Aldosterone Receptor Blockade in Patients with Left Ventricular Systolic Dysfunction Following Acute Myocardial Infarction

Left ventricular systolic dysfunction (LVSD) is a common complication of acute myocardial infarction (AMI) that occurs in approximately 30% of post-AMI patients, and results in a threefold increase in in-hospital and 6-month mortality, regardless of type of AMI. Post-AMI care has evolved to include early reperfusion, antiplatelet therapy, hydroxymethylglutaryl coenzyme A reductase inhibitors (stains), beta blockers, angiotentsin-converting enzyme inhibitors, and angiotensin receptor blockers. Despite these therapies, however, there is still an excess of sudden cardiac death (SCD), especially in patients with severe LVSD and in the first 30 days post-AMI. Aldosterone has been shown to be elevated in patients with post-AMI LVSD and to have deleterious effects on the myocardium, including endothelial dysfunction, collagen deposition, inflammation, apoptosis, and autonomic instability, leading to left ventricular remodeling and SCD. Aldosterone blockade with eplerenone has been shown to reduce mortality even in the presence of optimal post-AMI therapy in patients with post-AMI LVSD. Despite this, eplerenone is underutilized in real-world clinical practice. Care must be taken to follow renal function and potassium balance in patients treated with eplerenone. © 2008 Elsevier Inc. All rights reserved

The Distance to the Cygnus Loop from Hubble Space Telescope Imaging of the Primary Shock Front

We present a Hubble Space Telescope/WFPC2 narrow-band H-alpha image of a region on the northeastern limb of the Cygnus Loop supernova remnant. This location provides a detailed example of where the primary blast wave first encounters the surrounding interstellar medium. The filament structure is seen in exquisite detail in this image, which was obtained primarily as an EARLY ACQuisition image for a follow-up spectroscopic program. We compare the HST image to a digitized version of the POSS-I red plate to measure the proper motion of this filament. By combining this value for the proper motion with previous measurements of the shock velocity at this position we find that the distance to the Cygnus Loop is 440 (+130, -100) pc, considerably smaller than the canonical value of 770 pc. We briefly discuss the ramifications of this new distance estimate for our understanding of this prototypical supernova remnant.Comment: 18 pages, 3 Figures (2 JPEG and one Postscript

Local light-ray rotation

We present a sheet structure that rotates the local ray direction through an arbitrary angle around the sheet normal. The sheet structure consists of two parallel Dove-prism sheets, each of which flips one component of the local direction of transmitted light rays. Together, the two sheets rotate transmitted light rays around the sheet normal. We show that the direction under which a point light source is seen is given by a Mobius transform. We illustrate some of the properties with movies calculated by ray-tracing software.Comment: 9 pages, 6 figure

Cyclooxygenase-2 expression in oligodendrocytes increases sensitivity to excitotoxic death

<p>Abstract</p> <p>Background</p> <p>We previously found that cyclooxygenase 2 (COX-2) was expressed in dying oligodendrocytes at the onset of demyelination in the Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) model of multiple sclerosis (MS) (Carlson et al. J.Neuroimmunology 2006, 149:40). This suggests that COX-2 may contribute to death of oligodendrocytes.</p> <p>Objective</p> <p>The goal of this study was to examine whether COX-2 contributes to excitotoxic death of oligodendrocytes and potentially contributes to demyelination.</p> <p>Methods</p> <p>The potential link between COX-2 and oligodendrocyte death was approached using histopathology of MS lesions to examine whether COX-2 was expressed in dying oligodendrocytes. COX-2 inhibitors were examined for their ability to limit demyelination in the TMEV-IDD model of MS and to limit excitotoxic death of oligodendrocytes <it>in vitro</it>. Genetic manipulation of COX-2 expression was used to determine whether COX-2 contributes to excitotoxic death of oligodendrocytes. A transgenic mouse line was generated that overexpressed COX-2 in oligodendrocytes. Oligodendrocyte cultures derived from these transgenic mice were used to examine whether increased expression of COX-2 enhanced the vulnerability of oligodendrocytes to excitotoxic death. Oligodendrocytes derived from COX-2 knockout mice were evaluated to determine if decreased COX-2 expression promotes a greater resistance to excitotoxic death.</p> <p>Results</p> <p>COX-2 was expressed in dying oligodendrocytes in MS lesions. COX-2 inhibitors limited demyelination in the TMEV-IDD model of MS and protected oligodendrocytes against excitotoxic death <it>in vitro</it>. COX-2 expression was increased in wild-type oligodendrocytes following treatment with Kainic acid (KA). Overexpression of COX-2 in oligodendrocytes increased the sensitivity of oligodendrocytes to KA-induced excitotoxic death eight-fold compared to wild-type. Conversely, oligodendrocytes prepared from COX-2 knockout mice showed a significant decrease in sensitivity to KA induced death.</p> <p>Conclusions</p> <p>COX-2 expression was associated with dying oligodendrocytes in MS lesions and appeared to increase excitotoxic death of oligodendrocytes in culture. An understanding of how COX-2 expression influences oligodendrocyte death leading to demyelination may have important ramifications for future treatments for MS.</p

Rhodacyanine Derivative Selectively Targets Cancer Cells and Overcomes Tamoxifen Resistance

MKT-077, a rhodacyanine dye, was shown to produce cancer specific cell death. However, complications prevented the use of this compound beyond clinical trials. Here we describe YM-1, a derivative of MKT-077. We found that YM-1 was more cytotoxic and localized differently than MKT-077. YM-1 demonstrated this cytotoxicity across multiple cancer cell lines. This toxicity was limited to cancer cell lines; immortalized cell models were unaffected. Brief applications of YM-1 were found to be non-toxic. Brief treatment with YM-1 restored tamoxifen sensitivity to a refractory tamoxifen-resistant MCF7 cell model. This effect is potentially due to altered estrogen receptor alpha phosphorylation, an outcome precipitated by selective reductions in Akt levels (Akt/PKB). Thus, modifications to the rhodocyanine scaffold could potentially be made to improve efficacy and pharmacokinetic properties. Moreover, the impact on tamoxifen sensitivity could be a new utility for this compound family

Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden

Abstract Background It has traditionally been thought that the pathological accumulation of tau in Alzheimer's disease and other tauopathies facilitates neurodegeneration, which in turn leads to cognitive impairment. However, recent evidence suggests that tau tangles are not the entity responsible for memory loss, rather it is an intermediate tau species that disrupts neuronal function. Thus, efforts to discover therapeutics for tauopathies emphasize soluble tau reductions as well as neuroprotection. Results Here, we found that neuroprotection alone caused by methylene blue (MB), the parent compound of the anti-tau phenothiaziazine drug, Rember&#8482;, was insufficient to rescue cognition in a mouse model of the human tauopathy, progressive supranuclear palsy (PSP) and fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP17): Only when levels of soluble tau protein were concomitantly reduced by a very high concentration of MB, was cognitive improvement observed. Thus, neurodegeneration can be decoupled from tau accumulation, but phenotypic improvement is only possible when soluble tau levels are also reduced. Conclusions Neuroprotection alone is not sufficient to rescue tau-induced memory loss in a transgenic mouse model. Development of neuroprotective agents is an area of intense investigation in the tauopathy drug discovery field. This may ultimately be an unsuccessful approach if soluble toxic tau intermediates are not also reduced. Thus, MB and related compounds, despite their pleiotropic nature, may be the proverbial "magic bullet" because they not only are neuroprotective, but are also able to facilitate soluble tau clearance. Moreover, this shows that neuroprotection is possible without reducing tau levels. This indicates that there is a definitive molecular link between tau and cell death cascades that can be disrupted.http://deepblue.lib.umich.edu/bitstream/2027.42/78314/1/1750-1326-5-45.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78314/2/1750-1326-5-45.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/78314/3/1750-1326-5-45-S1.PDFPeer Reviewe

NilD CRISPR RNA contributes to Xenorhabdus nematophila colonization of symbiotic host nematodes

The bacterium Xenorhabdus nematophila is a mutualist of entomopathogenic Steinernema carpocapsae nematodes and facilitates infection of insect hosts. X. nematophila colonizes the intestine of S. carpocapsae which carries it between insects. In the X. nematophila colonization-defective mutant nilD6::Tn5, the transposon is inserted in a region lacking obvious coding potential. We demonstrate that the transposon disrupts expression of a single CRISPR RNA, NilD RNA. A variant NilD RNA also is expressed by X. nematophila strains from S. anatoliense and S. websteri nematodes. Only nilD from the S. carpocapsae strain of X. nematophila rescued the colonization defect of the nilD6::Tn5 mutant, and this mutant was defective in colonizing all three nematode host species. NilD expression depends on the presence of the associated Cas6e but not Cas3, components of the Type I-E CRISPR-associated machinery. While cas6e deletion in the complemented strain abolished nematode colonization, its disruption in the wild-type parent did not. Likewise, nilD deletion in the parental strain did not impact colonization of the nematode, revealing that the requirement for NilD is evident only in certain genetic backgrounds. Our data demonstrate that NilD RNA is conditionally necessary for mutualistic host colonization and suggest that it functions to regulate endogenous gene expression