Short-Term Effects of Carbon Monoxide on Mortality: An Analysis within the APHEA Project

Objectives: We investigated the short-term effects of carbon monoxide on total and cardiovascular mortality in 19 European cities participating in the APHEA-2 (Air Pollution and Health: A European Approach) project. Methods: We examined the association using hierarchical models implemented in two stages. In the first stage, data from each city were analyzed separately, whereas in the second stage the city-specific air pollution estimates were regressed on city-specific covariates to obtain overall estimates and to explore sources of possible heterogeneity. We evaluated the sensitivity of our results by applying different degrees of smoothing for seasonality control in the city-specific analysis. Results: We found significant associations of CO with total and cardiovascular mortality. A 1-mg/m$^3$ increase in the 2-day mean of CO levels was associated with a 1.20% [95% confidence interval (CI), 0.63–1.77%] increase in total deaths and a 1.25% (95% CI, 0.30–2.21%) increase in cardiovascular deaths. There was indication of confounding with black smoke and nitrogen dioxide, but the pollutant-adjusted effect of CO on mortality remained at least marginally statistically significant. The effect of CO on total and cardiovascular mortality was observed mainly in western and southern European cities and was larger when the standardized mortality rate was lower. Conclusions: The results of this large study are consistent with an independent effect of CO on mortality. The heterogeneity found in the effect estimates among cities may be explained partly by specific city characteristics

Callous-unemotional traits only versus the multidimensional psychopathy construct as predictors of various antisocial outcomes during early adolescence

New methods for child psychiatric diagnosis and treatment outcome evaluatio

Patterns of Coupled Theta Activity in Amygdala-Hippocampal-Prefrontal Cortical Circuits during Fear Extinction

Signals related to fear memory and extinction are processed within brain pathways involving the lateral amygdala (LA) for formation of aversive stimulus associations, the CA1 area of the hippocampus for context-dependent modulation of these associations, and the infralimbic region of the medial prefrontal cortex (mPFC) for extinction processes. While many studies have addressed the contribution of each of these modules individually, little is known about their interactions and how they function as an integrated system. Here we show, by combining multiple site local field potential (LFP) and unit recordings in freely behaving mice in a fear conditioning paradigm, that theta oscillations may provide a means for temporally and functionally connecting these modules. Theta oscillations occurred with high specificity in the CA1-LA-mPFC network. Theta coupling increased between all areas during retrieval of conditioned fear, and declined during extinction learning. During extinction recall, theta coupling partly rebounded in LA-mPFC and CA1-mPFC, and remained at a low level in CA1-LA. Interfering with theta coupling through local electrical microstimulation in CA1-LA affected conditioned fear and extinction recall depending on theta phase. These results support the hypothesis that theta coupling provides a means for inter-areal coordination in conditioned behavioral responsiveness. More specifically, theta oscillations seem to contribute to a population code indicating conditioned stimuli during recall of fear memory before and after extinction

Brugia malayi Microfilariae Induce a Regulatory Monocyte/Macrophage Phenotype That Suppresses Innate and Adaptive Immune Responses

Background Monocytes and macrophages contribute to the dysfunction of immune responses in human filariasis. During patent infection monocytes encounter microfilariae in the blood, an event that occurs in asymptomatically infected filariasis patients that are immunologically hyporeactive. Aim To determine whether blood microfilariae directly act on blood monocytes and in vitro generated macrophages to induce a regulatory phenotype that interferes with innate and adaptive responses. Methodology and principal findings Monocytes and in vitro generated macrophages from filaria non-endemic normal donors were stimulated in vitro with Brugia malayi microfilarial (Mf) lysate. We could show that monocytes stimulated with Mf lysate develop a defined regulatory phenotype, characterised by expression of the immunoregulatory markers IL-10 and PD-L1. Significantly, this regulatory phenotype was recapitulated in monocytes from Wuchereria bancrofti asymptomatically infected patients but not patients with pathology or endemic normals. Monocytes from non-endemic donors stimulated with Mf lysate directly inhibited CD4+ T cell proliferation and cytokine production (IFN-γ, IL-13 and IL-10). IFN-γ responses were restored by neutralising IL-10 or PD-1. Furthermore, macrophages stimulated with Mf lysate expressed high levels of IL-10 and had suppressed phagocytic abilities. Finally Mf lysate applied during the differentiation of macrophages in vitro interfered with macrophage abilities to respond to subsequent LPS stimulation in a selective manner. Conclusions and significance Conclusively, our study demonstrates that Mf lysate stimulation of monocytes from healthy donors in vitro induces a regulatory phenotype, characterized by expression of PD-L1 and IL-10. This phenotype is directly reflected in monocytes from filarial patients with asymptomatic infection but not patients with pathology or endemic normals. We suggest that suppression of T cell functions typically seen in lymphatic filariasis is caused by microfilaria-modulated monocytes in an IL-10-dependent manner. Together with suppression of macrophage innate responses, this may contribute to the overall down-regulation of immune responses observed in asymptomatically infected patients

Kypho-IORT - a novel approach of intraoperative radiotherapy during kyphoplasty for vertebral metastases

<p>Abstract</p> <p>Background</p> <p>Instable and painful vertebral metastases in patients with progressive visceral metastases present a common therapeutic dilemma. We developed a novel approach to deliver intraoperative radiotherapy (IORT) during kyphoplasty and report the first treated case.</p> <p>Methods/Results</p> <p>60 year old patient with metastasizing breast cancer under chemotherapy presented with a newly diagnosed painful metastasis in the 12^ththoracic vertebra. Under general anaesthesia, a bipedicular approach into the vertebra was chosen with insertion of specially designed metallic sleeves to guide the electron drift tube of the miniature X-ray generator (INTRABEAM, Carl Zeiss Surgical, Oberkochen, Germany). This was inserted with a novel sheet designed for this approach protecting the drift tube. A radiation dose of 8 Gy in 5 mm distance (50 kV X-rays) was delivered. The kyphoplasty balloons (KyphX, Kyphon Inc, Sunnyvale) were inflated after IORT and polymethylmethacrylate cement was injected. The whole procedure lasted less than 90 minutes.</p> <p>Conclusion</p> <p>In conclusion, this novel, minimally invasive procedure can be performed in standard operating rooms and may become a valuable option for patients with vertebral metastases providing immediate stability and local control. A phase I/II study is under way to establish the optimal dose prescription.</p

Role of Muscarinic Acetylcholine Receptors in Serial Feature-Positive Discrimination Task during Eyeblink Conditioning in Mice.

We investigated the role of muscarinic acetylcholine receptors (mAChRs) in eyeblink serial feature-positive discrimination learning in mice using the mAChR antagonist. A 2-s light cue was delivered 5 or 6 s before the presentation of a 350-ms tone paired with a 100-ms periorbital electrical shock (cued trial) but not before the tone-alone presentation (non-cued trial). Mice received 30 cued and 30 non-cued trials each day in a random order. We found that saline-injected control mice were successfully discriminating between cued and non-cued trials within a few days of conditioning. The mice responded more frequently to the tone in cued trials than in non-cued trials. Analysis of conditioned response (CR) dynamics revealed that the CR onset latency was shorter in cued trials than in non-cued trials, despite the CR peak amplitude not differing significantly between the two conditions. In contrast, scopolamine-injected mice developed an equal number of CRs with similar temporal patterns irrespective of the presence of the cue during the 7 days of conditioning, indicating in a failure to acquire conditional discrimination. In addition, the scopolamine administration to the control mice after they had successfully acquired discrimination did not impair the conditional discrimination and expression of pre-acquired CR. These results suggest that mAChRs may play a pivotal role in memory formation in the conditional brain state associated with the feature cue; however they are unlikely to be involved in the development of discrimination after conditional memory had formed in the serial feature-positive discrimination task during eyeblink conditioning

Assessment of Cardiovascular Fibrosis Using Novel Fluorescent Probes

Cardiovascular fibrosis resulted from pressure overload or ischemia could alter myocardial stiffness and lead to ventricular dysfunction. Fluorescently labeled collagen-binding protein CNA 35, derived from the surface component of Staphylococcus aureus, and a novel synthetic biphenylalanine containing peptide are applied to stain fibrosis associated collagen and myocytes, respectively. Detailed pathological characteristics of cardiovascular fibrosis could be identified clearly in 2 hours. This staining pair requires only simple staining and brief washing, generating less than 10 ml of waste. The image information collected by this novel fluorescent staining pair is compatible with it collected by the traditional Masson's Trichrome and Picrosirius Red staining which are widely used to stain cardiovascular fibrosis and isolated cells

On-chip generation of high-dimensional entangled quantum states and their coherent control

Optical quantum states based on entangled photons are essential for solving questions in fundamental physics and are at the heart of quantum information science1. Specifically, the realization of high-dimensional states (D-level quantum systems, that is, qudits, with D > 2) and their control are necessary for fundamental investigations of quantum mechanics2, for increasing the sensitivity of quantum imaging schemes3, for improving the robustness and key rate of quantum communication protocols4, for enabling a richer variety of quantum simulations5, and for achieving more efficient and error-tolerant quantum computation6. Integrated photonics has recently become a leading platform for the compact, cost-efficient, and stable generation and processing of non-classical optical states7. However, so far, integrated entangled quantum sources have been limited to qubits (D = 2)8, 9, 10, 11. Here we demonstrate on-chip generation of entangled qudit states, where the photons are created in a coherent superposition of multiple high-purity frequency modes. In particular, we confirm the realization of a quantum system with at least one hundred dimensions, formed by two entangled qudits with D = 10. Furthermore, using state-of-the-art, yet off-the-shelf telecommunications components, we introduce a coherent manipulation platform with which to control frequency-entangled states, capable of performing deterministic high-dimensional gate operations. We validate this platform by measuring Bell inequality violations and performing quantum state tomography. Our work enables the generation and processing of high-dimensional quantum states in a single spatial mode

Rationale and design of decision: a double-blind, randomized, placebo-controlled phase III trial evaluating the efficacy and safety of sorafenib in patients with locally advanced or metastatic radioactive iodine (RAI)-refractory, differentiated thyroid cancer

<p>Abstract</p> <p>Background</p> <p>The incidence of thyroid cancer and the number of patients who die from this disease are increasing globally. Differentiated thyroid cancer (DTC) is the histologic subtype present in most patients and is primarily responsible for the increased overall incidence of thyroid cancer. Sorafenib is a multikinase inhibitor that targets several molecular signals believed to be involved in the pathogenesis of thyroid cancer, including those implicated in DTC. In phase II studies of patients with DTC, sorafenib treatment has yielded a median progression-free survival (PFS) of 58 to 84 weeks and disease control rates of 59% to 100%. The DECISION trial was designed to assess the ability of sorafenib to improve PFS in patients with locally advanced or metastatic, radioactive iodine (RAI)-refractory DTC.</p> <p>Methods/design</p> <p>DECISION is a multicenter, double-blind, randomized, placebo-controlled phase III study in patients with locally advanced/metastatic RAI<b>-</b>refractory DTC. Study treatment will continue until radiographically documented disease progression, unacceptable toxicity, noncompliance, or withdrawal of consent. Efficacy will be evaluated every 56 days (2 cycles), whereas safety will be evaluated every 28 days (1 cycle) for the first 8 months and every 56 days thereafter. Following disease progression, patients may continue or start sorafenib, depending on whether they were randomized to receive sorafenib or placebo, at investigator discretion. Patients originally randomized to receive sorafenib will be followed up every 3 months for overall survival (OS); patients originally randomized to receive placebo will be followed up every month for 8 months after cross-over to sorafenib. The duration of the trial is expected to be 30 months from the time the first patient is randomized until the planned number of PFS events is attained. The primary endpoint is PFS; secondary endpoints include OS, time to disease progression, disease control rate, response rate, duration of response, safety, and pharmacokinetic analysis.</p> <p>Discussion</p> <p>The DECISION study has been designed to test whether sorafenib improves PFS in patients with locally advanced or metastatic RAI-refractory DTC.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov Identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00984282">NCT00984282</a>; EudraCT: 2009-012007-25.</p