Giant thermal Hall conductivity in the pseudogap phase of cuprate superconductors.

The nature of the pseudogap phase of the copper oxides ('cuprates') remains a puzzle. Although there are indications that this phase breaks various symmetries, there is no consensus on its fundamental nature1. Fermi-surface, transport and thermodynamic signatures of the pseudogap phase are reminiscent of a transition into a phase with antiferromagnetic order, but evidence for an associated long-range magnetic order is still lacking2. Here we report measurements of the thermal Hall conductivity (in the x-y plane, κxy) in the normal state of four different cuprates-La1.6-xNd0.4SrxCuO4, La1.8-xEu0.2SrxCuO4, La2-xSrxCuO4 and Bi2Sr2-xLaxCuO6+δ. We show that a large negative κxy signal is a property of the pseudogap phase, appearing at its critical hole doping, p*. It is also a property of the Mott insulator at p ≈ 0, where κxy has the largest reported magnitude of any insulator so far3. Because this negative κxy signal grows as the system becomes increasingly insulating electrically, it cannot be attributed to conventional mobile charge carriers. Nor is it due to magnons, because it exists in the absence of magnetic order. Our observation is reminiscent of the thermal Hall conductivity of insulators with spin-liquid states4-6, pointing to neutral excitations with spin chirality7 in the pseudogap phase of cuprates.

ARCTIC CHANGE AND POSSIBLE INFLUENCE ON MID-LATITUDE CLIMATE AND WEATHER: A US CLIVAR White Paper.

The Arctic has warmed more than twice as fast as the global average since the mid 20th century, a phenomenon known as Arctic amplification (AA). These profound changes to the Arctic system have coincided with a period of ostensibly more frequent events of extreme weather across the Northern Hemisphere (NH) mid-latitudes, including extreme heat and rainfall events and recent severe winters. Though winter temperatures have generally warmed since 1960 over mid-to-high latitudes, the acceleration in the rate of warming at high-latitudes, relative to the rest of the NH, started approximately in 1990. Trends since 1990 show cooling over the NH continents, especially in Northern Eurasia. The possible link between Arctic change and mid-latitude climate and weather has spurred a rush of new observational and modeling studies. A number of workshops held during 2013-2014 have helped frame the problem and have called for continuing and enhancing efforts for improving our understanding of Arctic-mid-latitude linkages and its attribution to the occurrence of extreme climate and weather events. Although these workshops have outlined some of the major challenges and provided broad recommendations, further efforts are needed to synthesize the diversified research results to identify where community consensus and gaps exist. Building upon findings and recommendations of the previous workshops, the US CLIVAR Working Group on Arctic Change and Possible Influence on Mid-latitude Climate and Weather convened an international workshop at Georgetown University in Washington, DC, on February 1-3, 2017. Experts in the fields of atmosphere, ocean, and cryosphere sciences assembled to assess the rapidly evolving state of understanding, identify consensus on knowledge and gaps in research, and develop specific actions to accelerate progress within the research community. With more than 100 participants, the workshop was the largest and most comprehensive gathering of climate scientists to address the topic to date. In this white paper, we synthesize and discuss outcomes from this workshop and activities involving many of the working group members. WORKSHOP FINDINGS: Rapid Arctic change - Emergence of new forcing (external and internal) of atmospheric circulation: Rapid Arctic change is evident in the observations and is simulated and projected by global climate models. AA has been attributed to sea ice and snow decline (regionally and seasonally varying). However this cannot explain why AA is greatest in winter and weakest in summer. It was argued at the workshop that other factors can also greatly contribute to AA including: increased downwelling longwave radiation from greenhouse gases (including greater water vapor concentrations from local and remote sources); increasing ocean heat content, due to local and remote processes; regional and hemispheric atmospheric circulation changes; increased poleward heat transport in the atmosphere and ocean; and cloud radiative forcing. In particular, there is emerging observational evidence that an enhanced poleward transport of sensible and latent heat plays a very important role in the AA of the recent decades, and that this enhancement is mostly fueled by changes in the atmospheric circulation. We concluded that our understanding of AA is incomplete, especially the relative contributions from the different radiative, thermodynamic, and dynamic processes.Arctic mid-latitude linkages - Focusing on seasonal and regional linkages and addressing sources of inconsistency and uncertainty among studies: The topic of Arctic mid-latitude linkages is controversial and was vigorously debated at the workshop. However, we concluded that rapid Arctic change is contributing to changes in mid-latitude climate and weather, as well as the occurrence of extreme events. But how significant the contribution is and what mechanisms are responsible are less well understood. Based on the synthesis efforts of observational and modeling studies, we identified a list of proposed physical processes or mechanisms that may play important roles in linking Arctic change to mid-latitude climate and weather. The list, ordered from high to low confidence, includes: increasing geopotential thickness over the polar cap; weakening of the thermal wind; modulating stratosphere-troposphere coupling; exciting anomalous planetary waves or stationary Rossby wave trains in winter and modulating transient synoptic waves in summer; altering storm tracks and behavior of blockings; and increasing frequency of occurrence of summer wave resonance. The pathway considered most robust is the propagation of planetary/Rossby waves excited by the diminished Barents-Kara sea ice, contributing to a northwestward expansion and intensification of the Siberian high leading to cold Eurasian winters. OPPORTUNITIES AND RECOMMENDATIONS: An important goal of the workshop was achieved: to hasten progress towards consensus understanding and identification of knowledge gaps. Based on the workshop findings, we identify specific opportunities to utilize observations and models, particularly a combination of them, to enable and accelerate progress in determining the mechanisms of rapid Arctic change and its mid-latitude linkages.Observations: Due to the remoteness and harsh environmental conditions of the Arctic, in situ observational time series are highly limited spatially and temporally in the region.Six recommendations to expand approaches using observational datasets and analyses of Arctic change and mid-latitude linkages include: Synthesize new Arctic observations;Create physically-based sea ice-ocean surface forcing datasets;Systematically employ proven and new metrics;Analyze paleoclimate data and new longer observational datasets;Utilize new observational analysis methods that extend beyond correlative relationships; andConsider both established and new theories of atmospheric and oceanic dynamics to interpret and guide observational and modeling studies.Model experiments: We acknowledge that models provide the primary tool for gaining a mechanistic understanding of variability and change in the Arctic and at mid-latitudes. Coordinated modeling studies should include approaches using a hierarchy of models from conceptual, simple component, or coupled models to complex atmospheric climate models or fully coupled Earth system models. We further recommend to force dynamical models with consistent boundary forcings.Three recommendations to advance modeling and synthesis understanding of Arctic change and mid-latitude linkages include: Establish a Modeling Task Force to plan protocols, forcing, and output parameters for coordinated modeling experiments (Polar Amplification Model Intercomparison Project; PAMIP);Furnish experiment datasets to the community through open access (via Earth System Grid); andPromote analysis within the community of the coordinated modeling experiments to understand mechanisms for AA and to further understand pathways for Arctic mid-latitude linkages.

Pseudogap phase of cuprate superconductors confined by Fermi surface topology.

The properties of cuprate high-temperature superconductors are largely shaped by competing phases whose nature is often a mystery. Chiefly among them is the pseudogap phase, which sets in at a doping p* that is material-dependent. What determines p* is currently an open question. Here we show that the pseudogap cannot open on an electron-like Fermi surface, and can only exist below the doping p FS at which the large Fermi surface goes from hole-like to electron-like, so that p* ≤ p FS. We derive this result from high-magnetic-field transport measurements in La1.6-x Nd0.4Sr x CuO4 under pressure, which reveal a large and unexpected shift of p* with pressure, driven by a corresponding shift in p FS. This necessary condition for pseudogap formation, imposed by details of the Fermi surface, is a strong constraint for theories of the pseudogap phase. Our finding that p* can be tuned with a modest pressure opens a new route for experimental studies of the pseudogap.

Change of carrier density at the pseudogap critical point of a cuprate superconductor.

The pseudogap is a partial gap in the electronic density of states that opens in the normal (non-superconducting) state of cuprate superconductors and whose origin is a long-standing puzzle. Its connection to the Mott insulator phase at low doping (hole concentration, p) remains ambiguous and its relation to the charge order that reconstructs the Fermi surface at intermediate doping is still unclear. Here we use measurements of the Hall coefficient in magnetic fields up to 88 tesla to show that Fermi-surface reconstruction by charge order in the cuprate YBa2Cu3Oy ends sharply at a critical doping p = 0.16 that is distinctly lower than the pseudogap critical point p* = 0.19 (ref. 11). This shows that the pseudogap and charge order are separate phenomena. We find that the change in carrier density n from n = 1 + p in the conventional metal at high doping (ref. 12) to n = p at low doping (ref. 13) starts at the pseudogap critical point. This shows that the pseudogap and the antiferromagnetic Mott insulator are linked.

Atmospheric dynamics. Constrained work output of the moist atmospheric heat engine in a warming climate.

Incoming and outgoing solar radiation couple with heat exchange at Earth's surface to drive weather patterns that redistribute heat and moisture around the globe, creating an atmospheric heat engine. Here, we investigate the engine's work output using thermodynamic diagrams computed from reanalyzed observations and from a climate model simulation with anthropogenic forcing. We show that the work output is always less than that of an equivalent Carnot cycle and that it is constrained by the power necessary to maintain the hydrological cycle. In the climate simulation, the hydrological cycle increases more rapidly than the equivalent Carnot cycle. We conclude that the intensification of the hydrological cycle in warmer climates might limit the heat engine's ability to generate work.

Evidence for a small hole pocket in the Fermi surface of underdoped YBa2Cu3Oy.

In underdoped cuprate superconductors, the Fermi surface undergoes a reconstruction that produces a small electron pocket, but whether there is another, as yet, undetected portion to the Fermi surface is unknown. Establishing the complete topology of the Fermi surface is key to identifying the mechanism responsible for its reconstruction. Here we report evidence for a second Fermi pocket in underdoped YBa2Cu3Oy, detected as a small quantum oscillation frequency in the thermoelectric response and in the c-axis resistance. The field-angle dependence of the frequency shows that it is a distinct Fermi surface, and the normal-state thermopower requires it to be a hole pocket. A Fermi surface consisting of one electron pocket and two hole pockets with the measured areas and masses is consistent with a Fermi-surface reconstruction by the charge-density-wave order observed in YBa2Cu3Oy, provided other parts of the reconstructed Fermi surface are removed by a separate mechanism, possibly the pseudogap.

Prasugrel vs. clopidogrel in acute coronary syndrome patients treated with prasugrel.

WHAT IS KNOWN AND OBJECTIVE: Current guidelines recommend a combination of clopidogrel and aspirin for management of patients who have experienced an acute coronary syndrome (ACS). Additional antiplatelet agents have been recently approved. Few comparative effectiveness studies are available for these new agents. Accordingly, we evaluated effect on time to hospital admission and resource utilization (number of hospitalizations, ER visits and outpatient visits) of prasugrel vs. clopidogrel in prasugrel-treated patients as assessed in a matched cohort. METHODS: Based on the Truven Health Analytics MarketScan database from 01 January 2009 through 31 July 2012, a retrospective prasugrel-clopidogrel matched cohort was created. Inferences for average treatment effect over 1 and 12 months on time to hospitalization and resource utilization were performed by (i) frequentist Kaplan-Meier estimation with a Cox proportional hazard model and Lin's cost history method for censored resource utilization outcomes and (ii) Bayesian discrete-time hazard and negative binomial models. RESULTS AND DISCUSSION: The 10,963 matched pairs were well balanced on baseline characteristics. Frequentist analyses of time to hospital admission over 365 days and mean all-cause resource utilization over 30 and 365 days showed no statistical differences between prasugrel and clopidogrel (P-values > 0·05). Based on Bayesian analysis of time to admission over 12 months, there was positive evidence of equivalence (0·987 probability of equivalence at a 10% equivalence margin and a Bayes factor of 0·611). Although the frequentist analyses for number of all-cause hospitalizations showed a lack of a significant difference at Months 1 and 12, the Bayesian data analysis showed positive evidence of superiority of clopidogrel at Month 1 (Bayes factor: 5·369); however, at Month 12, there was little evidence of superiority of one treatment over the other (Bayes factor: 0·422). WHAT IS NEW AND CONCLUSION: Using frequentist and Bayesian data analyses, in prasugrel-treated patients, clopidogrel was equivalent to prasugrel for time to hospital admission over 12 months and there was positive evidence that it was superior to prasugrel for number of hospitalizations over the first month of treatment.

Direct measurement of the upper critical field in cuprate superconductors.

In the quest to increase the critical temperature Tc of cuprate superconductors, it is essential to identify the factors that limit the strength of superconductivity. The upper critical field Hc2 is a fundamental measure of that strength, yet there is no agreement on its magnitude and doping dependence in cuprate superconductors. Here we show that the thermal conductivity can be used to directly detect Hc2 in the cuprates YBa2Cu3Oy, YBa2Cu4O8 and Tl2Ba2CuO6+δ, allowing us to map out Hc2 across the doping phase diagram. It exhibits two peaks, each located at a critical point where the Fermi surface of YBa2Cu3Oy is known to undergo a transformation. Below the higher critical point, the condensation energy, obtained directly from Hc2, suffers a sudden 20-fold collapse. This reveals that phase competition-associated with Fermi-surface reconstruction and charge-density-wave order-is a key limiting factor in the superconductivity of cuprates.

Risk factors associated with myocardial infarction in venous thromboembolism patients.

BACKGROUND: Although risk factors for MI have been described in the general population, there is a lack of data on the assessment of risk factors associated with MI in venous thromboembolism (VTE) patients. OBJECTIVE: The purpose of this study was to identify risk factors associated with MI in VTE patients. PATIENTS AND METHODS: Health insurance claims between January 2004 and September 2008 from the Ingenix IMPACT database were analyzed. Patients aged ≥18 years were identified as of the date of their first VTE diagnosis with ≥1 year of continuous insurance coverage before the index VTE. The risk of MI for VTE patients with 1, 2, and ≥3 major risk factors as identified by published guidelines was calculated. Multivariate Cox proportional hazard models were conducted to identify the most predictive risk factors associated with MI. RESULTS: A total of 177,885 VTE patients were identified; 4412 (2.5%) developed an MI during a mean follow-up period of 1.3 years. Previous MI, age (≥65 years), and coronary artery disease were the most predictive risk factors of MI with adjusted hazard ratios (HRs; 95% CI) of 5.47 (5.01-5.97), 1.78 (1.66-1.91), and 1.60 (1.48-1.74), respectively. Adjusted HRs (95% CI) for VTE patients with 1, 2, and ≥3 major risk factors relative to no major risk factor were 2.34 (1.94-2.81), 3.21 (2.67-3.85), and 6.93 (5.85-8.22), respectively. LIMITATIONS: These included possible inaccuracies or omissions in diagnoses, classification bias such as the identification of false-positive MI events, and the likely undercoding of some risk factors such as social issues. CONCLUSIONS: Traditional major cardiovascular risk factors are also predictive of MI in VTE patients. Having multiple major risk factors significantly increases the probability of developing MI events in VTE patients.

In-hospital risk of venous thromboembolism and bleeding and associated costs for patients undergoing total hip or knee arthroplasty.

OBJECTIVE: Benefits of anti-coagulation for venous thromboembolism (VTE) prevention in total hip and knee arthroplasty (THA/TKA) may be offset by increased risk of bleeding. The aim was to assess in-hospital risk of VTE and bleeding after THA/TKA and quantify any increased costs. METHODS: Healthcare claims from the Premier Perspective(TM) Comparative Hospital Database (January 2000-September 2008) were selected for subjects ≥ 18 years with ≥ 1 diagnosis code for THA/TKA. VTE was defined as ≥ 1 code for deep vein thrombosis or pulmonary embolism. Bleeding was classified as major/non-major. Incremental in-hospital costs associated with VTE and bleeding were calculated as cost differences between inpatients with VTE or bleeding matched 1:1 with inpatients without VTE or bleeding. RESULTS: A total of 820,197 inpatient stays were identified: 8042 had a VTE event and 7401 a bleeding event (2740 major bleeding). The risks of VTE, any bleeding, and major bleeding were 0.98, 0.90, and 0.33/100 inpatient stays, respectively. Mean incremental in-hospital costs per inpatient were $2663 for VTE, $2028 for bleeding, and $3198 for major bleeding. LIMITATIONS: These included possible inaccuracies or omissions in procedures, diagnoses, or costs of claims data; no information on the amount of blood transfused or decreases in the hemoglobin level to evaluate bleeding event severity; and potential biases due to the observational design of the study. CONCLUSIONS: In-hospital risk and incremental all-cause costs with THA/TKA were higher for VTE than for bleeding. Despite higher costs, major bleeding occurred less frequently than VTE, suggesting a favorable benefit/risk profile for VTE prophylaxis in THA/TKA.

Fermi-surface reconstruction by stripe order in cuprate superconductors.

The origin of pairing in a superconductor resides in the underlying normal state. In the cuprate high-temperature superconductor YBa(2)Cu(3)O(y) (YBCO), application of a magnetic field to suppress superconductivity reveals a ground state that appears to break the translational symmetry of the lattice, pointing to some density-wave order. Here we use a comparative study of thermoelectric transport in the cuprates YBCO and La(1.8-x)Eu(0.2)Sr(x)CuO(4) (Eu-LSCO) to show that the two materials exhibit the same process of Fermi-surface reconstruction as a function of temperature and doping. The fact that in Eu-LSCO this reconstruction coexists with spin and charge modulations that break translational symmetry shows that stripe order is the generic non-superconducting ground state of hole-doped cuprates.

Nerve growth factor localization in the nasal mucosa of patients with persistent allergic rhinitis.

BACKGROUND AND OBJECTIVES: Nerve growth factor (NGF) and NGF receptors have been shown to be expressed by structural and infiltrating inflammatory cells in the human allergic bronchial mucosa and conjunctiva. In the nose, a positive immunostaining for NGF was recently reported in biopsies of subjects undergoing surgery for refractory nasal obstruction. This study was aimed at studying by immunohistochemistry NGF expression and localization in the nasal mucosa from subjects with moderate/severe persistent allergic rhinitis and natural allergen exposure. METHODS: Immunostaining for NGF, tryptase and eosinophil cationic protein was performed in human nasal turbinate sections of 25 patients affected by persistent allergic rhinitis and sensitization to Dermatophagoides pteronyssinus. RESULTS: NGF was consistently expressed in the epithelium and in the submucosa of allergic rhinitic subjects, preferentially localized in eosinophils and mast cells. A strong NGF immunostaining was found in mucous cells of the epithelial lining and in the submucosal glands. CONCLUSIONS: As previously shown for allergic asthma and allergic conjunctivitis, NGF is also detectable in the nasal mucosa of patients with persistent allergic rhinitis. The preferential NGF localization in mucous cells of the epithelial lining and in the submucosal glands suggests a possible role for NGF in modulating secretion in allergic rhinitis and possibly other allergic diseases.

L-454,560, a potent and selective PDE4 inhibitor with in vivo efficacy in animal models of asthma and cognition.

Type 4 phosphodiesterases (PDE4) inhibitors are emerging therapeutics in the treatment of a number of chronic disorders including asthma, chronic obstructive pulmonary disease (COPD) and cognitive disorders. This study delineates the preclinical profile of L-454,560, which is a potent, competitive and preferential inhibitor of PDE4A, 4B, and 4D with IC50 values of 1.6, 0.5 and 1.2 nM, respectively. In contrast to the exclusive binding of cilomilast and the preferential binding of roflumilast to the PDE4 holoenzyme state (Mg2+-bound form), L-454,560 binds to both the apo-(Mg2+-free) and holoenzyme states of PDE4. The intrinsic enzyme potency for PDE4 inhibition by L-454,560 also results in an effective blockade of LPS-induced TNFalpha formation in whole blood (IC50 = 161 nM) and is comparable to the human whole blood potency of roflumilast. The cytokine profile of inhibition of L-454,560 is mainly a Th1 profile with significant inhibition of IFNgamma and no detectable inhibition of IL-13 formation up to 1 microM. L-454,560 was also found to be efficacious in two models of airway hyper-reactivity, the ovalbumin (OVA) sensitized and challenged guinea pig and the ascaris sensitized sheep model. Furthermore, L-454560 was also effective in improving performance in the delayed matching to position (DMTP) version of the Morris watermaze, at a dose removed from that associated with potential emesis. Therefore, L-454,560 is a novel PDE4 inhibitor with an overall in vivo efficacy profile at least comparable to roflumilast and clearly superior to cilomilast.

Neuroanatomical and pharmacological assessment of Fos expression induced in the rat brain by the phosphodiesterase-4 inhibitor 6-(4-pyridylmethyl)-8-(3-nitrophenyl) quinoline.

A major obstacle in the therapeutic development of phosphodiesterase-4 (PDE4) inhibitors is the production of adverse side effects such as nausea and vomiting. Immunohistochemical detection of Fos-like immunoreactivity (FLI) was used to address the neuroanatomical basis for the pharmacological actions of PDE4 inhibitors. The potent and selective PDE4 inhibitors 6-(4-pyridylmethyl)-8-(3-nitrophenyl) quinoline (PMNPQ) and rolipram elevated FLI in brain regions potentially relevant to the anti-depressant and emetic effects of PDE4 inhibition. PMNPQ and rolipram elevated FLI in the locus coeruleus, habenula, paraventricular nucleus of the thalamus, amygdala and nucleus accumbens, all structures with strong limbic connectivity implicated in arousal, memory and affective aspects of behaviour. Consistent with the emetic effects of PDE4 inhibitors such as PMNPQ and rolipram, these compounds elevated FLI in caudal brainstem nuclei such as the area postrema and nucleus of the solitary tract. Administration of the NK(1) antagonist RP 67580 prior to PMNPQ reversed increases in FLI produced by PMNPQ in these regions. RP 67580 did not, however, reduce PMNPQ-induced FLI in limbic structures. These findings suggest that PDE4 inhibitors produce emesis by increasing NK(1) receptor activation in the AP/NTS and implicate brain regions associated with reward and mood such as the amygdala, paraventricular nucleus of the thalamus, habenula and nucleus accumbens in the anti-depressant activity of such compounds.

Dissecting the cofactor-dependent and independent bindings of PDE4 inhibitors.

Type 4 phosphodiesterases (PDE4s) are metallohydrolases that catalyze the hydrolysis of cAMP to AMP. At the bottom of its active site lie two divalent metal ions in a binuclear motif which are involved in both cAMP binding and catalysis [(2000) Science 288, 1822-1825; (2000) Biochemistry 39, 6449-6458]. Using a SPA-based equilibrium [(3)H]rolipram binding assay, we have determined that Mg(2+), Mn(2+), and Co(2+) all mediated a high-affinity (K(d) between 3 and 8 nM) and near stoichiometric (R)-rolipram binding to PDE4. In their absence, (R)-rolipram binds stoichiometrically to the metal ion-free apoenzyme with a K(d) of approximately 150 nM. The divalent cation dose responses in mediating the high-affinity rolipram/PDE4 interaction mirror their efficacy in catalysis, suggesting that both metal ions of the holoenzyme are involved in mediating the high-affinity (R)-rolipram/PDE4 interaction. The specific rolipram binding to the apo- and holoenzyme is differentially displaced by cAMP, AMP, and other inhibitors, providing a robust tool to dissect the components of metal ion-dependent and independent PDE4/ligand interactions. cAMP binds to the holoenzyme with a K(s) of 1.9 microM and nonproductively to the apoenzyme with a K(d) of 179 microM. In comparison, AMP binds to the holo- and apoenzyme with K(d) values of 7 and 11 mM, respectively. The diminished Mg(2+)-dependent component of AMP binding to PDE4 suggests that most of the Mg(2+)/phosphate interaction in the cAMP/PDE4 complex is disrupted upon the hydrolysis of the cyclic phosphoester bond, leading to the rapid release of AMP.

Local safety of intranasal triamcinolone acetonide: clinical and histological aspects of nasal mucosa in the long-term treatment of perennial allergic rhinitis.

Intranasal corticosteroids are increasingly used to treat allergic rhinitis and their long-term use is generally safe. However, the long-term safety of each molecule should be assessed. The main aim of this multicenter, prospective, randomized, open-label study was to evaluate the effect of triamcinolone acetonide aqueous intranasal spray on nasal mucosal thickness, macroscopic appearance, and mucociliary function. Patients with perennial allergic rhinitis were treated with triamcinolone acetonide 220 micrograms/day for six months. Nasal biopsies taken before and after treatment were compared with biopsies from patients who had been randomized to oral cetirizine 10 mg day or intranasal beclomethasone dipropionate 400 micrograms/day. In the evaluable population (n = 70), there were no significant differences between groups in terms of histologically evaluated thickness and endoscopically evaluated macroscopic appearance of the nasal mucosa, or indigocarmine saccharine test mucociliary function. In the intent-to-treat population (n = 92), there was no difference between treatment groups in the incidence of overall adverse events. This study indicates that sustained treatment with intranasal triamcinolone acetonide does not lead to atrophy of the nasal mucosa or impairment of mucociliary function.

Clinical and pathologic methods to assess the long-term safety of nasal corticosteroids. French Triamcinolone Acetonide Study Group.

BACKGROUND: The main objective of this long-term prospective local safety study was to evaluate endoscopic and histologic changes in nasal epithelium after 6-month treatment with triamcinolone acetonide (TAA). We describe here a method to measure quantitatively epithelium thickness. Results were compared with those seen with the use of cetirizine (an antihistamine) and another oral intranasal corticosteroid, beclomethasone dipropionate (BDP). METHODS: Patients were examined by an ENT specialist who first performed an endoscopic evaluation of the nasal cavities, assessing any morphologic abnormalities and the aspect of the mucosa. Biopsies were taken from the inferior turbinate before and after 24 weeks of treatment. Biopsies were immediately fixed in cold acetone (-20 degrees C) and embedded in glycolmethacrylate; sections of 2 microm were cut on an ultramicrotome. Morphometric evaluations were done in a blinded fashion by computerized image analysis to measure an epithelial area over a minimum length of 50 microm. The thickness was ascertained by the ratio of area to length. RESULTS: 1) For all three treatment groups, the nasal epithelium thickness decreased slightly from pretreatment to the end of treatment. 2) No statistically significant differences between the three treatment groups were found in epithelium thickness. 3) Macroscopically, nasal tissues in all treated groups were normal. CONCLUSIONS: These results clearly indicate that long-term treatment with TAA has no atrophic effect on nasal mucosa.

Conformational difference between PDE4 apoenzyme and holoenzyme.

The type 4 cAMP-specific phosphodiesterases (PDE4s) are Mg(2+)-dependent hydrolases that catalyze the hydrolysis of 3', 5'-cAMP to AMP. Previous studies indicate that PDE4 exists in two conformations that bind the inhibitor rolipram with affinities differing by more than 100-fold. Here we report that these two conformations are the consequence of PDE4 binding to its metal cofactor such as Mg(2+). Using a fluorescence resonance energy transfer (FRET)-based equilibrium binding assay, we identified that L-791,760, a fluorescent inhibitor, binds to the apoenzyme (free enzyme) and the holoenzyme (enzyme bound to Mg(2+)) with comparable affinities (K(d) approximately 30 nM). By measuring the displacement of the bound L-791,760, we have also identified that other inhibitors bind differentially with the apoenzyme and the holoenzyme depending upon their structure. CDP-840, SB-207499, and RP-73401 bind preferentially to the holoenzyme. The conformational-sensitive inhibitor (R)-rolipram binds to the holoenzyme and apoenzyme with affinities (K(d)) of 5 and 300 nM, respectively. In contrast to its high affinity (K(d) approximately 2 microM) and active holoenzyme complex, cAMP binds to the apoenzyme nonproductively with a reduced affinity (K(d) approximately 170 microM). These results demonstrate that cofactor binding to PDE4 is responsible for eliciting its high-affinity interaction with cAMP and the activation of catalysis.

Substituted furans as inhibitors of the PDE4 enzyme.

The synthesis and in vitro activity of a series of substituted furans as a novel structural class of PDE4 inhibitors is described. Comparison of emetic threshold with known PDE4 inhibitors is presented.