Searching for a Stochastic Background of Gravitational Waves with LIGO

The Laser Interferometer Gravitational-wave Observatory (LIGO) has performed the fourth science run, S4, with significantly improved interferometer sensitivities with respect to previous runs. Using data acquired during this science run, we place a limit on the amplitude of a stochastic background of gravitational waves. For a frequency independent spectrum, the new limit is $\Omega_{\rm GW} < 6.5 \times 10^{-5}$. This is currently the most sensitive result in the frequency range 51-150 Hz, with a factor of 13 improvement over the previous LIGO result. We discuss complementarity of the new result with other constraints on a stochastic background of gravitational waves, and we investigate implications of the new result for different models of this background.Comment: 37 pages, 16 figure

Carotid endarterectomy and carotid artery stenting utilization trends over time

<p>Abstract</p> <p>Background</p> <p>Carotid endarterectomy (CEA) has been the standard in atherosclerotic stroke prevention for over 2 decades. More recently, carotid artery stenting (CAS) has emerged as a less invasive alternative for revascularization. The purpose of this study was to investigate whether an increase in stenting parallels a decrease in endarterectomy, if there are specific patient factors that influence one intervention over the other, and how these factors may have changed over time.</p> <p>Methods</p> <p>Using a nationally representative sample of US hospital discharge records, data on CEA and CAS procedures performed from 1998 to 2008 were obtained. In total, 253,651 cases of CEA and CAS were investigated for trends in utilization over time. The specific data elements of age, gender, payer source, and race were analyzed for change over the study period, and their association with type of intervention was examined by multiple logistic regression analysis.</p> <p>Results</p> <p>Rates of intervention decreased from 1998 to 2008 (P < 0.0001). Throughout the study period, endarterectomy was the much more widely employed procedure. Its use displayed a significant downward trend (P < 0.0001), with the lowest rates of intervention occurring in 2007. In contrast, carotid artery stenting displayed a significant increase in use over the study period (P < 0.0001), with the highest intervention rates occurring in 2006. Among the specific patient factors analyzed that may have altered utilization of CEA and CAS over time, the proportion of white patients who received intervention decreased significantly (P < 0.0001). In multivariate modeling, increased age, male gender, white race, and earlier in the study period were significant positive predictors of CEA use.</p> <p>Conclusions</p> <p>Rates of carotid revascularization have decreased over time, although this has been the result of a reduction in CEA despite an overall increase in CAS. Among the specific patient factors analyzed, age, gender, race, and time were significantly associated with the utilization of these two interventions.</p

A Micro RNA Processing Defect in Rapidly Progressing Idiopathic Pulmonary Fibrosis

BACKGROUND: Idiopathic pulmonary fibrosis exhibits differential progression from the time of diagnosis but the molecular basis for varying progression rates is poorly understood. The aim of the present study was to ascertain whether differential miRNA expression might provide one explanation for rapidly versus slowly progressing forms of IPF. METHODOLOGY AND PRINCIPAL FINDINGS: miRNA and mRNA were isolated from surgical lung biopsies from IPF patients with a clinically documented rapid or slow course of disease over the first year after diagnosis. A quantitative PCR miRNA array containing 88 of the most abundant miRNA in the human genome was used to profile lung biopsies from 9 patients with rapidly progressing IPF, 6 patients with slowly progressing IPF, and 10 normal lung biopsies. Using this approach, 11 miRNA were significantly increased and 36 were significantly decreased in rapid biopsies compared with normal biopsies. Slowly progressive biopsies exhibited 4 significantly increased miRNA and 36 significantly decreased miRNA compared with normal lung. Among the miRNA present in IPF with validated mRNA targets were those with regulatory effects on epithelial-mesenchymal transition (EMT). Five miRNA (miR-302c, miR-423-5p, miR-210, miR-376c, and miR-185) were significantly increased in rapid compared with slow IPF lung biopsies. Additional analyses of rapid biopsies and fibroblasts grown from the same biopsies revealed that the expression of AGO1 and AGO2 (essential components of the miRNA processing RISC complex) were lower compared with either slow or normal lung biopsies and fibroblasts. CONCLUSION: These findings suggest that the development and/or clinical progression of IPF might be the consequence of aberrant miRNA processing

Search of the Orion spur for continuous gravitational waves using a loosely coherent algorithm on data from LIGO interferometers

We report results of a wideband search for periodic gravitational waves from isolated neutron stars within the Orion spur towards both the inner and outer regions of our Galaxy. As gravitational waves interact very weakly with matter, the search is unimpeded by dust and concentrations of stars. One search disk (A) is 6.87° in diameter and centered on 20h10m54.71s+33°33′25.29′′, and the other (B) is 7.45° in diameter and centered on 8h35m20.61s-46°49′25.151′′. We explored the frequency range of 50-1500 Hz and frequency derivative from 0 to -5×10-9 Hz/s. A multistage, loosely coherent search program allowed probing more deeply than before in these two regions, while increasing coherence length with every stage. Rigorous follow-up parameters have winnowed the initial coincidence set to only 70 candidates, to be examined manually. None of those 70 candidates proved to be consistent with an isolated gravitational-wave emitter, and 95% confidence level upper limits were placed on continuous-wave strain amplitudes. Near 169 Hz we achieve our lowest 95% C.L. upper limit on the worst-case linearly polarized strain amplitude h0 of 6.3×10-25, while at the high end of our frequency range we achieve a worst-case upper limit of 3.4×10-24 for all polarizations and sky locations. © 2016 American Physical Society

A role for NPY-NPY2R signaling in albuminuric kidney disease

Albuminuria is an independent risk factor for the progression to end-stage kidney failure, cardiovascular morbidity, and premature death. As such, discovering signaling pathways that modulate albuminuria is desirable. Here, we studied the transcriptomes of podocytes, key cells in the prevention of albuminuria, under diabetic conditions. We found that Neuropeptide Y (NPY) was significantly down-regulated in insulin-resistant vs. insulin-sensitive mouse podocytes and in human glomeruli of patients with early and late-stage diabetic nephropathy, as well as other nondiabetic glomerular diseases. This contrasts with the increased plasma and urinary levels of NPY that are observed in such conditions. Studying NPY-knockout mice, we found that NPY deficiency in vivo surprisingly reduced the level of albuminuria and podocyte injury in models of both diabetic and nondiabetic kidney disease. In vitro, podocyte NPY signaling occurred via the NPY2 receptor (NPY2R), stimulating PI3K, MAPK, and NFAT activation. Additional unbiased proteomic analysis revealed that glomerular NPY-NPY2R signaling predicted nephrotoxicity, modulated RNA processing, and inhibited cell migration. Furthermore, pharmacologically inhibiting the NPY2R in vivo significantly reduced albuminuria in adriamycin-treated glomerulosclerotic mice. Our findings suggest a pathogenic role of excessive NPY-NPY2R signaling in the glomerulus and that inhibiting NPY-NPY2R signaling in albuminuric kidney disease has therapeutic potential. Chronic kidney disease (CKD) is a major global healthcare concern, affecting over 10% of the general population, and frequently occurs secondary to other systemic disorders including diabetes, obesity, hypertension, and the metabolic syndrome. A common early hallmark of CKD is albuminuria, which not only reflects damage to the glomerular filtration barrier (GFB) in the kidney but also is an important independent risk factor for the progression to end-stage renal failure and cardiovascular disease (1⇓–3). Thus, strategies to prevent albuminuria have important therapeutic potential, particularly in the early stages of CKD progression. Podocytes are highly specialized epithelial cells of the glomerulus, lining the urinary side of the filtration barrier. Owing to their complex, dynamic structures and their ability to secrete (and adapt to) a number of growth factors, these cells have a central role in filtration barrier maintenance (4). As such, podocyte damage is a key driver of albuminuria and glomerular disease in numerous settings and occurs early in the pathogenesis of many albuminuric conditions (5⇓⇓⇓–9). While it is well-established that podocyte damage is a major cause of albuminuria (8), the pathways and molecules involved in podocyte injury are incompletely understood. We (10, 11) and others (12, 13) have highlighted the importance of podocyte insulin responses in maintaining glomerular function, and it is now evident that circulating factors associated with common systemic disorders, including diabetes, obesity, and the metabolic syndrome, can directly induce podocyte insulin resistance (14⇓⇓–17) and associated damage (15, 18). In this study, we analyzed the transcriptomes of insulin-sensitive and insulin-resistant podocytes with the aim of identifying molecules that are differentially regulated in podocyte damage, which may play a role in albuminuric kidney disease. This unbiased transcriptome analysis revealed that Neuropeptide Y (Npy) was the most highly down-regulated transcript in insulin-resistant vs. insulin-sensitive podocytes. Analysis of patient cohorts also revealed a significant reduction in glomerular NPY expression in both early and late-stage diabetic nephropathy (DN), as well as in several other human albuminuric conditions. This contrasts with the increased plasma and urinary levels of NPY that are observed in diabetes and CKD (19⇓⇓–22). This prompted us to further investigate the potential role of NPY (and NPY signaling) in the podocyte and glomerulus

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes