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    ABSTRACT: Late Epstein-Barr virus infection and hypovitaminosis-D as environmental risk factors in the pathogenesis of multiple sclerosis are gaining great interest. We, therefore, tested for in-vivo interdependence between Epstein-Barr-virus (EBV)-status and 25-hydroxyvitamin D3 (25(OH)D3) -level in healthy young individuals from a United Kingdom (UK) autumn cohort. EBV-load was measured by quantitative polymerase chain reaction and 25(OH)D3 levels by isotope-dilution liquid chromatography-tandem mass spectrometry. This young, healthy UK autumn cohort showed surprisingly low levels of 25(OH)D3 (mean value: 40.5 nmol/L ± 5.02). Furthermore, we found that low 25(OH)D3 levels did not impact on EBV load and anti-EBV nuclear antigen-1 (EBNA-1) titers. However, we observed a correlation between EBV load and EBNA-1 titers. These observations should be of value in the study of the potential relationship between hypovitaminosis-D and EBV-status in the pathophysiology of multiple sclerosis.
    Multiple Sclerosis 11/2013; 20(6). DOI:10.1177/1352458513509507
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    ABSTRACT: The potential to use Schwann cells (SCs) in neural repair for patients suffering from neurotrauma and neurodegenerative diseases is well recognized. However, significant cell death after transplantation hinders the clinical translation of SC-based therapies. Various factors may contribute to the death of transplanted cells. It is known that prolonged activation of P2X7 purinoceptors (P2X7R) can lead to death of certain types of cells. In this study, we show that rat SCs express P2X7R and exposure of cultured SCs to high concentrations of ATP (3-5 mM) or a P2X7R agonist, 2'(3')-O-(4-benzoylbenzoyl)ATP (BzATP) induced significant cell death rapidly. High concentrations of ATP and BzATP increased ethidium uptake by SCs, indicating increased membrane permeability to large molecules, a typical feature of prolonged P2X7R activation. SC death, as well as ethidium uptake, induced by ATP was blocked by an irreversible P2X7R antagonist oxidized ATP (oxATP) or a reversible P2X7R antagonist A438079. oxATP also significantly inhibits the increase of intracellular free calcium induced by minimolar ATP concentrations. Furthermore, ATP did not cause death of SCs isolated from P2X7R-knockout mice. All these results suggest that P2X7R is responsible for ATP-induced SC death in vitro. When rat SCs were treated with oxATP before transplantation into uninjured rat spinal cord, 35% more SCs survived than untreated SCs 1 week after transplantation. Moreover, 58% more SCs isolated from P2X7R-knockout mice survived after being transplanted into rat spinal cord than SCs from wild-type mice. This further confirms that P2X7R is involved in the death of transplanted SCs. These results indicate that targeting P2X7R on SCs could be a potential strategy to improve the survival of transplanted cells. As many other types of cells, including neural stem cells, also express P2X7R, deactivating P2X7R may improve the survival of other types of transplanted cells.
    Cell Death & Disease 10/2013; 4(10):e829. DOI:10.1038/cddis.2013.343
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    ABSTRACT: Sudden head drops and axial extensions were recently proposed as a pathognomonic clinical sign for chorea-acanthocytosis (NAC).(1) Here, we challenge this observation, describing 3 patients with Huntington disease (HD) showing this sign as a major clinical feature. Moreover, we employed EMG to clarify the mechanism of these involuntary movements. Written informed consent for the videos was obtained.
    Neurology 07/2013; 81(8). DOI:10.1212/WNL.0b013e3182a1aa55
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    ABSTRACT: Nogo receptor 1 (NgR1) mediates the inhibitory effects of the several myelin-associated inhibitors (MAIs) on axonal regeneration in the central nervous system. A truncated soluble NgR1 (sNgR) has been reported to act as a decoy receptor to block the actions of MAIs. In this study, we fused the sNgR to nerve growth factor (NGF) and used NGF as a carrier to deliver sNgR to the intercellular space to neutralize MAIs. NGF in NGF-sNgR remained biologically active and induced sprouting of calcitonin gene related peptide containing axons when expressed in spinal cord using a lentiviral vector (LV). Secreted NGF-sNgR promoted neurite outgrowth of dissociated dorsal root ganglion neurons on myelin protein substrate. In a rat dorsal column transection model, regenerating sensory axons were found to grow into the lesion cavity in animals injected with LV/NGF-sNgR, while in animals injected with LV/GFP or LV/NGF-GFP few sensory axons entered the lesion cavity. The results indicate that NGF-sNgR fusion protein can reduce the inhibition of MAIs and facilitate sensory axon regeneration. The fusion constructs may be modified to target other molecules to promote axonal regeneration and the concept may also be adapted to develop gene therapy strategies to treat other disorders.
    Neurobiology of Disease 06/2013; 58. DOI:10.1016/j.nbd.2013.06.008
  • Expert Review of Neurotherapeutics 03/2013; 13(3):235-7. DOI:10.1586/ern.13.13
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    ABSTRACT: OBJECTIVES: Suboptimal bone health is increasingly recognised as an important cause of morbidity. Multiple sclerosis (MS) has been consistently associated with an increased risk of osteoporosis and fracture. Various fracture risk screening tools have been developed, two of which are in routine use and a further one is MS-specific. We set out to compare the results obtained by these in the MS clinic population. DESIGN: This was a service development study. The 10-year risk estimates of any fracture and hip fracture generated by each of the algorithms were compared. SETTING: The MS clinic at the Royal London Hospital. PARTICIPANTS: 88 patients with a confirmed diagnosis of MS. OUTCOME MEASURES: Mean 10-year overall fracture risk and hip fracture risk were calculated using each of the three fracture risk calculators. The number of interventions that would be required as a result of using each of these tools was also compared. RESULTS: Mean 10-year fracture risk was 4.7%, 2.3% and 7.6% using FRAX, QFracture and the MS-specific calculator, respectively (p<0.0001 for difference). The agreement between risk scoring tools was poor at all levels of fracture risk. CONCLUSIONS: The agreement between these three fracture risk scoring tools is poor in the MS population. Further work is required to develop and validate an accurate fracture risk scoring system for use in MS. TRIAL REGISTRATION: This service development study was approved by the Clinical Effectiveness Department at Barts Health NHS Trust (project registration number 156/12).
    BMJ Open 03/2013; 3(3). DOI:10.1136/bmjopen-2012-002508
  • Neuroscience & Biobehavioral Reviews 02/2013; 37(6). DOI:10.1016/j.neubiorev.2013.02.018
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    ABSTRACT: Tourette syndrome (TS) is the primary tic disorder that reaches most commonly medical attention and monitoring, with an estimated prevalence close to 1% between 5 and 18 years of age. Motor and phonic tics are the core features of TS. In addition to their well-characterized phenomenology, tics display a peculiar variability over time, which is strongly influenced by a variety of contextual factors. The sensory phenomena of TS are increasingly recognized as another crucial symptom of TS and consist of premonitory urges and somatic hypersensitivity. A relevant proportion of patients with TS display complex, tic-like, repetitive behaviors that include echophenomena, coprophenomena, and nonobscene socially inappropriate behaviors (NOSIBs). The burden of behavioral comorbidities is very important in determining the degree of disability of TS patients. Only a small minority of TS patients presents exclusively with a tic disorder. Obsessive-compulsive symptoms and related disorder (OCD) are common in TS, and the clinical distinction between compulsions and complex tics may be difficult in some cases. Probably, the presence of comorbid attention deficit hyperactivity disorder (ADHD) is the main determinant of cognitive dysfunction in TS patients and influences heavily also the risk of developing disruptive behaviors. Affective disorders, impulse control disorders, autism spectrum disorders, and personality disorders complete the wide psychopathological spectrum of this condition, but have been less investigated than OCD and ADHD. The complexity of the Tourette spectrum has been confirmed by cluster and factor analytical approaches, and is likely to inform the study of the genetic basis of this disorder, as well as future reappraisal of its nosography, with the development of novel clinical subtypes.
    International Review of Neurobiology 01/2013; 112:1-33. DOI:10.1016/B978-0-12-411546-0.00001-9
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    ABSTRACT: There is sparse evidence suggesting the participation of neuroendocrine mechanisms, mainly involving sex and stress steroid hormones, to the pathophysiology of neurodevelopmental disorders such as Tourette syndrome (TS) and obsessive-compulsive disorder (OCD). Patients with TS exhibit a sex-specific variability in gender distribution (male/female ratio=3-4/1) and in its natural history, with a severity peak in the period around puberty. The administration of exogenous androgens may worsen tics in males with TS, whereas drugs counteracting the action of testosterone might show some antitic efficacy. This suggests a higher susceptibility of patients with TS to androgen steroids. There are insufficient data on the regulation of the hypothalamic-pituitary-gonadal (HPG) axis in TS. However, preliminary evidence suggests that a subgroup of women with TS might be more sensitive to the premenstrual trough of estrogen levels. Patients with TS exhibit differences in a number of behavioral, cognitive, and anatomical traits that appear to be sex related. There is a body of evidence supporting, albeit indirectly, the hypothesis of an increased exposure to androgenic steroids during the very early phases of neural development. Animal models in rodents suggest a complex role of gonadal hormones upon the modulation of anxiety-related and stereotyped behaviors during adult life. Patients with TS exhibit an enhanced reactivity of the hypothalamic-pituitary-adrenal axis to external stressors, despite a preserved diurnal cortisol rhythm and a normal restoration of the baseline activity of the axis following the acute stress response. Preliminary evidence suggests the possible implication of oxytocin (OT) in disorders related to the TS spectrum, especially non-tic-related OCD. The injection of OT in the amygdala of rodents was shown to be able to induce hypergrooming, suggesting the possible involvement of this neuropeptide in the pathophysiology of complex, stereotyped behaviors. In contrast, there is anecdotal clinical evidence that tics improve following periods of affectionate touch and sexual intercourse.
    International Review of Neurobiology 01/2013; 112:239-79. DOI:10.1016/B978-0-12-411546-0.00009-3
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    ABSTRACT: Factors modifying the clinical penetrance of DYT1 dystonia are incompletely defined. Particularly, the contribution of extragenetic factors has been subject to only limited investigation and remains largely unexplored. A possible effect of childhood infections has been proposed, and the effect of other factors, such as perinatal adversity and trauma, has not been systematically investigated. We performed an exploratory analysis of the exposure to perinatal adversity, childhood infections, general anaesthesia and trauma comparing 39 manifesting carriers of the ∆GAG mutation, 23 non-manifesting carriers and 48 non-carriers from a multi-centre European series of 28 families with DYT1 dystonia, by means of a self-completed questionnaire and clinical interview. Detailed information on perinatal adversities (pre-term birth, complications at natural delivery, urgent caesarean section), previous childhood infections, and prior general anaesthesia or physical trauma was recorded. A positive association between a history of complications of vaginal delivery and manifestation of dystonia was detected, which was not confounded by age, gender, or education level (odds ratio 8.47, 95 % confidence interval 1.45-49.4, p = 0.02). We could not observe any significant association between presence of dystonia and the other investigated variables. Comparing non-manifesting carriers to non-carriers, the presence of the ∆GAG mutation per se was not associated with any of the environmental exposures explored. Perinatal adversities might modulate the clinical penetrance of DYT1 dystonia; their interaction with known genetic factors modifying penetrance of this condition should be investigated in new, larger collaborative studies.
    Journal of Neurology 12/2012; 260(4). DOI:10.1007/s00415-012-6765-2
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