Toward Fulfilling the Promise of Molecular Medicine in Fragile X

Fragile X syndrome (FXS) is the most common inherited form of mental retardation and a leading known cause of autism. It is caused by loss of expression of the fragile X mental retardation protein (FMRP), an RNA-binding protein that negatively regulates protein synthesis. In neurons, multiple lines of evidence suggest that protein synthesis at synapses is triggered by activation of group 1 metabotropic glutamate receptors (Gp1 mGluRs) and that many functional consequences of activating these receptors are altered in the absence of FMRP. These observations have led to the theory that exaggerated protein synthesis downstream of Gp1 mGluRs is a core pathogenic mechanism in FXS. This excess can be corrected by reducing signaling by Gp1 mGluRs, and numerous studies have shown that inhibition of mGluR5, in particular, can ameliorate multiple mutant phenotypes in animal models of FXS. Clinical trials based on this therapeutic strategy are currently under way. FXS is therefore poised to be the first neurobehavioral disorder in which corrective treatments have been developed from the bottom up: from gene identification to pathophysiology in animals to novel therapeutics in humans. The insights gained from FXS and other autism-related single-gene disorders may also assist in identifying molecular mechanisms and potential treatment approaches for idiopathic autism.Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.)National Institute of Mental Health (U.S.)FRAXA Research Foundatio

Developing a utility index for the Aberrant Behavior Checklist (ABC-C) for fragile X syndrome

Purpose This study aimed to develop a utility index (the ABC-UI) from the Aberrant Behavior Checklist-Community (ABC-C), for use in quantifying the benefit of emerging treatments for fragile X syndrome (FXS). Methods The ABC-C is a proxy-completed assessment of behaviour and is a widely used measure in FXS. A subset of ABC-C items across seven dimensions was identified to include in health state descriptions. This item reduction process was based on item performance, factor analysis and Rasch analysis performed on an observational study dataset, and consultation with five clinical experts and a methodological expert. Dimensions were combined into health states using an orthogonal design and valued using time trade-off (TTO), with lead-time TTO methods used where TTO indicated a state valued as worse than dead. Preference weights were estimated using mean, individual level, ordinary least squares and random-effects maximum likelihood estimation [RE (MLE)] regression models. Results A representative sample of the UK general public (n = 349; mean age 35.8 years, 58.2 % female) each valued 12 health states. Mean observed values ranged from 0.92 to 0.16 for best to worst health states. The RE (MLE) model performed best based on number of significant coefficients and mean absolute error of 0.018. Mean utilities predicted by the model covered a similar range to that observed. Conclusions The ABC-UI estimates a wide range of utilities from patient-level FXS ABC-C data, allowing estimation of FXS health-related quality of life impact for economic evaluation from an established FXS clinical trial instrument

The ‘heritagisation’ of the British seaside resort: The rise of the ‘old penny’ arcade.

Amusement arcades have long been a key component of the British seaside resort. For almost a century, they enjoyed popularity and success and became established as a quintessential feature of the British seaside holiday. However, the advent of home-based video games along with recent gambling legislation has led to a decline of the seaside amusement arcade sector. Arcades gained a reputation as unsavoury places and their appearance and fortunes often mirrored those of the resorts in which they were located. However, over the past decade, a new variant of the seaside amusement arcade has appeared, featuring mechanical machines working on pre-decimal currency. Such ‘old penny arcades’ frequently describe themselves as museums or heritage centres and they offer an experience based on a nostalgic affection for the ‘traditional’ seaside holiday. They have appeared in the context of an increasing interest in the heritage of the British seaside resort and constitute one element of the ‘heritagisation’ of such resorts. This paper argues that such arcades can be important elements of strategies to reposition and rebrand resorts for the heritage tourism market

The question of access to the Japanese market

This survey focuses on the question of how market structure and different corporate organisational forms might affect access to the Japanese market for industrial goods. The question is how and whether keiretsu corporate structures in Japan constitute an important unofficial barrier in access to the Japanese market for manufactured goods

Velocity Space Snapshots of Continuum Electrons Produced by Slow, Bare, Highly Charged Ions: Saddle-Point Electrons?

Comprehensive velocity-space snapshots of the electron continua produced by the impact of ions on He at a projectile velocity of 1.63 a.u. have been measured for the bare projectiles of p, He, C, O and Ne. For the three highly charged ions, this velocity lies in the ionization threshold region where electron capture dominates the reaction. The experimental technique projects the distribution of soft continuum electrons onto a two-dimensional detector in such a way that the velocity-space distribution for all electrons with laboratory energies in the range from 0-30eV is accurately imaged. The data show no evidence for a saddle-point feature for the highest three projectile charges

Open-label add-on treatment trial of minocycline in fragile X syndrome

<p>Abstract</p> <p>Background</p> <p>Fragile X syndrome (FXS) is a disorder characterized by a variety of disabilities, including cognitive deficits, attention-deficit/hyperactivity disorder, autism, and other socio-emotional problems. It is hypothesized that the absence of the fragile X mental retardation protein (FMRP) leads to higher levels of matrix metallo-proteinase-9 activity (MMP-9) in the brain. Minocycline inhibits MMP-9 activity, and alleviates behavioural and synapse abnormalities in <it>fmr1 </it>knockout mice, an established model for FXS. This open-label add-on pilot trial was conducted to evaluate safety and efficacy of minocycline in treating behavioural abnormalities that occur in humans with FXS.</p> <p>Methods</p> <p>Twenty individuals with FXS, ages 13-32, were randomly assigned to receive 100 mg or 200 mg of minocycline daily. Behavioural evaluations were made prior to treatment (baseline) and again 8 weeks after daily minocycline treatment. The primary outcome measure was the Aberrant Behaviour Checklist-Community Edition (ABC-C) Irritability Subscale, and the secondary outcome measures were the other ABC-C subscales, clinical global improvement scale (CGI), and the visual analog scale for behaviour (VAS). Side effects were assessed using an adverse events checklist, a complete blood count (CBC), hepatic and renal function tests, and antinuclear antibody screen (ANA), done at baseline and at 8 weeks.</p> <p>Results</p> <p>The ABC-C Irritability Subscale scores showed significant improvement (p < 0.001), as did the VAS (p = 0.003) and the CGI (p < 0.001). The only significant treatment-related side effects were minor diarrhea (n = 3) and seroconversion to a positive ANA (n = 2).</p> <p>Conclusions</p> <p>Results from this study demonstrate that minocycline provides significant functional benefits to FXS patients and that it is well-tolerated. These findings are consistent with the <it>fmr1 </it>knockout mouse model results, suggesting that minocycline modifies underlying neural defects that account for behavioural abnormalities. A placebo-controlled trial of minocycline in FXS is warranted.</p> <p>Trial registration</p> <p>ClinicalTrials.gov Open-Label Trial NCT00858689.</p

A pilot open label, single dose trial of fenobam in adults with fragile X syndrome

ObjectiveA pilot open label, single dose trial of fenobam, an mGluR5 antagonist, was conducted to provide an initial evaluation of safety and pharmacokinetics in adult males and females with fragile X syndrome (FXS).MethodsTwelve subjects, recruited from two fragile X clinics, received a single oral dose of 50-150 mg of fenobam. Blood for pharmacokinetic testing, vital signs and side effect screening was obtained at baseline and numerous time points for 6 h after dosing. Outcome measures included prepulse inhibition (PPI) and a continuous performance test (CPT) obtained before and after dosing to explore the effects of fenobam on core phenotypic measures of sensory gating, attention and inhibition.ResultsThere were no significant adverse reactions to fenobam administration. Pharmacokinetic analysis showed that fenobam concentrations were dose dependent but variable, with mean (SEM) peak values of 39.7 (18.4) ng/ml at 180 min after the 150 mg dose. PPI met a response criterion of an improvement of at least 20% over baseline in 6 of 12 individuals (4/6 males and 2/6 females). The CPT did not display improvement with treatment due to ceiling effects.ConclusionsClinically significant adverse effects were not identified in this study of single dose fenobam across the range of dosages utilised. The positive effects seen in animal models of FXS treated with fenobam or other mGluR5 antagonists, the apparent lack of clinically significant adverse effects, and the potential beneficial clinical effects seen in this pilot trial support further study of the compound in adults with FXS

Single Ionization of He by Low-Velocity Protons and [Formula Presented]: Ejected Electron Momentum Distributions

A technique for electron spectroscopy which yields full two-dimensional momentum distributions for continuum electrons has been used to study ejected electrons from single ionization of He by [Formula Presented] and proton projectiles at low velocities. Projectile velocities of 1.63, 1.38, and 1.16 a.u. for [Formula Presented] and 2.39, 1.71, 1.15,. 85, and 0.63 a.u. for protons were used. All spectra show much broader distributions along the beam than transverse to the beam. For the case of proton bombardment, the spectra are strongly influenced by both target and projectile potentials, maximizing near the velocity of the saddle in the potential between the two receding ion cores for the lowest projectile velocities. For [Formula Presented] projectiles, the spectra appear to be dominated by the projectile potential and the center of the distribution is strongly shifted toward the projectile velocity. Theoretical results from the continuum-distorted-wave–eikonal-initial-state and classical-trajectory–Monte Carlo methods are in rather good agreement with the proton data but do not agree well with the [Formula Presented] data. © 1996 The American Physical Society

Histone deacetylases suppress cgg repeat-induced neurodegeneration via transcriptional silencing in models of Fragile X Tremor Ataxia Syndrome

Fragile X Tremor Ataxia Syndrome (FXTAS) is a common inherited neurodegenerative disorder caused by expansion of a CGG trinucleotide repeat in the 59UTR of the fragile X syndrome (FXS) gene, FMR1. The expanded CGG repeat is thought to induce toxicity as RNA, and in FXTAS patients mRNA levels for FMR1 are markedly increased. Despite the critical role of FMR1 mRNA in disease pathogenesis, the basis for the increase in FMR1 mRNA expression is unknown. Here we show that overexpressing any of three histone deacetylases (HDACs 3, 6, or 11) suppresses CGG repeat-induced neurodegeneration in a Drosophila model of FXTAS. This suppression results from selective transcriptional repression of the CGG repeat-containing transgene. These findings led us to evaluate the acetylation state of histones at the human FMR1 locus. In patient-derived lymphoblasts and fibroblasts, we determined by chromatin immunoprecipitation that there is increased acetylation of histones at the FMR1 locus in pre-mutation carriers compared to control or FXS derived cell lines. These epigenetic changes correlate with elevated FMR1 mRNA expression in pre-mutation cell lines. Consistent with this finding, histone acetyltransferase (HAT) inhibitors repress FMR1 mRNA expression to control levels in pre-mutation carrier cell lines and extend lifespan in CGG repeat-expressing Drosophila. These findings support a disease model whereby the CGG repeat expansion in FXTAS promotes chromatin remodeling in cis, which in turn increases expression of the toxic FMR1 mRNA. Moreover, these results provide proof of principle that HAT inhibitors or HDAC activators might be used to selectively repress transcription at the FMR1 locus.open293

Electron-Transfer from H-2 and Ar to Stored Multiply Charged Argon Ions Produced by Synchrotron Radiation

Journals published by the American Physical Society can be found at http://publish.aps.org/The rate coefficients for electron transfer from Ar and H-2 to Ar(q+) ions (3 less-than-or-equal-to q less-than-or-equal-to 6) have been measured using an ion-storage technique in a Penning ion trap. The ions were produced in the trap by K-shell photoionization of Ar atoms, using broadband synchrotron x-ray radiation. K-electron removal resulted in vacancy cascading, yielding a distribution of argon-ion charge states peaked near Ar4+. The stored ion gas had an initial temperature near 480 K. The basic data determining the rate coefficients k(Ar(q+)) are the storage time constants of each charge state in the trap, in the presence of a measured pressure of target gas. The results of the measurements (in units of 10(-9) cm3 s-1) are k(Ar3+, H-2) = 4.3(0.7), k(Ar3+, Ar) = 1.6(0.2), k(Ar4+, H-2) = 5.2(0.6), k(Ar4+, Ar) = 2.5(0.3), k(Ar5+, H-2) = 5.9(0.7), k(Ar5+, Ar) = 2.9(0.3), k(Ar6+, H-2) = 8.5(l.2), and k(Ar6+, Ar) = 2.5(0.3)