613 research outputs found
Drug Development for Rare Paediatric Epilepsies: Current State and Future Directions
Rare diseases provide a challenge in the evaluation of new therapies. However, orphan drug development is of increasing interest because of the legislation enabling facilitated support by regulatory agencies through scientific advice, and the protection of the molecules with orphan designation. In the landscape of the rare epilepsies, very few syndromes, namely Dravet syndrome, Lennox-Gastaut syndrome and West syndrome, have been subject to orphan drug development. Despite orphan designations for rare epilepsies having dramatically increased in the past 10 years, the number of approved drugs remains limited and restricted to a handful of epilepsy syndromes. In this paper, we describe the current state of orphan drug development for rare epilepsies. We identified a large number of compounds currently under investigation, but mostly in the same rare epilepsy syndromes as in the past. A rationale for further development in rare epilepsies could be based on the match between the drug mechanisms of action and the knowledge of the causative gene mutation or by evidence from animal models. In case of the absence of strong pathophysiological hypotheses, exploratory/basket clinical studies could be helpful to identify a subpopulation that may benefit from the new drug. We provide some suggestions for future improvements in orphan drug development such as promoting paediatric drug investigations, better evaluation of the incidence and the prevalence, together with the natural history data, and the development of new primary outcomes
Clinical Chorioamnionitis and Neurodevelopment at 5 Years of Age in Children Born Preterm: The EPIPAGE-2 Cohort Study.
OBJECTIVE
To assess the association between clinical chorioamnionitis and neurodevelopmental disorders at 5 years of age in children born preterm.
STUDY DESIGN
EPIPAGE 2 is a national, population-based cohort study of children born before 35 weeks of gestation in France in 2011. We included infants born alive between 24+0 and 34+6 weeks following preterm labor (PTL) or preterm premature rupture of membranes (PPROM). Clinical chorioamnionitis was defined as maternal fever before labor (>37.8°C) with at least two of the following criteria: maternal tachycardia, hyperleukocytosis, uterine contractions, purulent amniotic fluid, or fetal tachycardia. The primary outcome was a composite including cerebral palsy, coordination disorders, cognitive disorders, sensory disorders, or behavioral disorders. We also analyzed each of these disorders separately as secondary outcomes. We performed a multivariable analysis using logistic regression models. We accounted for the non-independence of twins and missing data by generalized estimating equation models and multiple imputations, respectively.
RESULTS
Among 2927 children alive at 5 years of age, 124 (3%) were born in a context of clinical chorioamnionitis. Overall, 8.2% and 9.6% of children exposed and unexposed respectively to clinical chorioamnionitis had moderate-to-severe neurodevelopmental disorders. After multiple imputations and multivariable analysis, clinical chorioamnionitis was not associated with the occurrence of moderate-to-severe neurodevelopmental disorders (adjusted odds ratio = 0.9, 95%CI: 0.5-1.8).
CONCLUSION
We did not find any association between clinical chorioamnionitis and neurodevelopmental disorders at 5 years of age in children born before 35 weeks of gestation after PTL or PPROM
On directed information theory and Granger causality graphs
Directed information theory deals with communication channels with feedback.
When applied to networks, a natural extension based on causal conditioning is
needed. We show here that measures built from directed information theory in
networks can be used to assess Granger causality graphs of stochastic
processes. We show that directed information theory includes measures such as
the transfer entropy, and that it is the adequate information theoretic
framework needed for neuroscience applications, such as connectivity inference
problems.Comment: accepted for publications, Journal of Computational Neuroscienc
Critical change in the Fermi surface of iron arsenic superconductors at the onset of superconductivity
The phase diagram of a correlated material is the result of a complex
interplay between several degrees of freedom, providing a map of the material's
behavior. One can understand (and ultimately control) the material's ground
state by associating features and regions of the phase diagram, with specific
physical events or underlying quantum mechanical properties. The phase diagram
of the newly discovered iron arsenic high temperature superconductors is
particularly rich and interesting. In the AE(Fe1-xTx)2As2 class (AE being Ca,
Sr, Ba, T being transition metals), the simultaneous structural/magnetic phase
transition that occurs at elevated temperature in the undoped material, splits
and is suppressed by carrier doping, the suppression being complete around
optimal doping. A dome of superconductivity exists with apparent equal ease in
the orthorhombic / antiferromagnetic (AFM) state as well as in the tetragonal
state with no long range magnetic order. The question then is what determines
the critical doping at which superconductivity emerges, if the AFM order is
fully suppressed only at higher doping values. Here we report evidence from
angle resolved photoemission spectroscopy (ARPES) that critical changes in the
Fermi surface (FS) occur at the doping level that marks the onset of
superconductivity. The presence of the AFM order leads to a reconstruction of
the electronic structure, most significantly the appearance of the small hole
pockets at the Fermi level. These hole pockets vanish, i. e. undergo a Lifshitz
transition, at the onset of superconductivity. Superconductivity and magnetism
are competing states in the iron arsenic superconductors. In the presence of
the hole pockets superconductivity is fully suppressed, while in their absence
the two states can coexist.Comment: Updated version accepted in Nature Physic
Long-term complete responses after 131I-tositumomab therapy for relapsed or refractory indolent non-Hodgkin's lymphoma
We present the long-term results of 18 chemotherapy relapsed indolent (N=12) or transformed (N=6) NHL patients of a phase II anti-CD20 131I-tositumomab (Bexxar®) therapy study. The biphasic therapy included two injections of 450 mg unlabelled antibody combined with 131I-tositumomab once as dosimetric and once as therapeutic activity delivering 75 or 65 cGy whole-body radiation dose to patients with normal or reduced platelet counts, respectively. Two patients were not treated due to disease progression during dosimetry. The overall response rate was 81% in the 16 patients treated, including 50% CR/CRu and 31% PR. Median progression free survival of the 16 patients was 22.5 months. Median overall survival has not been reached after a median observation of 48 months. Median PFS of complete responders (CR/CRu) has not been reached and will be greater than 51 months. Short-term side effects were mainly haematological and transient. Among the relevant long-term side effects, one patient previously treated with CHOP chemotherapy died from secondary myelodysplasia. Four patients developed HAMA. In conclusion, 131I-tositumomab RIT demonstrated durable responses especially in those patients who achieved a complete response. Six of eight CR/CRu are ongoing after 46–70 months
Shear Modes, Criticality and Extremal Black Holes
We consider a (2+1)-dimensional field theory, assumed to be holographically
dual to the extremal Reissner-Nordstrom AdS(4) black hole background, and
calculate the retarded correlators of charge (vector) current and
energy-momentum (tensor) operators at finite momentum and frequency. We show
that, similar to what was observed previously for the correlators of scalar and
spinor operators, these correlators exhibit emergent scaling behavior at low
frequency. We numerically compute the electromagnetic and gravitational
quasinormal frequencies (in the shear channel) of the extremal
Reissner-Nordstrom AdS(4) black hole corresponding to the spectrum of poles in
the retarded correlators. The picture that emerges is quite simple: there is a
branch cut along the negative imaginary frequency axis, and a series of
isolated poles corresponding to damped excitations. All of these poles are
always in the lower half complex frequency plane, indicating stability. We show
that this analytic structure can be understood as the proper limit of finite
temperature results as T is taken to zero holding the chemical potential fixed.Comment: 28 pages, 7 figures, added reference
Bosonic excitations of the AdS4 Reissner-Nordstrom black hole
We study the long-lived modes of the charge density and energy density
correlators in the strongly-coupled, finite density field theory dual to the
AdS4 Reissner-Nordstrom black hole. For small momenta q<<\mu, these correlators
contain a pole due to sound propagation, as well as a pole due to a long-lived,
purely imaginary mode analogous to the \mu=0 hydrodynamic charge diffusion
mode. As the temperature is raised in the range T\lesssim\mu, the sound
attenuation shows no significant temperature dependence. When T\gtrsim\mu, it
quickly approaches the \mu=0 hydrodynamic result where it decreases like 1/T.
It does not share any of the temperature-dependent properties of the 'zero
sound' of Landau Fermi liquids observed in the strongly-coupled D3/D7 field
theory. For such small momenta, the energy density spectral function is
dominated by the sound mode at all temperatures, whereas the charge density
spectral function undergoes a crossover from being dominated by the sound mode
at low temperatures to being dominated by the diffusion mode when T \mu^2/q.
This crossover occurs due to the changing residue at each pole. We also compute
the momentum dependence of these spectral functions and their corresponding
long-lived poles at fixed, low temperatures T<<\mu.Comment: 33 pages, 21 figures, 6 animation
Features of mammalian microRNA promoters emerge from polymerase II chromatin immunoprecipitation data
Background: MicroRNAs (miRNAs) are short, non-coding RNA regulators of protein coding genes. miRNAs play a very important role in diverse biological processes and various diseases. Many algorithms are able to predict miRNA genes and their targets, but their transcription regulation is still under investigation. It is generally believed that intragenic miRNAs (located in introns or exons of protein coding genes) are co-transcribed with their host genes and most intergenic miRNAs transcribed from their own RNA polymerase II (Pol II) promoter. However, the length of the primary transcripts and promoter organization is currently unknown. Methodology: We performed Pol II chromatin immunoprecipitation (ChIP)-chip using a custom array surrounding regions of known miRNA genes. To identify the true core transcription start sites of the miRNA genes we developed a new tool (CPPP). We showed that miRNA genes can be transcribed from promoters located several kilobases away and that their promoters share the same general features as those of protein coding genes. Finally, we found evidence that as many as 26% of the intragenic miRNAs may be transcribed from their own unique promoters. Conclusion: miRNA promoters have similar features to those of protein coding genes, but miRNA transcript organization is more complex. © 2009 Corcoran et al
Investigation of the Role of Mitochondrial DNA in Multiple Sclerosis Susceptibility
Several lines of evidence suggest that mitochondrial genetic factors may influence susceptibility to multiple sclerosis. To explore this hypothesis further, we re-sequenced the mitochondrial genome (mtDNA) from 159 patients with multiple sclerosis and completed a haplogroup analysis including a further 835 patients and 1,506 controls. A trend towards over-representation of super-haplogroup U was the only evidence for association with mtDNA that we identified in these samples. In a parallel analysis of nuclear encoded mitochondrial genes, we also found a trend towards association with the complex I gene, NDUFS2. These results add to the evidence suggesting that variation in mtDNA and nuclear encoded mitochondrial genes may contribute to disease susceptibility in multiple sclerosis
Treating Cancer as an Infectious Disease—Viral Antigens as Novel Targets for Treatment and Potential Prevention of Tumors of Viral Etiology
Nearly 20% of human cancers worldwide have an infectious etiology with the most prominent examples being hepatitis B and C virus-associated hepatocellular carcinoma and human papilloma virus-associated cervical cancer. There is an urgent need to find new approaches to treatment and prevention of virus-associated cancers.Viral antigens have not been previously considered as targets for treatment or prevention of virus-associated cancers. We hypothesized that it was possible to treat experimental HPV16-associated cervical cancer (CC) and Hepatitis B-associated hepatocellular carcinoma (HCC) by targeting viral antigens expressed on cancer cells with radiolabeled antibodies to viral antigens. Treatment of experimental CC and HCC tumors with (188)Re-labeled mAbs to E6 and HBx viral proteins, respectively, resulted in significant and dose-dependent retardation of tumor growth in comparison with untreated mice or mice treated with unlabeled antibodies.This strategy is fundamentally different from the prior uses of radioimmunotherapy in oncology, which targeted tumor-associated human antigens and promises increased specificity and minimal toxicity of treatment. It also raises an exciting possibility to prevent virus-associated cancers in chronically infected patients by eliminating cells infected with oncogenic viruses before they transform into cancer
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