Profile of Xeomin® (incobotulinumtoxinA) for the treatment of blepharospasm

Even though conventional botulinum neurotoxin (BoNT) products have shown successful treatment results in patients with benign blepharospasm (BEB), the main, potential long-term side effect of BoNT use is the development of immunologic resistance due to the production of neutralizing antibody to the neurotoxin after repeated injections. Xeomin® (incobotulinumtoxinA), a unique botulinum neurotoxin type A (BoNT/A) drug free of complexing proteins otherwise contained in all conventional BoNT/A drugs, was recently approved by US Food and Drug Administration for the treatment of cervical dystonia or blepharospasm in adults. The newly approved BoNT/A drug may overcome this limitation of previous conventional products, since it contains pure neurotoxin (150 kDa) through a manufacturing process that separates it from complexing proteins such as hemagglutinins produced by fermentation of Clostridium botulinum. Many studies have also shown that Xeomin® has the same efficacy and safety profile as complexing protein-containing products such as Botox® and is exchangeable with Botox® using a simple 1:1 conversion ratio. Xeomin® represents a new treatment option for the repeated treatment of patients with blepharospasm in that it may reduce antibody-induced therapy failure. But, long-term comparative trials in naïve patients between Xeomin® and conventional BoNT/A drugs are required to confirm the low immunogenicity of Xeomin®

High Resolution X-ray Spectroscopy of G292.0+1.8/MSH 11-54

We present a preliminary analysis of XMM-Newton observations of the oxygen-rich supernova remnant G292.0+1.8 (MSH 11-54). Although the spatial extent of the remnant is 8 arcmin the bright central bar is narrow (1'-2') resulting in RGS spectra of a high spectral quality. This allows us to spectroscopically identify a cool, Te = 0.3 keV, and underionized component, resolve details of the Fe-L complex, and resolve the forbidden and resonant lines of the O VII triplet. We are also able to constrain the kinematics of the remnant using Ne IX as observed in the second order spectrum, and O VIII in the first order spectrum. We do not find evidence for O VII line shifts or Doppler broadening (sigma_v < 731 km/s), but line broadening of the Ne X Ly-alpha line seems to be present, corresponding to sigma_v ~ 1500 km/s.Comment: To appear in Proc. of the BeppoSAX Symposium: "The Restless High-Energy Universe", E.P.J. van den Heuvel, J.J.M. in 't Zand, and R.A.M.J. Wijers (Eds

Incommensurate Transverse Anisotropy Induced by Disorder and Spin-Orbit-Vibron Coupling in Mn12-acetate

It has been shown within density-functional theory that in Mn$_{12}$-acetate there are effects due to disorder by solvent molecules and a coupling between vibrational and electronic degrees of freedom. We calculate the in-plane principal axes of the second-order anisotropy caused by the second effect and compare them with those of the fourth-order anisotropy due to the first effect. We find that the two types of the principal axes are not commensurate with each other, which results in a complete quenching of the tunnel-splitting oscillation as a function of an applied transverse field.Comment: Will be presented at MMM conference 200

Isolating Triggered Star Formation

Galaxy pairs provide a potentially powerful means of studying triggered star formation from galaxy interactions. We use a large cosmological N-body simulation coupled with a well-tested semi-analytic substructure model to demonstrate that the majority of galaxies in close pairs reside within cluster or group-size halos and therefore represent a biased population, poorly suited for direct comparison to ``field'' galaxies. Thus, the frequent observation that some types of galaxies in pairs have redder colors than ``field'' galaxies is primarily a selection effect. We select galaxy pairs that are isolated in their dark matter halos with respect to other massive subhalos (N=2 halos) and a control sample of isolated galaxies (N=1 halos) for comparison. We then apply these selection criteria to a volume-limited subset of the 2dF Galaxy Redshift Survey with M_Bj <= -19 and obtain the first clean measure of the typical fraction of galaxies affected by triggered star formation and the average elevation in the star formation rate. We find that 24% (30.5%) of these L^\star and sub-L^{\star} galaxies in isolated 50 (30) kpc/h pairs exhibit star formation that is boosted by a factor of >~ 5 above their average past value, while only 10% of isolated galaxies in the control sample show this level of enhancement. Thus, 14% (20 %) of the galaxies in these close pairs show clear triggered star formation. The isolation criteria we develop provide a means to constrain star formation and feedback prescriptions in hydrodynamic simulations and a very general method of understanding the importance of triggered star formation in a cosmological context. (Abridged.)Comment: 12 pages, 10 figures, emulateapj format, accepted by Ap

Molecular determinants of chaperone interactions on MHC-I for folding and antigen repertoire selection.

The interplay between a highly polymorphic set of MHC-I alleles and molecular chaperones shapes the repertoire of peptide antigens displayed on the cell surface for T cell surveillance. Here, we demonstrate that the molecular chaperone TAP-binding protein related (TAPBPR) associates with a broad range of partially folded MHC-I species inside the cell. Bimolecular fluorescence complementation and deep mutational scanning reveal that TAPBPR recognition is polarized toward the α2 domain of the peptide-binding groove, and depends on the formation of a conserved MHC-I disulfide epitope in the α2 domain. Conversely, thermodynamic measurements of TAPBPR binding for a representative set of properly conformed, peptide-loaded molecules suggest a narrower MHC-I specificity range. Using solution NMR, we find that the extent of dynamics at "hotspot" surfaces confers TAPBPR recognition of a sparsely populated MHC-I state attained through a global conformational change. Consistently, restriction of MHC-I groove plasticity through the introduction of a disulfide bond between the α1/α2 helices abrogates TAPBPR binding, both in solution and on a cellular membrane, while intracellular binding is tolerant of many destabilizing MHC-I substitutions. Our data support parallel TAPBPR functions of 1) chaperoning unstable MHC-I molecules with broad allele-specificity at early stages of their folding process, and 2) editing the peptide cargo of properly conformed MHC-I molecules en route to the surface, which demonstrates a narrower specificity. Our results suggest that TAPBPR exploits localized structural adaptations, both near and distant to the peptide-binding groove, to selectively recognize discrete conformational states sampled by MHC-I alleles, toward editing the repertoire of displayed antigens

Supersymmetry and Positive Energy in Classical and Quantum Two-Dimensional Dilaton Gravity

An $N = 1$ supersymmetric version of two dimensional dilaton gravity coupled to matter is considered. It is shown that the linear dilaton vacuum spontaneously breaks half the supersymmetries, leaving broken a linear combination of left and right supersymmetries which squares to time translations. Supersymmetry suggests a spinorial expression for the ADM energy $M$, as found by Witten in four-dimensional general relativity. Using this expression it is proven that ${M}$ is non-negative for smooth initial data asymptotic (in both directions) to the linear dilaton vacuum, provided that the (not necessarily supersymmetric) matter stress tensor obeys the dominant energy condition. A {\it quantum} positive energy theorem is also proven for the semiclassical large-$N$ equations, despite the indefiniteness of the quantum stress tensor. For black hole spacetimes, it is shown that $M$ is bounded from below by $e^{- 2 \phi_H}$, where $\phi_H$ is the value of the dilaton at the apparent horizon, provided only that the stress tensor is positive outside the apparent horizon. This is the two-dimensional analogue of an unproven conjecture due to Penrose. Finally, supersymmetry is used to prove positive energy theorems for a large class of generalizations of dilaton gravity which arise in consideration of the quantum theory.Comment: 21 page

Association between Outdoor Air Pollution and Childhood Leukemia: A Systematic Review and Dose-Response Meta-Analysis.

BackgroundA causal link between outdoor air pollution and childhood leukemia has been proposed, but some older studies suffer from methodological drawbacks. To the best of our knowledge, no systematic reviews have summarized the most recently published evidence and no analyses have examined the dose-response relation.ObjectiveWe investigated the extent to which outdoor air pollution, especially as resulting from traffic-related contaminants, affects the risk of childhood leukemia.MethodsWe searched all case-control and cohort studies that have investigated the risk of childhood leukemia in relation to exposure either to motorized traffic and related contaminants, based on various traffic-related metrics (number of vehicles in the closest roads, road density, and distance from major roads), or to measured or modeled levels of air contaminants such as benzene, nitrogen dioxide, 1,3-butadiene, and particulate matter. We carried out a meta-analysis of all eligible studies, including nine studies published since the last systematic review and, when possible, we fit a dose-response curve using a restricted cubic spline regression model.ResultsWe found 29 studies eligible to be included in our review. In the dose-response analysis, we found little association between disease risk and traffic indicators near the child's residence for most of the exposure range, with an indication of a possible excess risk only at the highest levels. In contrast, benzene exposure was positively and approximately linearly associated with risk of childhood leukemia, particularly for acute myeloid leukemia, among children under 6 y of age, and when exposure assessment at the time of diagnosis was used. Exposure to nitrogen dioxide showed little association with leukemia risk except at the highest levels.DiscussionOverall, the epidemiologic literature appears to support an association between benzene and childhood leukemia risk, with no indication of any threshold effect. A role for other measured and unmeasured pollutants from motorized traffic is also possible. https://doi.org/10.1289/EHP4381

Kaposi's Sarcoma-Associated Herpesvirus-Related Solid Lymphoma Involving the Heart and Brain

Since its discovery in 1994, Kaposi's sarcoma-associated herpesvirus (KSHV) has been associated with lymphoproliferative disorders, particularly in patients infected with human immunodeficiency virus (HIV). The disorders most strongly linked to KSHV are multicentric Castleman's Disease (MCD), primary effusion lymphoma, and diffuse large B-cell lymphomas. We report an unusual case of KSHV-associated lymphoma in an HIV-infected patient manifesting with myocardial and central nervous system involvement. We discuss this case in the context of increasing array of KSHV-associated lymphomas. In the HIV-infected patient with a mass lesion, a history of cutaneous Kaposi's sarcoma and prolonged immunosuppression should alert clinicians as to the possibility of KSHV-associated lymphoproliferative disorders, in order to establish a timely diagnosis