old man with history of bio-prosthetic aortic valve was admitted with chest pain, skin rash and renal impairment and on examination found it necessary to operate on him.
Abstract: A 64-year-old man with history of bio-prosthetic aortic valve was admitted with chest pain, skin rash and renal impairment. On examination …
TL;DR: Concern arose in this case that treatment of the acromegaly with a somatostatin analogue might adversely affect the natural course of his ALS through lowering of potentially beneficial IGF-1 levels, but it is suggested that this concern was unfounded.
Abstract: We report a patient presenting with ALS in whom acromegaly was later confirmed. Insulin-like growth factor-1 (IGF-1) has been tried in the treatment of ALS and despite equivocal results from clinical trials, efforts have continued to try to harness the significant positive effects on motor neuron growth observed in vitro and in survival of mouse models of the disease. One subsequent study has reported an association between higher circulating serum IGF-1 levels and longer disease duration in ALS patients. Concern therefore arose in our case that treatment of the acromegaly with a somatostatin analogue might adversely affect the natural course of his ALS through lowering of potentially beneficial IGF-1 levels. Through clinical observation and prognostic modelling we suggest that this concern was unfounded. The potential interaction of these two rarely coincident disorders in our patient is discussed.