Disrupting LXRα phosphorylation promotes FoxM1 expression and modulates atherosclerosis by inducing macrophage proliferation.

Macrophages are key immune cells for the initiation and development of atherosclerotic lesions. However, the macrophage regulatory nodes that determine how lesions progress in response to dietary challenges are not fully understood. Liver X receptors (LXRs) are sterol-regulated transcription factors that play a central role in atherosclerosis by integrating cholesterol homeostasis and immunity. LXR pharmacological activation elicits a robust antiatherosclerotic transcriptional program in macrophages that can be affected by LXRα S196 phosphorylation in vitro. To investigate the impact of these transcriptional changes in atherosclerosis development, we have generated mice carrying a Ser-to-Ala mutation in myeloid cells in the LDL receptor (LDLR)-deficient atherosclerotic background (M-S196ALdlr-KO). M-S196ALdlr-KO mice fed a high-fat diet exhibit increased atherosclerotic plaque burden and lesions with smaller necrotic cores and thinner fibrous caps. These diet-induced phenotypic changes are consistent with a reprogramed macrophage transcriptome promoted by LXRα-S196A during atherosclerosis development. Remarkably, expression of several proliferation-promoting factors, including the protooncogene FoxM1 and its targets, is induced by LXRα-S196A. This is consistent with increased proliferation of plaque-resident cells in M-S196ALdlr-KO mice. Moreover, disrupted LXRα phosphorylation increases expression of phagocytic molecules, resulting in increased apoptotic cell removal by macrophages, explaining the reduced necrotic cores. Finally, the macrophage transcriptome promoted by LXRα-S196A under dietary perturbation is markedly distinct from that revealed by LXR ligand activation, highlighting the singularity of this posttranslational modification. Overall, our findings demonstrate that LXRα phosphorylation at S196 is an important determinant of atherosclerotic plaque development through selective changes in gene transcription that affect multiple pathways.

The Boltzmann project.

The International Committee for Weights and Measures (CIPM), at its meeting in October 2017, followed the recommendation of the Consultative Committee for Units (CCU) on the redefinition of the kilogram, ampere, kelvin and mole. For the redefinition of the kelvin, the Boltzmann constant will be fixed with the numerical value 1.380 649 × 10-23 J K-1. The relative standard uncertainty to be transferred to the thermodynamic temperature value of the triple point of water will be 3.7 × 10-7, corresponding to an uncertainty in temperature of 0.10 mK, sufficiently low for all practical purposes. With the redefinition of the kelvin, the broad research activities of the temperature community on the determination of the Boltzmann constant have been very successfully completed. In the following, a review of the determinations of the Boltzmann constant k, important for the new definition of the kelvin and performed in the last decade, is given.

Highly accurate intensity factors of pure CO2 lines near 2 µm.

Line intensities for carbon dioxide are measured with a novel spectroscopic approach, assisted by an optical frequency comb synthesizer for frequency calibration purposes. The main feature of the spectrometer consists in the exploitation of optical feedback from a V-shaped high-finesse optical resonator to effectively narrow a distributed feedback diode laser at the wavelength of 2 µm. Laser-gas interaction takes place inside an isothermal cell, which is placed on the transmission from the cavity. High quality, self-calibrated, absorption spectra are observed in pure CO2 samples at different gas pressures, in coincidence with three lines of the R-branch of the ν1 + 2ν2 + ν3 band. Line intensities are determined using a global fitting approach in which a manifold of spectra are simultaneously analyzed across the range of pressures between 5 and 100 Torr, sharing a restricted number of unknown parameters. Various sources of uncertainty have been identified and carefully quantified, thus leading to an overall uncertainty ranging between 0.17% and 0.23%. The measured values are in a very good agreement with recent ab initio predictions.

Characterization of the frequency stability of an optical frequency standard at 1.39 µm based upon noise-immune cavity-enhanced optical heterodyne molecular spectroscopy.

Frequency fluctuations of an optical frequency standard at 1.39 µm have been measured by means of a highly-sensitive optical frequency discriminator based on the fringe-side transmission of a high finesse optical resonator. Built on a Zerodur spacer, the optical resonator exhibits a finesse of 5500 and a cavity-mode width of about 120 kHz. The optical frequency standard consists of an extended-cavity diode laser that is tightly stabilized against the center of a sub-Doppler H(2) (18)O line, this latter being detected by means of noise-immune cavity-enhanced optical heterodyne molecular spectroscopy. The emission linewidth has been carefully determined from the frequency-noise power spectral density by using a rather simple approximation, known as ß-line approach, as well as the exact method based on the autocorrelation function of the laser light field. It turns out that the linewidth of the optical frequency standard amounts to about 7 kHz (full width at half maximum) for an observation time of 1 ms. Compared to the free-running laser, the measured width corresponds to a line narrowing by a factor of ~220.

A prospective, active haemovigilance study with combined cohort analysis of 19,175 transfusions of platelet components prepared with amotosalen-UVA photochemical treatment.

BACKGROUND AND OBJECTIVES: A photochemical treatment process (PCT) utilizing amotosalen and UVA light (INTERCEPT(™) Blood System) has been developed for inactivation of viruses, bacteria, parasites and leucocytes that can contaminate blood components intended for transfusion. The objective of this study was to further characterize the safety profile of INTERCEPT-treated platelet components (PCT-PLT) administered across a broad patient population. MATERIALS AND METHODS: This open-label, observational haemovigilance programme of PCT-PLT transfusions was conducted in 21 centres in 11 countries. All transfusions were monitored for adverse events within 24 h post-transfusion and for serious adverse events (SAEs) up to 7 days post-transfusion. All adverse events were assessed for severity (Grade 0-4), and causal relationship to PCT-PLT transfusion. RESULTS: Over the course of 7 years in the study centres, 4067 patients received 19,175 PCT-PLT transfusions. Adverse events were infrequent, and most were of Grade 1 severity. On a per-transfusion basis, 123 (0.6%) were classified an acute transfusion reaction (ATR) defined as an adverse event related to the transfusion. Among these ATRs, the most common were chills (77, 0.4%) and urticaria (41, 0.2%). Fourteen SAEs were reported, of which 2 were attributed to platelet transfusion (<0.1%). No case of transfusion-related acute lung injury, transfusion-associated graft-versus-host disease, transfusion-transmitted infection or death was attributed to the transfusion of PCT-PLT. CONCLUSION: This longitudinal haemovigilance safety programme to monitor PCT-PLT transfusions demonstrated a low rate of ATRs, and a safety profile consistent with that previously reported for conventional platelet components.

Determination of the Boltzmann constant by means of precision measurements of H2(18)O line shapes at 1.39 µm.

We report on a new implementation of Doppler broadening thermometry based on precision absorption spectroscopy by means of a pair of offset-frequency locked extended-cavity diode lasers at 1.39 µm. The method consists in the highly accurate observation of the shape of the 4(4,1)→4(4,0) line of the H2(18)O ν1+ν3 band, in a water vapor sample at thermodynamic equilibrium. A sophisticated and extremely refined spectral analysis procedure is adopted for the retrieval of the Doppler width as a function of the gas pressure, taking into account the Dicke narrowing effect, the speed dependence of relaxation rates, and the physical correlation between velocity-changing and dephasing collisions. A spectroscopic determination of the Boltzmann constant with a combined (type A and type B) uncertainty of 24 parts over 10(6) is reported. This is the best result obtained so far by means of an optical method. Our determination is in agreement with the recommended CODATA value.

Velocity effects on the shape of pure H2O isolated lines: complementary tests of the partially correlated speed-dependent Keilson-Storer model.

Complementary tests of the partially correlated speed-dependent Keilson-Storer (pCSDKS) model for the shape of isolated transition of pure water vapor [N. H. Ngo et al., J. Chem. Phys. 136, 154310 (2012)] are made using new measurements. The latter have been recorded using a high sensitivity cavity ring down spectrometer, for seven self-broadened H(2)O lines in the 1.6 µm region at room temperature and for pressures from 0.5 to 15 Torr. Furthermore, the H(2) (18)O spectra of [M. D. De Vizia et al., Phys. Rev. A 83, 052506 (2011)] in the 1.38 µm region, measured at 273.15 K and for pressures from 0.3 to 3.75 Torr have also been used for comparison with the model. Recall that the pCSDKS model takes into account the collision-induced velocity changes, the speed dependences of the broadening and shifting coefficients as well as the partial correlation between velocity and rotational-state changes. All parameters of the model have been fixed at values previously determined, except for a scaling factor applied to the input speed-dependent line broadening. Comparisons between predictions and experiments have been made by looking at the results obtained when fitting the calculated and measured spectra by Voigt profiles. The good agreement obtained for all considered lines, at different temperature and pressure conditions, confirms the consistency and the robustness of the model. Limiting cases of the model have been then derived, showing the influence of different contributions to the line shape.

Reproducibility of observables and coherent control in molecular photoionization: from continuous wave to ultrashort pulsed radiation.

One-photon single ionization of molecules has been at the focus of several discussions concerning the reconstruction of observables obtained with ultrashort pulses from those obtained from continuous wave radiation (and vice versa). A related controversy on the conditions and observables that allow for coherent control in one-photon processes has been recently revisited (Science 2006, 313, 1257; J. Chem. Phys. 2010, 133, 151101). Our benchmark to investigate these issues is photoionization of the hydrogen molecule, where the autoionization events are the time-dependent processes in field-free evolution that could serve as a target for coherent control. We show that the variation of one-photon ionization probabilities with pulse duration are solely due to spectral effects and thus cannot be coherently controlled. We then discuss for which observables and under which conditions phase control of autoionization dynamics is possible.

High-precision molecular interrogation by direct referencing of a quantum-cascade-laser to a near-infrared frequency comb.

This work presents a very simple yet effective way to obtain direct referencing of a quantum-cascade-laser at 4.3 µm to a near-IR frequency-comb. Precise tuning of the comb repetition-rate allows the quantum-cascade-laser to be scanned across absorption lines of a CO2 gaseous sample and line profiles to be acquired with extreme reproducibility and accuracy. By averaging over 50 acquisitions, line-centre frequencies are retrieved with an uncertainty of 30 kHz in a linear interaction regime. The extension of this methodology to other lines and molecules, by the use of widely tunable extended-cavity quantum-cascade-lasers, paves the way to a wide availability of high-quality and traceable spectroscopic data in the most crucial region for molecular detection and interrogation.

Protein kinase Cepsilon is required for macrophage activation and defense against bacterial infection.

To assess directly the role of protein kinase C (PKC)epsilon in the immune system, we generated mice that carried a homozygous disruption of the PKCepsilon locus. PKCepsilon(-/-) animals appeared normal and were generally healthy, although female mice frequently developed a bacterial infection of the uterus. Macrophages from PKCepsilon(-/-) animals demonstrated a severely attenuated response to lipopolysaccharide (LPS) and interferon (IFN)gamma, characterized by a dramatic reduction in the generation of NO, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta. Further analysis revealed that LPS-stimulated macrophages from PKCepsilon(-/-) mice were deficient in the induction of nitric oxide synthase (NOS)-2, demonstrating a decrease in the activation of IkappaB kinase, a reduction in IkappaB degradation, and a decrease in nuclear factor (NF)kappaB nuclear translocation. After intravenous administration of Gram-negative or Gram-positive bacteria, PKCepsilon(-/-) mice demonstrated a significantly decreased period of survival. This study provides direct evidence that PKCepsilon is critically involved at an early stage of LPS-mediated signaling in activated macrophages. Furthermore, we demonstrate that in the absence of PKCepsilon, host defense against bacterial infection is severely compromised, resulting in an increased incidence of mortality.

Observing the intrinsic linewidth of a quantum-cascade laser: beyond the Schawlow-Townes limit.

A comprehensive investigation of the frequency-noise spectral density of a free-running midinfrared quantum-cascade laser is presented for the first time. It provides direct evidence of the leveling of this noise down to a white-noise plateau, corresponding to an intrinsic linewidth of a few hundred hertz. The experiment is in agreement with the most recent theory on the fundamental mechanism of line broadening in quantum-cascade lasers, which provides a new insight into the Schawlow-Townes formula and predicts a narrowing beyond the limit set by the radiative lifetime of the upper level.

Diphtheritic angina in the tongue and floor of the mouth: unusual presentation.

Diphtheria is an infectious disease caused by Corynebacterium diphtheriae, and is generally characterised by proliferation of the bacteria in the upper respiratory tract, formation of a pseudomembrane, and systemic diffusion of the diphtheria toxin throughout the body. We present the case of a young man with pseudomembranous plaques on the tongue and floor of the mouth, who received systemic and locoregional medical treatment, with a satisfactory outcome after 14 days.

Lamb-dip-locked quantum cascade laser for comb-referenced IR absolute frequency measurements.

The frequency of a DFB quantum cascade laser (QCL) emitting at 4.3 microm has been long-term stabilized to the Lamb-dip center of a CO2 ro-vibrational transition by means of first-derivative locking to the saturated absorption signal. Thanks to the non-linear sum-frequency generation (SFG) process with a fiber-amplified Nd:YAG laser, the QCL mid-infrared (IR) radiation has been linked to an optical frequency-comb synthesizer (OFCS) and its absolute frequency counted with a kHz-level precision and an overall uncertainty of 75 kHz.

Inhibition of IkappaB kinase and IkappaB phosphorylation by 15-deoxy-Delta(12,14)-prostaglandin J(2) in activated murine macrophages.

Activation of the macrophage cell line RAW 264.7 with lipopolysaccharide (LPS) and gamma interferon (IFN-gamma) induces the expression of gene products involved in host defense, among them type 2 nitric oxide synthase. Treatment of cells with 15-deoxy-Delta(12,14)-prostaglandin J(2) (15dPGJ(2)) inhibited the LPS- and IFN-gamma-dependent synthesis of NO, a process that was not antagonized by similar concentrations of prostaglandin J(2), prostaglandin E(2), or rosiglitazone, a peroxisomal proliferator-activated receptor gamma ligand. Incubation of activated macrophages with 15dPGJ(2) inhibited the degradation of IkappaBalpha and IkappaBbeta and increased their levels in the nuclei. NF-kappaB activity, as well as the transcription of NF-kappaB-dependent genes, such as those encoding type 2 nitric oxide synthase and cyclooxygenase 2, was impaired under these conditions. Analysis of the steps leading to IkappaB phosphorylation showed an inhibition of IkappaB kinase by 15dPGJ(2) in cells treated with LPS and IFN-gamma, resulting in an impaired phosphorylation of IkappaBalpha, at least in the serine 32 residue required for targeting and degradation of this protein. Incubation of partially purified activated IkappaB kinase with 2 microM 15dPGJ(2) reduced by 83% the phosphorylation in serine 32 of IkappaBalpha, suggesting that this prostaglandin exerts direct inhibitory effects on the activity of the IkappaB kinase complex. These results show rapid actions of 15dPGJ(2), independent of peroxisomal proliferator receptor gamma activation, in macrophages challenged with low doses of LPS and IFN-gamma.

Isolated scaphotrapeziotrapezoid osteoarthritis treatment using resurfacing arthroplasty with scaphoid anchorage. / Tratamiento de la artrosis escafotrapeciotrapezoidea aislada con artroplastia de recubrimiento con anclaje escafoideo.

OBJECTIVE: The aim of this study is to show the results of scaphotrapeziotrapezoid (STT) joint osteoarthritis treatment performing resurfacing arthroplasty with scaphoid anchorage. MATERIAL AND METHOD: An observational, descriptive and retrospective study was performed. Ten patients with isolated STT joint osteoarthritis were studied between 2013 and 2015. The mean follow-up time was 26months. Clinical results, functional and subjective scores were reviewed. RESULTS: The patients were satisfied, achieving an average of 2.1 (0-3) on the VAS score and 16 (2 to 28) in the DASH questionnaire, and returning to work in the first three months post-surgery. Recovery of range of motion compared to the contralateral wrist was 96% in extension, 95% in flexion, 87% in ulnar deviation and 91% in radial deviation. The average handgrip strength of the wrist was 95% and pinch strength was 95% compared to the contralateral side. There were no intraoperative complications or alterations in postoperative carpal alignment. CONCLUSION: Resurfacing arthroplasty is proposed as a good and novel alternative in treating isolated SST joint arthritis. Achieving the correct balance between the strength and mobility of the wrist, without causing carpal destabilisation, is important to obtain satisfactory clinical and functional results.

Gait Disorder in a Cohort of Patients With Mild and Moderate Alzheimer's Disease.

Gait disturbance results in an increase in the risk of falls in patients with Alzheimer's disease (AD). The falls are events that might be related to an increase in the number of fractures, loss of mobility, being bedridden, early institutionalization, and increased use of medication. Therefore, the reduction in the number of falls is important for the maintenance of the functional independence of the patients as well as for the prevention of sequelae resulting from those events. Alterations in the gait occur very frequently in AD, and the gait disturbance occurs relatively early in the course of the disease. This study has important implications for public health and clinical practice. This study and previous studies have reported that abnormal gait predicts greater risk of falls, dementia, institutionalization, and death. The high prevalence and incidence of abnormal gait and its association with multiple adverse outcomes in older adults require urgent attention. Our results allow us to identify the risk factors.

Induction of apoptosis by nitric oxide in macrophages is independent of apoptotic volume decrease.

Apoptosis occurs through a sequence of specific biochemical and morphological alterations that define the progress of cell death. The changes of the mitochondrial inner membrane potential (DeltaPsi(m)), the release of cytochrome c to the cytosol, the apoptotic volume decrease (AVD) and the activation of caspases have been measured in RAW 264.7, HeLa and Jurkat T cells incubated with molecules that induce apoptosis through the mitochondrial pathway. Our data show that NO, staurosporine, etoposide and camptothecin increased DeltaPsi(m) in macrophages but not in HeLa and Jurkat cells, that exhibited a DeltaPsi(m) decrease. Moreover, the apoptosis induced by NO in macrophages, but not that promoted by staurosporine, might occur in the absence of AVD. Analysis of the sequence of apoptotic manifestations shows that DeltaPsi(m) precedes AVD and caspase activation in RAW 264.7 cells. Inhibition of AVD abrogates apoptosis in HeLa and Jurkat T cells regardless of the stimuli used. These data suggest that the changes of DeltaPsi(m) are cell-type dependent and that AVD is dispensable for apoptosis in macrophages.

Intracellular water motion decreases in apoptotic macrophages after caspase activation.

Triggering of the macrophage cell line RAW 264.7 with lipopolysaccharide and interferon-gamma promoted apoptosis that was prevented by inhibitors of type 2 nitric oxide synthase or caspase. Using (1)H NMR analysis, we have investigated the changes of the intracellular transverse relaxation time (T(2)) and apparent diffusion coefficient (ADC) as parameters reflecting the rotational and translational motions of water in apoptotic macrophages. T(2) values decreased significantly from 287 to 182 ms in cells treated for 18 h with NO-donors. These changes of T(2) were prevented by caspase inhibitors and were not due to mitochondrial depolarization or microtubule depolymerization. The decrease of the intracellular values of T(2) and ADC in apoptotic macrophages was observed after caspase activation, but preceded phosphatidylserine exposure and nucleosomal DNA cleavage. The changes of water motion were accompanied by an enhancement of the hydrophobic properties of the intracellular milieu, as detected by fluorescent probes. These results indicate the occurrence of an alteration in the physicochemical properties of intracellular water during the course of apoptosis.

Inhibitory effect of IGF-I on type 2 nitric oxide synthase expression in Ins-1 cells and protection against activation-dependent apoptosis: involvement of phosphatidylinositol 3-kinase.

Challenge of Ins-1 cells, a rat beta-pancreatic cell line, with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) promoted the expression of type 2 nitric oxide synthase (NOS-2) in a cooperative way. Treatment of Ins-1 cells with IGF-I significantly inhibited the expression of NOS-2, especially at subsaturating concentrations of LPS and IFN-gamma. The inhibitory effect of IGF-I on NOS-2 expression was abrogated when cells were incubated with wortmannin or LY294002, two inhibitors of phosphatidylinositol 3-kinase. Transient expression of the p110 subunit of phosphatidylinositol 3-kinase impaired the LPS and IFN-gamma-dependent NOS-2 promoter activity in cells transfected with a 1-kb fragment corresponding to the 5'-flanking region of the NOS-2 gene. However, expression of a dominant negative form of p85 abolished the inhibitory action of IGF-I on the NOS-2 promoter activity. Analysis of the decreased NOS-2 promoter activity in cells incubated with IGF-I showed a lower nuclear factor KB binding as determined by electrophoretic mobility shift assays. The synthesis of NO, produced after LPS and IFN-gamma challenge, triggered an apoptotic response in these cells. IGF-I reduced apoptosis mainly through the decreased synthesis of NO. However, in activated cells treated with N-[3-(aminomethyl)benzyl]acetamidine, a specific NOS-2 inhibitor, IGF-I completely abolished the NO-independent apoptosis. This protection from apoptosis was dependent on phosphatidylinositol 3-kinase activity. These results suggest an important anti-inflammatory and anti-apoptotic role for IGF-I in beta-pancreatic cells, with both actions depending on the activation of phosphatidylinositol 3-kinase.

[Treatment of Bowen's disease of the penis with imiquimod 5% cream]. / Tratamiento tópico con imiquimod crema al 5% de la enfermedad de Bowen del pene.

We present an alternative treatment of the intraepithelial neoplasms of penis (Bowen's disease), the topical application of imiquimod 5% cream. It was applied 3 times weekly for 5 weeks. Imiquimod is an imidazoquinolone immune response modifier that has been shown to have indirect antiviral and antitumor effects with few adverse effects. Imiquimod 5% cream may represent an alternative treatment option for Bowen's disease.