The Case for Abandoning Therapeutic Chelation of Copper Ions in Alzheimer's Disease

The “therapeutic chelation” approach to treating Alzheimer's disease (AD) evolved from the metals hypothesis, with the premise that small molecules can be designed to prevent transition metal-induced amyloid deposition and oxidative stress within the AD brain. Over more than 20 years, countless in vitro studies have been devoted to characterizing metal binding, its effect on Aβ aggregation, ROS production, and in vitro toxicity. Despite a lack of evidence for any clinical benefit, the conjecture that therapeutic chelation is an effective approach for treating AD remains widespread. Here, the author plays the devil's advocate, questioning the experimental evidence, the dogma, and the value of therapeutic chelation, with a major focus on copper ions

Near-Infrared Spectroscopy of McNeil's Nebula Object

We present 0.8-5.2 micron spectroscopy of the compact source at the base of a variable nebula (McNeil's Nebula Object) in the Lynds 1630 dark cloud that went into outburst in late 2003. The spectrum of this object reveals an extremely red continuum, CO bands at 2.3-2.5 microns in emission, a deep 3.0 micron ice absorption feature, and a solid state CO absorption feature at 4.7 microns. In addition, emission lines of H, Ca II, Mg I, and Na I are present. The Paschen lines exhibit P Cygni profiles, as do two lines of He I, although the emission features are very weak in the latter. The Brackett lines, however, are seen to be purely in emission. The P Cygni profiles clearly indicate that mass outflow is occurring in a wind with a velocity of ~400 km/s. The H line ratios do not yield consistent estimates of the reddening, nor do they agree with the extinction estimated from the ice feature (A_V ~ 11). We propose that these lines are optically thick and are produced in a dense, ionized wind. The near-infrared spectrum does not appear similar to any known FUor or EXor object. However, all evidence suggests that McNeil's Nebula Object is a heavily-embedded low-mass Class I protostar, surrounded by a disk, whose brightening is due to a recent accretion event.Comment: 11 pages, 2 ps figures, accepted for publication in ApJ Letter

The Antioxidant Moiety of MitoQ Imparts Minimal Metabolic Effects in Adipose Tissue of High Fat Fed Mice

Mitochondrial dysfunction is associated with a diverse array of diseases ranging from dystrophy and heart failure to obesity and hepatosteatosis. One of the major biochemical consequences of impaired mitochondrial function is an accumulation of mitochondrial superoxide, or reactive oxygen species (ROS). Excessive ROS can be detrimental to cellular health and is proposed to underpin many mitochondrial diseases. Accordingly, much research has been committed to understanding ways to therapeutically prevent and reduce ROS accumulation. In white adipose tissue (WAT), ROS is associated with obesity and its subsequent complications, and thus reducing mitochondrial ROS may represent a novel strategy for treating obesity related disorders. One therapeutic approach employed to reduce ROS abundance is the mitochondrial-targeted coenzyme Q (MitoQ), which enables mitochondrial specific delivery of a CoQ10 antioxidant via its triphenylphosphonium bromide (TPP+) cation. Indeed, MitoQ has been successfully shown to accumulate at the outer mitochondrial membrane and prevent ROS accumulation in several tissues in vivo; however, the specific effects of MitoQ on adipose tissue metabolism in vivo have not been studied. Here we demonstrate that mice fed high-fat diet with concomitant administration of MitoQ, exhibit minimal metabolic benefit in adipose tissue. We also demonstrate that both MitoQ and its control agent dTPP+ had significant and equivalent effects on whole-body metabolism, suggesting that the dTPP+ cation rather than the antioxidant moiety, was responsible for these changes. These findings have important implications for future studies using MitoQ and other TPP+ compounds

Stereotactic body radiotherapy for primary prostate cancer

Prostate cancer is the most common non-cutaneous cancer in males. There are a number of options for patients with localized early stage disease, including active surveillance for low-risk disease, surgery, brachytherapy, and external beam radiotherapy. Increasingly, external beam radiotherapy, in the form of dose-escalated and moderately hypofractionated regimens, is being utilized in prostate cancer, with randomized evidence to support their use. Stereotactic body radiotherapy, which is a form of extreme hypofractionation, delivered with high precision and conformality typically over 1 to 5 fractions, offers a more contemporary approach with several advantages including being non-invasive, cost-effective, convenient for patients, and potentially improving patient access. In fact, one study has estimated that if half of the patients currently eligible for conventional fractionated radiotherapy in the United States were treated instead with stereotactic body radiotherapy, this would result in a total cost savings of US$250 million per year. There is also a strong radiobiological rationale to support its use, with prostate cancer believed to have a low alpha/beta ratio and therefore being preferentially sensitive to larger fraction sizes. To date, there are no published randomized trials reporting on the comparative efficacy of stereotactic body radiotherapy compared to alternative treatment modalities, although multiple randomized trials are currently accruing. Yet, early results from the randomized phase III study of HYPOfractionated RadioTherapy of intermediate risk localized Prostate Cancer (HYPO-RT-PC) trial, as well as multiple single-arm phase I/II trials, indicate low rates of late adverse effects with this approach. In patients with low-to intermediate-risk disease, excellent biochemical relapse-free survival outcomes have been reported, albeit with relatively short median follow-up times. These promising early results, coupled with the enormous potential cost savings and implications for resource availability, suggest that stereotactic body radiotherapy will take center stage in the treatment of prostate cancer in the years to come

Growth anomalies on the coral genera Acropora and Porites are strongly associated with host density and human population size across the Indo-Pacific

Growth anomalies (GAs) are common, tumor-like diseases that can cause significant morbidity and decreased fecundity in the major Indo-Pacific reef-building coral genera, Acropora and Porites. GAs are unusually tractable for testing hypotheses about drivers of coral disease because of their pan-Pacific distributions, relatively high occurrence, and unambiguous ease of identification. We modeled multiple disease-environment associations that may underlie the prevalence of Acropora growth anomalies (AGA) (n = 304 surveys) and Porites growth anomalies (PGA) (n = 602 surveys) from across the Indo-Pacific. Nine predictor variables were modeled, including coral host abundance, human population size, and sea surface temperature and ultra-violet radiation anomalies. Prevalence of both AGAs and PGAs were strongly host density-dependent. PGAs additionally showed strong positive associations with human population size. Although this association has been widely posited, this is one of the first broad-scale studies unambiguously linking a coral disease with human population size. These results emphasize that individual coral diseases can show relatively distinct patterns of association with environmental predictors, even in similar diseases (growth anomalies) found on different host genera (Acropora vs. Porites). As human densities and environmental degradation increase globally, the prevalence of coral diseases like PGAs could increase accordingly, halted only perhaps by declines in host density below thresholds required for disease establishment

A two-domain elevator mechanism for sodium/proton antiport

Sodium/proton (Na+/H+) antiporters, located at the plasma membrane in every cell, are vital for cell homeostasis1. In humans, their dysfunction has been linked to diseases, such as hypertension, heart failure and epilepsy, and they are well-established drug targets2. The best understood model system for Na+/H+ antiport is NhaA from Escherichia coli1, 3, for which both electron microscopy and crystal structures are available4, 5, 6. NhaA is made up of two distinct domains: a core domain and a dimerization domain. In the NhaA crystal structure a cavity is located between the two domains, providing access to the ion-binding site from the inward-facing surface of the protein1, 4. Like many Na+/H+ antiporters, the activity of NhaA is regulated by pH, only becoming active above pH 6.5, at which point a conformational change is thought to occur7. The only reported NhaA crystal structure so far is of the low pH inactivated form4. Here we describe the active-state structure of a Na+/H+ antiporter, NapA from Thermus thermophilus, at 3 Å resolution, solved from crystals grown at pH 7.8. In the NapA structure, the core and dimerization domains are in different positions to those seen in NhaA, and a negatively charged cavity has now opened to the outside. The extracellular cavity allows access to a strictly conserved aspartate residue thought to coordinate ion binding1, 8, 9 directly, a role supported here by molecular dynamics simulations. To alternate access to this ion-binding site, however, requires a surprisingly large rotation of the core domain, some 20° against the dimerization interface. We conclude that despite their fast transport rates of up to 1,500 ions per second3, Na+/H+ antiporters operate by a two-domain rocking bundle model, revealing themes relevant to secondary-active transporters in general

State-resolved valence shell photoionization of Be-like ions: experiment and theory

High-resolution photoionization experiments were carried out using beams of Be-like C$^{2+}$, N$^{3+}$, and O$^{4+}$ ions with roughly equal populations of the $^1$S ground-state and the $^3$P$^o$ manifold of metastable components. The energy scales of the experiments are calibrated with uncertainties of 1 to 10 meV depending on photon energy. Resolving powers beyond 20,000 were reached allowing for the separation of contributions from the individual metastable $^3$P$^o_0$, $^3$P$^o_1$, and $^3$P$^o_2$ states. The measured data compare favourably with semi-relativistic Breit-Pauli R-matrixComment: 23 figures and 3 table

UWISH2 -- The UKIRT Widefield Infrared Survey for H2

We present the goals and preliminary results of an unbiased, near-infrared, narrow-band imaging survey of the First Galactic Quadrant (10deg<l<65deg ; -1.3deg<b<+1.3deg). This area includes most of the Giant Molecular Clouds and massive star forming regions in the northern hemisphere. The survey is centred on the 1-0S(1) ro-vibrational line of H2, a proven tracer of hot, dense molecular gas in star-forming regions, around evolved stars, and in supernova remnants. The observations complement existing and upcoming photometric surveys (Spitzer-GLIMPSE, UKIDSS-GPS, JCMT-JPS, AKARI, Herschel Hi-GAL, etc.), though we probe a dynamically active component of star formation not covered by these broad-band surveys. Our narrow-band survey is currently more than 60% complete. The median seeing in our images is 0.73arcsec. The images have a 5sigma detection limit of point sources of K=18mag and the surface brightness limit is 10^-19Wm^-2arcsec^-2 when averaged over our typical seeing. Jets and outflows from both low and high mass Young Stellar Objects are revealed, as are new Planetary Nebulae and - via a comparison with earlier K-band observations acquired as part of the UKIDSS GPS - numerous variable stars. With their superior spatial resolution, the UWISH2 data also have the potential to reveal the true nature of many of the Extended Green Objects found in the GLIMPSE survey.Comment: 14pages, 8figures, 2tables, accepted for publication by MNRAS, a version with higher resolution figures can be found at http://astro.kent.ac.uk/~df

Rectus sheath haematoma or leaking aortic aneurysm - a diagnostic challenge: a case report

© 2009 Shaw et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Infrared Properties of Cataclysmic Variables from 2MASS: Results from the 2nd Incremental Data Release

Because accretion-generated luminosity dominates the radiated energy of most cataclysmic variables, they have been ``traditionally'' observed primarily at short wavelengths. Infrared observations of cataclysmic variables contribute to the understanding of key system components that are expected to radiate at these wavelengths, such as the cool outer disk, accretion stream, and secondary star. We have compiled the J, H, and Ks photometry of all cataclysmic variables located in the sky coverage of the 2 Micron All Sky Survey (2MASS) 2nd Incremental Data Release. This data comprises 251 systems with reliably identified near-IR counterparts and S/N > 10 photometry in one or more of the three near-IR bands.Comment: 2 pages, including 1 figure. To appear in the proceedings of The Physics of Cataclysmic Variables and Related Objects, Goettingen, Germany. For our followup ApJ paper (in press), also see http://www.ctio.noao.edu/~hoard/research/2mass/index.htm