Tobacco, hypertension, and vascular disease: Risk factors for renal functional decline in an older population

Tobacco, hypertension, and vascular disease: Risk factors for renal functional decline in an older population.BackgroundA decline in renal function with age has been noted in some but not all individuals. The purpose of this study was to identify risk factors associated with a clinically significant increase in serum creatinine (of at least 0.3 mg/dL) in an older nondiabetic population.MethodsA retrospective case-control study was performed analyzing data obtained from 4142 nondiabetic participants of the Cardiovascular Health Study Cohort, all at least 65 years of age, who had two measurements of serum creatinine performed at least three years apart. Cases were identified as participants who developed an increase in serum creatinine of at least 0.3 mg/dL, with controls including participants who did not sustain such an increase.ResultsThere was an increase in the serum creatinine of at least 0.3 mg/dL in 2.8% of the population. In a multivariate “best-fit” model adjusted for gender, weight, black race, baseline serum creatinine, and age, the following factors were associated with an increase in serum creatinine: number of cigarettes smoked per day, systolic blood pressure, and maximum internal carotid artery intimal thickness.ConclusionsThese data suggest that three very preventable or treatable conditions—hypertension, smoking, and prevalent vascular disease, which are associated with large and small vessel disease—are highly associated with clinically important changes in renal function in an older population

Single cell based phosphorylation profiling identifies alterations in toll-like receptor 7 and 9 signaling in patients with primary Sjögren's syndrome

Primary Sjögren's syndrome (pSS) is associated with polymorphisms and mRNA expression profiles that are indicative of an exaggerated innate and type I IFN immune response. Excessive activation potential of signaling pathways may play a role in this profile, but the intracellular signaling profile of the disease is not well characterized. To gain insights into potentially dysfunctional intracellular signaling profiles of pSS patients we conducted an exploratory analysis of MAPK/ERK and JAK/STAT signaling networks in peripheral blood mononuclear cells (PBMC) from 25 female pSS patients and 25 female age-matched healthy donors using phospho-specific flow cytometry. We analyzed unstimulated samples, as well as samples during a 4 h time period following activation of Toll-like receptor (TLR) 7 and 9. Expression levels of MxA, IFI44, OAS1, GBP1, and GBP2 in PBMC were analyzed by real-time PCR. Cytokine levels in plasma were determined using a 25-plex Luminex-assay. Principal component analysis (PCA) showed that basal phosphorylation profiles could be used to differentiate pSS patients from healthy donor samples by stronger intracellular signaling pathway activation in NK and T cells relative to B cells. Stimulation of PBMC with TLR7 and −9 ligands showed significant differences in the phosphorylation profiles between samples from pSS patients and healthy donors. Including clinical parameters such as extraglandular manifestations (EGM), we observed stronger responses of NF-κB and STAT3 S727 in B cells from EGM-negative patients compared to EGM-positive patients and healthy controls. Plasma cytokine levels were correlated to the basal phosphorylation levels in these patients. In addition, 70% of the patients had a positive IFN score. These patients differed from the IFN score negative patients regarding their phosphorylation profiles and their plasma cytokine levels. In conclusion, we here report increased signaling potentials in peripheral B cells of pSS patients in response to TLR7 and −9 stimulation through STAT3 S727 and NF-κB that correlate with a type I IFN signature. Induction of these pathways could contribute to the generation of a type I IFN signature in pSS. Patients displaying elevated potentiation of STAT3 S727 and NF-κB signaling could therefore benefit from therapies targeting these pathways.publishedVersio

Spin-photon interface and spin-controlled photon switching in a nanobeam waveguide

Access to the electron spin is at the heart of many protocols for integrated and distributed quantum-information processing [1-4]. For instance, interfacing the spin-state of an electron and a photon can be utilized to perform quantum gates between photons [2,5] or to entangle remote spin states [6-9]. Ultimately, a quantum network of entangled spins constitutes a new paradigm in quantum optics [1]. Towards this goal, an integrated spin-photon interface would be a major leap forward. Here we demonstrate an efficient and optically programmable interface between the spin of an electron in a quantum dot and photons in a nanophotonic waveguide. The spin can be deterministically prepared with a fidelity of 96\%. Subsequently the system is used to implement a "single-spin photonic switch", where the spin state of the electron directs the flow of photons through the waveguide. The spin-photon interface may enable on-chip photon-photon gates [2], single-photon transistors [10], and efficient photonic cluster state generation [11]

Evidence for dark energy from the cosmic microwave background alone using the Atacama Cosmology Telescope lensing measurements

For the first time, measurements of the cosmic microwave background radiation (CMB) alone favor cosmologies with $w=-1$ dark energy over models without dark energy at a 3.2-sigma level. We demonstrate this by combining the CMB lensing deflection power spectrum from the Atacama Cosmology Telescope with temperature and polarization power spectra from the Wilkinson Microwave Anisotropy Probe. The lensing data break the geometric degeneracy of different cosmological models with similar CMB temperature power spectra. Our CMB-only measurement of the dark energy density $\Omega_\Lambda$ confirms other measurements from supernovae, galaxy clusters and baryon acoustic oscillations, and demonstrates the power of CMB lensing as a new cosmological tool.Comment: 4 pages, 3 figures; replaced with version accepted by Physical Review Letters, added sentence on models with non-standard primordial power spectr

Mass Splitting and Production of Σc0\Sigma_c^0 and Σc++\Sigma_c^{++} Measured in 500GeV500 {GeV} π−−\pi^- -N Interactions

From a sample of $2722 \pm 78$ $\Lambda_c^+$ decaying to the $pK^-\pi^+$ final state, we have observed, in the hadroproduction experiment E791 at Fermilab, $143 \pm 20$ $\Sigma_c^0$ and $122 \pm 18$ $\Sigma_c^{++}$ through their decays to $\Lambda_c^+ \pi^{\pm}$. The mass difference $M(\Sigma_c^0) - M(\Lambda_c^+$) is measured to be $(167.38\pm 0.29\pm 0.15) {MeV}$; for $M(\Sigma_c^{++}) - M(\Lambda_c^+)$, we find $(167.76\pm 0.29\pm0.15) {MeV}$. The rate of $\Lambda_c^+$ production from decays of the $\Sigma_c$ triplet is (22\pm 2\pm 3) {%} of the total $\Lambda_c^+$ production assuming equal rate of production from all three, as measured for $\Sigma_c^0$ and $\Sigma_c^{++}$. We do not observe a statistically significant $\Sigma_c$ baryon-antibaryon production asymmetry. The $x_F$ and $p_t^2$ spectra of $\Lambda_c^+$ from $\Sigma_c$ decays are observed to be similar to those for all $\Lambda_c^+$'s produced.Comment: 15 pages, uuencoded postscript 3 figures uuencoded, tar-compressed fil

PHF3 regulates neuronal gene expression through the Pol II CTD reader domain SPOC

The C-terminal domain (CTD) of the largest subunit of RNA polymerase II (Pol II) is a regulatory hub for transcription and RNA processing. Here, we identify PHD-finger protein 3 (PHF3) as a regulator of transcription and mRNA stability that docks onto Pol II CTD through its SPOC domain. We characterize SPOC as a CTD reader domain that preferentially binds two phosphorylated Serine-2 marks in adjacent CTD repeats. PHF3 drives liquid-liquid phase separation of phosphorylated Pol II, colocalizes with Pol II clusters and tracks with Pol II across the length of genes. PHF3 knock-out or SPOC deletion in human cells results in increased Pol II stalling, reduced elongation rate and an increase in mRNA stability, with marked derepression of neuronal genes. Key neuronal genes are aberrantly expressed in Phf3 knock-out mouse embryonic stem cells, resulting in impaired neuronal differentiation. Our data suggest that PHF3 acts as a prominent effector of neuronal gene regulation by bridging transcription with mRNA decay

Single Cell Based Phosphorylation Profiling Identifies Alterations in Toll-Like Receptor 7 and 9 Signaling in Patients With Primary Sjögren's Syndrome

Primary Sjögren's syndrome (pSS) is associated with polymorphisms and mRNA expression profiles that are indicative of an exaggerated innate and type I IFN immune response. Excessive activation potential of signaling pathways may play a role in this profile, but the intracellular signaling profile of the disease is not well characterized. To gain insights into potentially dysfunctional intracellular signaling profiles of pSS patients we conducted an exploratory analysis of MAPK/ERK and JAK/STAT signaling networks in peripheral blood mononuclear cells (PBMC) from 25 female pSS patients and 25 female age-matched healthy donors using phospho-specific flow cytometry. We analyzed unstimulated samples, as well as samples during a 4 h time period following activation of Toll-like receptor (TLR) 7 and 9. Expression levels of MxA, IFI44, OAS1, GBP1, and GBP2 in PBMC were analyzed by real-time PCR. Cytokine levels in plasma were determined using a 25-plex Luminex-assay. Principal component analysis (PCA) showed that basal phosphorylation profiles could be used to differentiate pSS patients from healthy donor samples by stronger intracellular signaling pathway activation in NK and T cells relative to B cells. Stimulation of PBMC with TLR7 and −9 ligands showed significant differences in the phosphorylation profiles between samples from pSS patients and healthy donors. Including clinical parameters such as extraglandular manifestations (EGM), we observed stronger responses of NF-κB and STAT3 S727 in B cells from EGM-negative patients compared to EGM-positive patients and healthy controls. Plasma cytokine levels were correlated to the basal phosphorylation levels in these patients. In addition, 70% of the patients had a positive IFN score. These patients differed from the IFN score negative patients regarding their phosphorylation profiles and their plasma cytokine levels. In conclusion, we here report increased signaling potentials in peripheral B cells of pSS patients in response to TLR7 and −9 stimulation through STAT3 S727 and NF-κB that correlate with a type I IFN signature. Induction of these pathways could contribute to the generation of a type I IFN signature in pSS. Patients displaying elevated potentiation of STAT3 S727 and NF-κB signaling could therefore benefit from therapies targeting these pathways

Randomized trial of achieving healthy lifestyles in psychiatric rehabilitation: the ACHIEVE trial

<p>Abstract</p> <p>Background</p> <p>Overweight and obesity are highly prevalent among persons with serious mental illness. These conditions likely contribute to premature cardiovascular disease and a 20 to 30 percent shortened life expectancy in this vulnerable population. Persons with serious mental illness need effective, appropriately tailored behavioral interventions to achieve and maintain weight loss. Psychiatric rehabilitation day programs provide logical intervention settings because mental health consumers often attend regularly and exercise can take place on-site. This paper describes the Randomized Trial of Achieving Healthy Lifestyles in Psychiatric Rehabilitation (ACHIEVE). The goal of the study is to determine the effectiveness of a behavioral weight loss intervention among persons with serious mental illness that attend psychiatric rehabilitation programs. Participants randomized to the intervention arm of the study are hypothesized to have greater weight loss than the control group.</p> <p>Methods/Design</p> <p>A targeted 320 men and women with serious mental illness and overweight or obesity (body mass index ≥ 25.0 kg/m²) will be recruited from 10 psychiatric rehabilitation programs across Maryland. The core design is a randomized, two-arm, parallel, multi-site clinical trial to compare the effectiveness of an 18-month behavioral weight loss intervention to usual care. Active intervention participants receive weight management sessions and physical activity classes on-site led by study interventionists. The intervention incorporates cognitive adaptations for persons with serious mental illness attending psychiatric rehabilitation programs. The initial intensive intervention period is six months, followed by a twelve-month maintenance period in which trained rehabilitation program staff assume responsibility for delivering parts of the intervention. Primary outcomes are weight loss at six and 18 months.</p> <p>Discussion</p> <p>Evidence-based approaches to the high burden of obesity and cardiovascular disease risk in person with serious mental illness are urgently needed. The ACHIEVE Trial is tailored to persons with serious mental illness in community settings. This multi-site randomized clinical trial will provide a rigorous evaluation of a practical behavioral intervention designed to accomplish and sustain weight loss in persons with serious mental illness.</p> <p>Trial Registration</p> <p>Clinical Trials.gov NCT00902694</p

Development and validation of an ultra?performance liquid chromatography quadrupole time of flight mass spectrometry method for rapid quantification of free amino acids in human urine

An ultra-performance liquid chromatography quadrupole time of flight mass spectrometry (UPLC-qTOFMS)method using hydrophilic interaction liquid chromatography was developed and validated for simultaneous quantification of 18 free amino acids in urine with a total acquisition time including the column re-equilibration of less than 18 min per sample. This method involves simple sample preparation steps which consisted of 15 times dilution with acetonitrile to give a final composition of 25 % aqueous and 75 % acetonitrile without the need of any derivatization. The dynamic range for our calibration curve is approximately two orders of magnitude (120-fold from the lowest calibration curve point) with good linearity (r2 ? 0.995 for all amino acids). Good separation of all amino acids as well as good intra- and inter-day accuracy (<15 %) and precision (<15 %) were observed using three quality control samples at a concentration of low, medium and high range of the calibration curve. The limits of detection (LOD) and lower limit of quantification of our method were ranging from approximately 1–300 nM and 0.01–0.5 µM, respectively. The stability of amino acids in the prepared urine samples was found to be stable for 72 h at 4 °C, after one freeze thaw cycle and for up to 4 weeks at ?80 °C. We have applied this method to quantify the content of 18 free amino acids in 646 urine samples from a dietary intervention study. We were able to quantify all 18 free amino acids in these urine samples, if they were present at a level above the LOD. We found our method to be reproducible (accuracy and precision were typically <10 % for QCL, QCM and QCH) and the relatively high sample throughput nature of this method potentially makes it a suitable alternative for the analysis of urine samples in clinical setting

Investigation of the Soot Formation in Ethylene Laminar Diffusion Flames When Diluted with Helium or Supplemented by Hydrogen

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Energy and Fuels, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/ef401970qA new optical diagnostic technique has been used to measure the spatially distributed temperatures, soot diameters, and soot volume fractions in several different ethylene laminar diffusion flames to investigate the effect of adding hydrogen and helium on the soot formation. The test results show that adding hydrogen increases the flame temperature in all regions, while adding helium does not significantly affect the flame temperature in the reaction region but does increase the flame temperature elsewhere. The flame heights when adding helium and hydrogen can be calculated using the correlation introduced by Roper if the ethylene diffusion coefficient is used. This indicates that the flame height is determined by the diffusion of ethylene molecules when the hydrogen fraction is below 20%. It was also found that either adding helium or hydrogen does not significantly affect the soot diameter but does reduce the soot volume fraction. A total of 20% of helium addition by volume was measured to reduce the total soot number by 19%, while a total of 20% of hydrogen addition reduced the total soot number by 23%. In comparison, replacing the hydrocarbon with hydrogen is much more effective in reducing soot formation. Replacement of 25% ethylene by hydrogen was measured to reduce the total soot number by 66%. Apart from demonstrating the influence of hydrogen and helium on ethylene diffusion flames, these measurements provide additional data for modelers of diffusion flames, especially those with an interest in the formation of particulate matter. © 2014 American Chemical Society